Regio- and stereoselectivity in preparation of benzene bridged bis- and tris-Troeger's bases

Article abstract of DOI:10.1135/cccc20020609

Synthetic strategy for novel multiple Troeger's base derivatives is presented. Compounds were prepared in three steps: o-nitrobenzoylation of benzene-1,2- and -1,3-diamines 3 followed by reduction of nitro and amide groups to amino functions and treatment

Full text of DOI:10.1135/cccc20020609

Benzene Bridged Tröger's Bases
609
REGIO- AND STEREOSELECTIVITY IN PREPARATION
OF BENZENE BRIDGED BIS- AND TRIS-TRÖGER’S BASES
b
Martin VALÍKa1, Bohumil DOLENSKYa2, Hana PETŘÍČKOVÁ
a3,
and Vladimír KRÁL
*
a
Department of Analytical Chemistry, Institute of Chemical Technology, Prague, Technická 5,
166 28 Prague 6, Czech Republic; e-mail: martin.valik@vscht.cz, blbek@seznam.cz,
1
2
3
kralv@vscht.cz
b
Department of Solid State Chemistry, Institute of Chemical Technology, Prague, Technická 5,
166 28 Prague 6, Czech Republic; e-mail: hana.petrickova@vscht.cz
Received March 27, 2002
Accepted April 29, 2002
Syn th etic strategy for n ovel m ultiple Tröger’s base derivatives is presen ted. Com poun ds were
prepared in th ree steps: o-n itroben zoylation of ben zen e-1,2- an d -1,3-diam in es 3 followed by
reduction of n itro an d am ide groups to am in o fun ction s an d treatm en t of th e obtain ed
tetraam in e com poun ds 6 with form aldeh yde lead to sim ultan eous form ation of bis-Tröger’s
base (bisTB) derivatives 7a, 7b. On ly products of 1,2,3,4-substituted regioisom ers with anti
con form ation were separated from reaction m ixtures. Th e sam e syn th etic procedure was
used for preparation of tris-Tröger’s base (trisTB) derivative 12b startin g from ben zen e-1,3,5-
triam in e (8).
Keyw ord s: Tröger’s bases; Receptors; Tweezers; Am in es; Supram olecular ch em istry.
On e of th e leadin g th em es of supram olecular ch em istry h as been prepara-
tion of h igh ly selective receptors. Th e h igh selectivity can be ach ieved by
design of suitable scaffold m olecule, wh ich support cooperation between
sin gle bin din g un its in proper geom etrical arran gem en t. Such syn th etic
protocol is com m on for m an y receptors described to date1.
On e of such scaffolds used for receptor preparation are Tröger’s base (TB)
derivatives2. Th e TB m otif is in creasin gly attractive in m olecular design of
receptors for its ch irality an d rigid V-sh aped con cave cavity. Th e TB deriva-
tives h ave been used for recogn ition based on th e cavity size, e.g.
α,ω-diam in es3,4, 9-eth yladen in e5 an d carboxylic acids6, or based on
ch irality, e.g. ben zyl esters of h istidin e an d lysin e7 or terpen es8.
Ph en an trolin e9,10 an d acridin e10,11 TB derivatives were reported to in teract
specifically with DNA (refs9,11,12). Very recen tly, com poun ds 1 con tain in g
two Tröger’s base un its h ave been reported13. For bisTB system s, syn con fig-
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20020609

610
Valík, Dolensky, Petříčková, Král:
uration (boat-like) is m ore attractive th an anti (ch air-like) allowin g con -
struction of m olecular tweezers. Moreover, som e regioisom ers of oligoTB
system s can provide “dish -like” con figuration s (see 2a in Fig. 1) resem blin g
calixaren es. Th e aim of th is work is evaluation of possible syn th etic ap-
proach to oligoTB derivatives an d determ in ation of con figuration of oligo-
TBs con structed on th e ben zen e core.
Th e TBs are usually prepared from para-substituted an ilin es by th e react-
ion with formaldehyde14, hexamethylenetetramine8 or dimethoxymethane15 un -
der acid catalysis an d by th e reaction with derivatives of isatoic an h ydride
(3,1-ben zoazin e-2,4(1H)-dion e) or 2-n itroben zoic acid followed by reduc-
tion of th e product an d its cyclization with form aldeh yde in acid m edia16
(Wilcox procedure). Un substituted Tröger′s base from an ilin e was n ot pre-
pared to date directly even by m ultistep sequen ce16. From th e m ech an istic
poin t of view, th e m ain com plication of TB form ation from an ilin e is oligo-
m erization s in para position s.
