Methodology for easy access to large sidewall bis-troeger's bases

Article abstract of DOI:10.1135/cccc20070392

4,6-Bis(bromomethyl)-N¹,N³-bis(terf-butoxycarbonyl) benzene-1,3-diamine is intioduced as a general starting compound for the preparation of bis-Troeger's base (bisTB) derivatives In excellent yield in just two steps. The synthetic se

Full text of DOI:10.1135/cccc20070392

392
Havlík, Král, Dolenský:
METHODOLOGY FOR EASY ACCESS TO LARGE SIDEWALL
BIS-TRÖGER’S BASES
1
2
3,
Martin HAVLÍK , Vladimír KRÁL and Bohumil DOLENSKÝ *
Department of Analytical Chemistry, Institute of Chemical Technology, Prague,
1
2
Technická 5, 166 28 Prague 6, Czech Republic; e-mail: havlikm@vscht.cz, kralv@vscht.cz,
dolenskb@vscht.cz
3
Received March 12, 2007
Accepted March 15, 2007
4,6-Bis(brom om eth yl)-N1,N3-bis(tert-butoxycarbon yl)ben zen e-1,3-diam in e is in troduced as
a gen eral startin g com poun d for th e preparation of bis-Tröger’s base (bisTB) derivatives in
excellen t yield in just two steps. Th e syn th etic sequen ce in cludes treatm en t of th e above-
m en tion ed protected diam in e with an arylam in e followed by in situ deprotection an d th e
fin al bisTB-form in g reaction . Th is sequen ce allows syn th esis of bisTB derivatives, wh ich are
n ot accessible by kn own procedures. Th e described approach is a gen eral n ew m eth od for
th e preparation of bisTB derivatives from “troegerable” arylam in es.
Keyw ord s: Bis-Tröger’s bases; Molecular tweezers; Syn th etic m eth odology.
Bis-Tröger’s bases derivatives 1 (bisTB) are com poun ds th at con tain a cen -
tral arom atic rin g fused to two 1,5-m eth an o-1,5-diazocin es (TB un its) con -
tain in g an n elated arom atic sidewalls. Typical TB derivatives1 exh ibit rigid
V-sh apes, causin g bisTBs to exist as syn- an d anti-diastereoisom eric form s2–4
.