Th e syn th etic strategy for our n ovel bisTB com poun ds was based on th e
Wilcox syn th etic protocol16. Treatm en t of ben zen ediam in es 3 with 2-n itro-
ben zoyl ch loride gave bisam ides 4 (ref.17 for 4b) in good yields. Altern ative
R
N
N
R
CH3
R
N
N
R
1a, R=CH3
1b, R=NO2
N
N
N
N
N
N
R
R
2a
~ 0.7 nm
N
N
N
N
N
N
~ 0.5 nm
2b
~ 0.3 nm
R
FIG. 1
Structural form ulas an d con figuration s of bis- an d tris-Tröger’s bases 1 an d 2
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Benzene Bridged Tröger's Bases
611
form ation of th e bisam ides via active ester (usin g DCC) gave m ostly m on o-
am ides. Th e reduction of bisam ides 4 was perform ed in two ways. Th e
on e-step reduction of bisam ides 4 to am in es 6 with lith ium alum in ium h y-
dride (LAH) gave irreproducible results. Th e reduction of n itro groups by
catalytic h ydrogen ation to am in oam ides 5 followed by LAH reduction of
am ide groups to am in es 6 was a m ore efficien t m eth od. Th e am in oam ides 5
can also be prepared by reaction of startin g ben zen ediam in es 3 with isatoic
an h ydride or an th ran yloyl ch loride. Depen din g on th e reduction m eth od,
th e overall reaction sequen ce leadin g to oligoTB system s in volves 3 (sim ul-
tan eous reduction of n itro an d am ide groups) or 4 steps. Th e fin al treat-
m en t of am in es 6a or 6b with form aldeh yde in m eth an ol with
h ydroch loric acid as catalyst gave bisTB derivative 7a (Sch em e 1) in 4%
yield an d 7b (Sch em e 2) in 6% yield. Work13 reported an eigh t-step syn th e-
sis of 1a in 1% overall yield, wh ile our approach gave in four steps 3% even
with out para substitution . It is im portan t to n ote th at th e yields of bisTB 7a
an d 7b are relatively h igh in com parison with th e reported results of m ulti-
step syn th esis13.
H2N
HN
NH2
NO2
NH
NH2
NH
O
(i)
(iii)
(ii)
O
HN
H2N
O
NH2
O
3a
N
H
N
H
NH2
NO2
5a
(iv)
6a
N
N
N
N
N
N
N
N
7a
7c
(i) 2-nitrobenzoyl chloride, DMF, pyridine, 12 h, rt; (ii) H2, Pd/C, methanol, DMF, 12 h, rt;
(iii) LiAlH4, dioxane, 4 h, reflux; (iv) 36% aq. CH2O, conc. HCl, MeOH, 20 h, rt
SCHEME 1
An in terestin g regio- an d stereoselectivity of th ese reaction s h as been ob-
served. In th e case of diam in e 6a, two regioisom ers 7a an d 7c can be
form ed; h owever, on ly 7a was obtain ed. Th is result is som ewh at surprisin g
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Valík, Dolensky, Petříčková, Král:
because th e substitution s of cen tral ben zen e rin g in position s 1,2,4,5 (struc-
ture 7c) would be preferred to th e 1,2,3,4-substitution (structure 7a) due to
steric effects. Based on possible cyclization s (rin g-form in g position s) of 6a,
th e calculated statistic ratio of 7a an d 7c in th e reaction m ixture sh ould be
3 : 1; wh ile our experim en tal data sh owed th e form ation of 7a on ly. Th e
form ation of 7a can be explain ed by h igh er reactivity of th e cen tral ben -
zen e meso position of 6a towards electroph ilic substitution . Furth erm ore,
th e sam e regioselectivity (1,2,3,4-substitution ) was observed for bisTB deriva-
tives (1a, 1b) prepared by a stepwise tech n ique13
.
O
NH NH2
NH NH2
NO2
NO2
NH2
NH2
NH
NH
(ii)
(i)
3b
O
4b
6b
(iii)
N
N
N
N
7b
(i) 2-nitrobenzoyl chloride, DMF, pyridine, 12 h, rt; (ii) LiAlH4, dioxane, 48 h, reflux;
(iii) 36% aq. CH2O, conc. HCl, MeOH, 20 h, rt
SCHEME 2
Assign m en ts of bisTB regioisom er structures are based on ch aracteristic
spin pattern s in 1H NMR spectra. In case of com poun d 7b just six doublets
an d on e sin glet are distin guish able for m eth ylen e proton s an d cen tral ben -
zen e rin g proton s. On th e oth er h an d, n on equivalen t m eth ylen e proton s of
asym m etric regioisom er 7a exh ibit un resolved m ultiplets in addition to two
doublets of proton s of cen tral ben zen e rin g.
As we m en tion ed before, diastereoselectivity of bisTBs is im portan t for
th eir poten tial application as buildin g blocks; at th at th e syn con figuration
bein g m ore in terestin g. However, th e X-ray structure an alysis (Table I) re-
vealed anti con figuration s for both bisTB derivatives 7a (Fig. 2) an d 7b
(Fig. 3). Th e sam e sh ape was observed for bisTB derivative 1a. In con trast,
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Benzene Bridged Tröger's Bases
613
bisTB derivative 1b was obtain ed in reverse con figuration 13. Th e predom i-
n an t form ation of syn diastereoisom er 1b is in terpreted by auth ors by stabi-
lizin g π-stackin g in teraction between th e extern al arom atic rin gs of
differen t polarity. Hen ce, it m ay be con cluded th at th e anti con figuration of
th e bisTB skeleton with cen tral ben zen e rin g is probably th erm odyn am ically
m ore stable. Indeed, the therm odynam ical stability of anti/syn configuration
of bisTB derivatives depends on the polarity of the substituents on the exter-
nal arom atic rings.
An oth er aim of th e presen t work was to prepare trisTB system 2, un -
kn own to date. We attem pted to build up th ree TB un its aroun d th e ben -
zen e rin g (1,2,3,4,5,6-substitution ). In th e sam e m an n er as described above,
th e startin g triam in o-1,3,5-ben zen e19 (8) was treated with 2-n itroben zoyl
ch loride givin g trisam ide 9a, wh ich was reduced in two steps (th rough
n itroam in e 10a) to am in e 11a. To our disappoin tm en t, th e reaction of 11a
TABLE I
Crystal data an d structure refin em en t for structures 7a an d 7b
Param eter
7a
7b
Form ula
Form ula weigh t, g m ol–1
2(C24N4H22)·(CH3OH)
764.97
C24N4H22
366.47
Crystal system
m on oclin ic
P21/c
triclin ic
P-1
Space group
a, Å
24.824(7)
8.8315(9)
9.770(1)
11.641(2)
87.91(1)
73.79(1)
73.50(1)
923.7(2)
2
b, Å
15.139(3)
c, Å
10.716(9)
α, °
90.00(0)
β, °
101.24(4)
γ, °
Volum e, Å3
90.00(0)
3 950(4)
Z
4 (two in asym . un it)
6.203
Absorption coefficien t, cm –1
Total n um ber of reflection s m easured
In depen den t reflection s, Rin t
Values of R, Rw, S
6.201
4 920
6 614
2 531, 0.056
0.109, 0.100, 1.0705
3 356, 0.023
0.0723, 0.038, 1.0197
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614
Valík, Dolensky, Petříčková, Král:
with form aldeh yde led to form ation of oligom eric products on ly. Th e ques-
tion was if th is un desirable process can be suppressed. Th e successful strat-
egy wh ich allows to elim in ate oligo- an d polym erization is based on th e use
of 5-m eth yl-2-n itroben zoyl ch loride20 in stead of 2-n itroben zoyl ch loride
an d th is sequen ce gave a n ovel trisTB 12b in 4% overall yield (Sch em e 3). It
is worth n otin g, th at our attem pts to prepare trisTB em ployin g th e
C22
C23
C21
C24
C1
C8
C20
C6
C2
C3
N4
C19
C12
N2
C10
C11
C5
C4
N3
C9
C7
C18
N1
C13
C14
C17
C16
C15
FIG. 2
ORTEP (ref.18) drawin g of X-ray structure of 7a
C15
C16
C17
C14
C1
C2
C8
C6
C13
C3
C18
N2
N4
C7
C11
C10
C5
C24
C4
N1
N3
C23
C22
C9
C12
C19
C20
C21
FIG. 3
ORTEP (ref.18) drawin g of X-ray structure of 7b
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Benzene Bridged Tröger's Bases
615
published strategy16 with nitroisatoic anhydride were unsuccessful due to insolu-
bility of in term ediate tris(n itroam in oam ides) m akin g th eir separation as well
as reduction im possible.
R
NH2
O2N
HN
(i)
O
H2N
NH2
O
O
R
R
8
HN
NO2
HN
O2N
9a, R=H
9b, R=CH3
(ii)
NH2
HN
H2N
HN
R
O
R
R
H2N
HN
(iii)
O
NH
NH2
O
R
R
HN
NH2
HN
(iv)
R
H2N
11a, R=H
10a, R=H
11b, R=CH3
10b, R=CH3
R
N
N
N
N
N
R
N
R
12a, R=H
12b, R=CH3
(i) 2-nitrobenzoyl chloride (for 9a), 5-methyl-2-nitrobenzoyl chloride (for 9b),
DMF, pyridine, 12 h, rt; (ii) H2, Pd/C, methanol, DMF, 10 h, rt; (iii) LiAlH4,
dioxane, 6 h, reflux; (iv) 36% aq. CH2O, conc. HCl, MeOH, 20 h, rt
SCHEME 3
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616
Valík, Dolensky, Petříčková, Král:
In form ation about con figuration of trisTB 12b cam e from an alysis of its
NMR spectra. Th ere are two possible con figuration al isom ers: h igh ly sym -
m etrical syn-syn an d syn-anti with a lower sym m etry. NMR spectra of 12b
are con sisten t with th e latter possible (cf. 2b, Fig. 1). Th ere are th ree sin glets
(2.18, 2.24 an d 2.26 ppm ) correspon din g to th ree n on equivalen t m eth yl
groups. Sim ilarly, th ree distin guish able doublets each of in tegral in ten sity
1 H in region of m eth ylen e proton s an d th ree close arom atic sin glets can be
observed in 1H NMR spectrum as well.
In sum m ary, we prepared n ovel bisTB an d trisTB derivatives with ben -
zen e as a cen tral un it. Th e sign ifican t regio- an d diastereoselectivity of
th ese n ovel com poun ds usin g a com m on protocol was observed. For both
bisTB derivatives on ly 1,2,3,4-substituted regioisom ers with anti con form a-
tion were separated from reaction m ixtures, wh ich is con sisten t with
Pardo’s results13. Moreover, our syn th etic protocol allowed for th e first tim e
to gen erate system s with th ree spatially orien ted TB un its on th e ben zen e
core. Oth er oligoTB system s with a differen t cen tral arom atic core an d th eir
bin din g properties are curren tly bein g in vestigated.
EXPERIMENTAL
Com m ercial solven ts for ch rom atograph y were purified by distillation . Meltin g poin ts were
determ in ed on a Kofler apparatus an d are un corrected. NMR spectra were obtain ed with
Varian Gem in i 300 HC (300.077 MHz for 1H NMR an d 75.460 MHz for 13C NMR spectra) at
23 °C in deuterioch loroform CDCl3, deuterated dim eth yl sulfoxide DMSO-d6 or deuterio-
aceton itrile CD3CN. Ch em ical sh ifts (δ) are presen ted in ppm an d couplin g con stan ts (J) in
Hz. In frared spectra (ν in cm –1) were recorded on a Nicolet 210 FTIR spectrom eter in KBr
tablets. Mass spectra were obtain ed by fast atom bom bardm en t (FAB) with a VG An alytical
ZAB-EQ spectrom eter. X-Ray data of 7 were m easured at 293 K with an En raf–Non ius CAD4
diffractom eter with graph ite m on och rom atized CuKα radiation . CCDC 163116 (7a) an d
CCDC 163115 (7b) con tain th e supplem en tary crystallograph ic data for th is paper. Th ese
data can be obtain ed free of ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from
th e Cam bridge Crystallograph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax:
+44 1223 336033; or deposit@ccdc.cam .ac.uk). Th in -layer ch rom atograph y was perform ed
on TLC-sh eet (Merck) with UV detection at 254 n m .
N,N′-(1,3-Ph en ylen e)bis(2-n itroben zam ide) (4a)
2-Nitroben zoyl ch loride (4.003 g, 21.33 m m ol) in DMF (10 m l) was added to 3a (0.498 g,
4.62 m m ol) in pyridin e (20 m l). Th e reaction m ixture was stirred at room tem perature for
12 h an d th an diluted with water (250 m l) an d m eth an ol (50 m l). Th e precipitated product
was filtered off an d wash ed with m eth an ol (50 m l) an d dich lorom eth an e (50 m l). A secon d
part of th e product was obtain ed by crystallization (m eth an ol–dich lorom eth an e) of th e resi-
due after evaporation of th e filtrate. Yield of 4a 1.750 g (93%), m .p. 253–257 °C. 1H NMR
(300 MHz, DMSO-d6): 7.34 m , 1 H (Ph ); 7.78 d, 2 H, J = 7.1 (Ph ); 7.80 m , 4 H (Ph ); 7.88 t,
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Benzene Bridged Tröger's Bases
617
2 H, J = 7.1 (Ph ); 8.14 m , 3 H (Ph ); 10.74 s, 2 H (CONH). 13C NMR (75 MHz, DMSO-d6):
111.07 (CH), 115.28 (CH), 124.18 (CH), 129.08 (CH), 129.29 (CH), 130.90 (CH), 132.66 (C),
134.06 (CH), 139.20 (C), 146.41 (C), 164.12 (CO). IR: 3 220, 3 142, 3 061, 2 928, 1 648, 1 606,
1 574, 1 546, 1 529, 1 351, 1 431, 1 267, 705, 789. MS: 406 (M+ C20H14N4O6, requires 406).
For C20H14N4O6 calculated: 59.12% C, 3.47% H, 13.79% N; foun d: 59.61% C, 3.77% H,
13.89% N.
N,N′-(1,2-Ph en ylen e)bis(2-n itroben zam ide) (4b)
Com poun d 4b was prepared in th e sam e way as 4a. Ch arges: ben zen e-1,2-diam in e (3b)
100 m g (0.93 m m ol), 2-n itroben zoyl ch loride 400 m g (2.16 m m ol), pyridin e 10 m l an d DMF
5 m l. Yield of 4b 368 m g (98%). 1H NMR (300 MHz, DMSO-d6): 7.33 m , 2 H (Ph ); 7.68–
7.90 m , 8 H (Ph ); 8.14 d, 2 H, J = 7.8 (Ph ); 10.12 s, 2 H (CONH). 13C NMR (75 MHz,
DMSO-d6): 124.37 (CH), 125.37 (CH), 125.93 (CH), 129.21 (CH), 130.45 (C), 131.17 (CH),
132.36 (C), 134.10 (CH), 146.67 (C), 164.51 (CO). MS: 406 (M+ C20H14N4O6, requires 406).
N,N′-(1,3-Ph en ylen e)bis(2-am in oben zam ide) (5a)
Com poun d 4a (1.005 g, 2.46 m m ol) an d catalyst (5% Pd/C, 100 m g) were added to a m ix-
ture of m eth an ol (50 m l) an d DMF (6 m l). After rem ovin g air th e reaction m ixture was
stirred for 10 h un der h ydrogen . Th e catalyst was filtered off un der argon an d th e solven t
evaporated. Com poun d 5a (810 m g, 95%) was obtain ed by crystallization (ch loroform ) of
th e residue, m .p. 177–180 °C. 1H NMR (300 MHz, CD3CN): 5.20–6.20 br s, 4 H (NH2);
6.65 dt, 2 H, J = 7.2, 1.1 (Ph ); 6.74 dd, 2 H, J = 7.1, 1.1 (Ph ); 7.22 dt, 2 H, J = 7.4, 8.0, 1.7
(Ph ); 7.27–7.39 m , 3 H (Ph ); 7.57 dd, 2 H, J = 8.0, 1.1, 1.6 (Ph ); 8.11 t, 1 H, J = 1.7, 2.2 (Ph );
8.64 s, 2 H (CONH). 13C NMR (75 MHz, CD3CN): 118.32 (CH), 120.97 (CH), 121.55 (CH),
121.96 (CH), 133.51 (CH), 134.01 (CH), 137.66 (CH), 144.41 (C), 154.75 (C), 173.14 (C),
176.92 (C). IR: 1 642, 1 612, 1 534, 1 490, 1 450, 1 340, 783, 751. MS: 346 (M+ C20H18N4O2,
requires 346). For C20H18N4O2·H2O calculated: 65.92% C, 5.53% H, 15.37% N; foun d:
66.73% C, 5.21% H, 15.53% N.
N,N′-Bis(2-am in oben zyl)ben zen e-1,3-diam in e (6a)
LAH (5 g) was added to 5a (500 m g, 1.45 m m ol) in dioxan e (50 m l). Th e reaction m ixture
was refluxed for 6 h , cooled an d diluted with water (12 m l), 15% solution of NaOH (14 m l)
an d water (18 m l). Th e in soluble part was filtered off an d wash ed with dieth yl eth er (2 ×
60 m l). Ligh t brown com poun d 6a (420 m g, 91%) was obtain ed from th e filtrate by evapora-
tion an d im m ediately used for preparation of 7a. 1H NMR (300 MHz, CDCl3): 3.70–4.20 br,
6 H (NH + NH2); 4.21 s, 4 H (CH2); 6.09 t, 1 H, J = 2.2 (Ph ); 6.20 dd, 2 H, J = 8.0, 2.2, 1.7
(Ph ); 6.75 m , 4 H (Ph ); 7.08 t, 1 H, J = 8.3, 7.7 (Ph ); 7.12–7.30 m , 4 H (Ph ). 13C NMR
(75 MHz, CDCl3): 46.95, 98.51, 104.14, 115.85, 118.30, 122.91, 128.85, 130.02, 130.09,
145.74, 149.52. MS: 319 (MH+ C20H23N4, requires 319).
N,N′-Bis(2-am in oben zyl)ben zen e-1,2-diam in e (6b)
Com poun d 6b was prepared directly from 4b in 70% yield. Th e reaction con dition s were
sam e as for reduction of 5a. Ch arges: 4b 500 m g (1.23 m m ol), LAH 5 g, dioxan e 50 m l; th e
reaction tim e was 48 h . 1H NMR (300 MHz, DMSO-d6): 3.26 br s, 2 H (NH); 4.03 br s, 4 H
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

618
Valík, Dolensky, Petříčková, Král:
(NH2); 4.15 s, 4 H (CH2); 6.64 dd, 2 H, J = 7.1, 1.2 (Ph ); 6.72 td, 2 H, J = 7.5, 1.2 (Ph );
6.82–6.92 m , 4 H (Ph ); 7.07–7.14 m , 4 H (Ph ). 13C NMR (75 MHz, DMSO-d6): 46.96, 111.84,
115.73, 118.06, 119.66, 122.62, 128.75, 129.99, 136.98, 145.84.
5α,9β,15β,17α-5,6,9,10,15,16,17,18-Octah ydro-5,17:9,15-dim eth an odiben zo[f,f ′]ben zo-
[1,2-b:3,4-b′]bis[1,5]diazocin e (7a)
Con cen trated HCl (1 m l) an d con cen trated solution of form aldeh yde (0.7 m l) were added to
a solution of 6a (400 m g, 1.26 m m ol) in m eth an ol (50 m l). Th e reaction m ixture was stirred
at room tem perature for 12 h , con cen trated by evaporation (to ca 5 m l), diluted with water
(20 m l), alkalin ized with con cen trated am m on ia solution (2 m l) an d extracted with di-
ch lorom eth an e (2 × 30 m l). Th e com bin ed extracts were dried with an h ydrous MgSO4 an d
evaporated. Th e residue was dissolved in dich lorom eth an e (5 m l) an d filtered th rough silica
gel (10 g, wash ed with 200 m l of dieth yl eth er). Product 7a (20 m g, 4%) was obtain ed from
th e filtrate by preparative TLC (20 × 20 cm , dich lorom eth an e–dieth yl eth er 8 : 2, eluted
twice), m .p. 157–161 °C. 1H NMR (300 MHz, CD3CN): 3.90–4.28 m , 7 H (CH2); 4.38–4.64 m ,
5 H (CH2); 9.72 d, 1 H, J = 8.2 (Ph ); 6.78 d, 1 H, J = 8.2 (Ph ); 6.88–7.00 m , 4 H (Ph ); 7.08 d,
1 H, J = 7.1 (Ph ); 7.05–7.18 m , 3 H (Ph ). 13C NMR (75 MHz, CD3CN): 59.47 (CH2), 60.37
(CH2), 62.64 (CH2), 63.25 (CH2), 71.14 (CH2), 71.32 (CH2), 125.01 (CH), 127.05 (C), 127.16
(C), 128.22 (CH), 128.33 (CH), 129.55 (CH), 129.65 (CH), 130.16 (CH), 131.61 (CH), 131.66
(CH), 137.79 (CH), 131.93 (CH), 133.02 (C), 133.13 (C), 149.59 (C), 152.40 (C), 153.17 (C).
MS: 367.1910 (MH+ C24H23N4, requires 367.1923).
5α,10β,16β,17α-5,6,9,10,15,16,17,18-Octah ydro-5,17:10,16-dim eth an odiben zo[f,f ′]ben zo-
[1,2-b:4,3-b′]bis[1,5]diazocin e (7b)
Com poun d 7b was prepared in th e sam e way as 7a. Ch arges: 6b 200 m g (0.63 m m ol), m eth -
an ol 50 m l, 36% aqueous form aldeh yde 1 m l, con cen trated HCl 1 m l. Yield of 7b 14 m g
(6%), m .p. > 220 °C (darken in g). 1H NMR (300 MHz, CDCl3): 4.10 d, 2 H, J = 16.8 (CH2);
4.25 d, 2 H, J = 12.6 (CH2); 4.35 d, 2 H, J = 12.6 (CH2); 4.53 d, 2 H, J = 17.4 (CH2); 4.61 d,
2 H, J = 15.9 (CH2); 4.85 d, 2 H, J = 17.1 (CH2); 6.53 s, 2 H (Ph ); 6.95–7.02 m , 4 H (Ph );
7.10–7.16 m , 4 H (Ph ). 13C NMR (75 MHz, CDCl3): 53.55 (CH2), 58.72 (CH2), 67.10 (CH2),
121.88 (CH), 123.91 (CH), 125.07 (CH), 126.11 (C), 126.94 (CH), 127.15 (CH), 129.41 (C),
141.10 (C), 147.73 (C). MS: 367.1917 (MH+ C24H23N4, requires 367.1923).
N,N′,N′′-(Ben zen e-1,3,5-triyl)tris(2-n itroben zam ide) (9a)
Com poun d 9a was prepared in th e sam e way as 4a. Ch arges: 8 340 m g (2.76 m m ol),
2-n itroben zoyl ch loride 3.192 g (17.07 m m ol), pyridin e 20 m l an d DMF 10 m l. Yield of
product 9a 820 m g (52%), m .p. > 320 °C. 1H NMR (300 MHz, DMSO-d6): 7.78–7.92 m , 12 H
(Ph ); 8.14 d, 3 H, J = 7.7 (Ph ); 10.82 s, 3 H (CONH). 13C NMR (75 MHz, DMSO-d6): 106.83
(CH), 124.14 (CH), 129.33 (CH), 130.88 (CH), 132.65 (C), 134.05 (CH), 139.35 (C), 146.40
(C), 164.21 (CO). IR: 3 305, 3 107, 3 037, 1 664, 1 617, 1 551, 1 529, 1 480, 1 451, 1 348,
1 296, 856, 789. MS: 571 (MH+ C27H19N6O9, requires 571). For C27H18N6O9 calculated:
56.85% C, 3.18% H, 14.73% N; foun d: 56.50% C, 3.18% H, 14.66% N.
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Benzene Bridged Tröger's Bases
619
N,N′,N′′-(Ben zen e-1,3,5-triyl)tris(5-m eth yl-2-n itroben zam ide) (9b)
Com poun d 9b was prepared in th e sam e way as 4a. Ch arges: 8 362 m g (2.94 m m ol),
5-m eth yl-2-n itroben zoyl ch loride 3.526 g (17.66 m m ol), pyridin e 10 m l an d DMF 10 m l.
Yield of product 9b 1.115 m g (62%), m .p. > 320 °C. 1H NMR (300 MHz, DMSO-d6): 2.48 s,
9 H (CH3); 7.53 m , 6 H (Ph ); 7.86 s, 3 H (Ph ); 8.03 d, 3 H, J = 8.5 (Ph ); 10.71 s, 3 H (CONH).
13C NMR (75 MHz, DMSO-d6): 20.85, 106.64, 124.07, 129.43, 130.78, 132.71, 139.18,
143.76, 145.09, 164.16. MS: 613 (MH+ C30H25N6O9, requires 613). For C30H24N6O9·H2O cal-
culated: 57.14% C, 4.16% H, 13.33% N; foun d: 57.28% C, 3.83% H, 13.13% N.
N,N′,N′′-(Ben zen e-1,3,5-triyl)tris(2-am in oben zam ide) (10a)
Com poun d 10a was prepared in th e sam e way as 5a. Ch arges: 9a 400 m g (0.70 m m ol), cata-
lyst (5% Pd/C) 50 m g, m eth an ol 30 m l an d DMF 5 m l. Yield of product 10a 330 m g (98%).
An alytical sam ple was obtain ed by precipitation (ch loroform –petroleum eth er). 1H NMR
(300 MHz, DMSO-d6): 6.13 s, 4 H (NH2); 6.65 t, 3 H, J = 7.2, 7.7 (Ph ); 6.79 d, 3 H, J = 7.7
(Ph ); 7.24 t, 3 H, J = 7.1 (Ph ); 7.70 d, 3 H, J = 7.7 (Ph ); 7.91 s, 3 H (Ph ); 9.87 s, 3 H (CONH).
13C NMR (75 MHz, DMSO-d6): 109.51 (CH), 114.62 (CH), 115.17 (C), 116.29 (CH), 128.79 (CH),
132.02 (CH), 139.01 (C), 149.76 (C), 167.79 (C). MS: 481 (MH+ C27H25N6O3, requires 481).
N,N′,N′′-(Ben zen e-1,3,5-triyl)tris(2-am in o-5-m eth ylben zam ide) (10b)
Com poun d 10b was prepared in th e sam e way as 5a. Ch arges: 9b 1.050 g (1.71 m m ol), cata-
lyst (5% Pd/C) 120 m g, m eth an ol 90 m l an d DMF 10 m l. Yield of product 10b 860 m g
(96%). 1H NMR (300 MHz, CDCl3): 2.19 s, 9 H (CH3); 4.40–5.80 br s, 6 H (NH2); 6.56 d, 3 H,
J = 6.6 (Ph ); 7.00 d, 3 H, J = 7.7 (Ph ); 7.21 s, 3 H (Ph ); 7.67 s, 3 H (Ph ); 8.25 s, 3 H (CONH).
13C NMR (75 MHz, CDCl3): 20.33 (CH3), 108.35 (CH), 116.26 (C), 117.64 (CH), 126.15 (C),
127.47 (CH), 133.50 (CH), 138.71 (C), 146.23 (C), 167.69 (C). MS: 523 (MH+ C30H31N6O3,
requires 523). For C30H30N6O3 calculated: 68.95% C, 5.79% H, 16.08% N; foun d: 68.03% C,
5.35% H, 15.25% N.
N,N′,N′′-Tris(2-am in oben zyl)ben zen e-1,3,5-triam in e (11a)
Com poun d 11a was prepared in th e sam e way as 6a. Ch arges: 10a 310 m g (0.65 m m ol),
LAH 2.5 g an d dioxan e 50 m l. Yield of product 11a 260 m g (92%). 1H NMR (300 MHz,
CDCl3): 3.71 br s, 3 H (NH); 4.16 s, 6 H (CH2); 5.57 s, 3 H (Ph ); 6.78 m , 6 H (Ph ); 7.13 m ,
6 H (Ph ). 13C NMR (75 MHz, CDCl3): 46.94, 89.97, 115.83, 118.27, 123.00, 128.79, 130.01,
145.73, 150.45. MS: 439 (MH+ C27H31N6, requires 439).
N,N′,N′′-Tris(2-am in o-5-m eth ylben zyl)ben zen e-1,3,5-triam in e (11b)
Com poun d 11b was prepared in th e sam e way as 6a. Ch arges: 10b 820 m g (1.57 m m ol),
LAH 4.2 g an d dioxan e 120 m l. Yield of product 11b 700 m g (93%). 1H NMR (300 MHz,
CDCl3): 2.26 s, 9 H (CH3); 3.20–4.40 br, 6 H (NH + NH2); 4.14 s, 6 H (CH2); 5.59 s, 2 H (Ph );
6.61 d, 3 H, J = 8.3 (Ph ); 6.93 m , 6 H (Ph ). 13C NMR (75 MHz, CDCl3): 20.40 (CH3), 46.86
(CH2), 87.72 (CH), 115.87 (CH), 123.04 (C), 127.32 (C), 129.07 (CH), 130.47 (CH), 142.97
(C), 150.30 (C). MS: 481 (MH+ C30H37N6, requires 481).
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620
Valík, Dolensky, Petříčková, Král:
5α,7α,13α,15β,21β,22α-2,10,18-Trim eth yl-5,6,7,8,13,14,15,16,21,22,23,24-dodecah ydro-
5,23:7,13:15,21-trim eth an otriben zo[f,f ′,f ′′]ben zo[1,2-b:3,4-b′:5,6-b′′]tris[1,5]diazocin e (12b)
Com poun d 12b was prepared in th e sam e way as 7a. Ch arges: 11b 720 m g (1.50 m m ol),
m eth an ol 500 m l, 36% aqueous form aldeh yde 10 m l, con cen trated HCl 10 m l. Com poun d
12b (67 m g, 8%) was obtain ed by colum n ch rom atograph y (dich lorom eth an e–dieth yl eth er
7 : 3) an d repurified by preparative TLC (20 × 20 cm , dich lorom eth an e–dieth yl eth er 7 : 3).
1H NMR (300 MHz, CDCl3): 2.18 s, 3 H (CH3); 2.24 m , 3 H (CH3); 2.26 m , 3 H (CH3); 3.60 d,
1 H, J = 16.5 (CH2); 3.73 d, 1 H, J = 16.8 (CH2); 3.86 d, 1 H, J = 16.5 (CH2); 4.00–4.65 m , 15 H
(CH2); 6.54 s, 1 H (Ph ); 6.70 s, 1 H (Ph ); 6.74 s, 1 H (Ph ); 6.86–7.14 m , 6 H (Ph ). 13C NMR
(75 MHz, CDCl3): 20.88 (CH3), 21.90 (CH3), 20.96 (CH3), 54.39 (CH2), 54.42 (CH2), 55.11
(CH2), 55.17 (CH2), 55.24 (CH2), 56.25 (CH2), 66.59 (2 CH2), 66.85 (CH2), 117.70 (C),
118.13 (C), 118.82 (C), 124.42 (CH), 124.99 (CH), 125.07 (CH), 126.87 (CH), 126.92 (CH),
127.19 (C), 127.35 (2 C), 127.38 (CH), 127.90 (CH), 127.98 (CH), 128.04 (CH), 133.36 (C),
133.38 (C), 133.48 (C), 143.74 (C), 144.03 (C), 144.07 (C), 144.99 (C), 145.09 (C),
145.34 (C). MS: 553.3086 (MH+ C36H37N6, requires 553.3072).
Financial support from the Howard Hughes Medical Institute (grant No. 75195-541101) and the
Grant Agency of the Czech Republic (grant No. 202/02/0933) is gratefully acknowledged. We also
thank J. Kroulík, MS for the help in preparation of the manuscript.
REFERENCES
1. Atwood J. L., Davies J. E. D., MacNicol D. D., Vögtle F., Lehn J. M.: Comprehensive
Supramolecular Chemistry, Vol. 2. Pergamon, Oxford 1996.
2. Tröger J.: J. Prakt. Chem. 1887, 36, 225.
3. a) Crossley M. J., Hambley T. W., Mackay L. G., Try A. C., Walton R.: J. Chem. Soc.,
Chem. Commun. 1995, 1077; b) Reek J. N. H., Schenning A. P. H. J., Bosman A. W.,
Meijer E. W., Crossley M. J.: Chem. Commun. 1998, 1, 11.
4. Hansson A. P., Norrby P. O., Waernmark K.: Tetrahedron Lett. 1998, 39, 4565.
5. Wilcox C. S., Adrian J. C., Webb T. H., Zawacki F. J.: J. Am. Chem. Soc. 1992, 114, 10189.
6. Goswami S., Ghosh K., Dasgupta S.: J. Org. Chem. 2000, 65, 1907.
7. a) Crossley M. J., Mackay L. G., Try A. C.: J. Chem. Soc., Chem. Commun. 1995, 1925;
b) Allen P. R., Reek J. N. H., Try A. C., Crossley M. J.: Tetrahedron: Asymmetry 1997, 8,
1161.
8. Webb T. H., Suh H., Wilcox C. S.: J. Am. Chem. Soc. 1991, 113, 8554.
9. Yashima E., Akashi M., Miyauchi N.: Chem. Lett. 1991, 1017.
10. Salez H., Wardani A., Demeunynck M., Tatibouet A., Lhomme J.: Tetrahedron Lett. 1995,
36, 1271.
11. Tatibouet A., Demeunynck M., Andraud Ch., Collet A., Lhomme J.: Chem. Commun.
1999, 2, 161.
12. Bailly Ch., Laine W., Demeunynck M., Lhomme J.: Biochem. Biophys. Res. Commun.
2000, 273, 681.
13. Pardo C., Sesmilo E., Gutierrez-Puebla E., Monge A., Elguero J., Fruchier A.: J. Org. Chem.
2001, 66, 1607.
14. Sucholeiki I., Lynch V., Phan L., Wilcox C. S.: J. Org. Chem. 1988, 53, 98.
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15. Bag B. G., Maitra U.: Synth. Commun. 1195, 25, 1849.
16. Webb T. H., Wilcox C. S.: J. Org. Chem. 1990, 55, 363.
17. Black D. S., Rothnie N. E.: Aust. J. Chem. 1983, 36, 1141.
18. Brueggemann R., Schmidt G.: ORTEP 3.21, PC adaptation, Ulm 1991.
19. Lukas A. S., Miller S. E., Wasielewski M. R.: J. Phys. Chem. B 2000, 104, 931.
20. McNab H., Smith G. S.: J. Chem. Soc., Perkin Trans. 1 1984, 381.
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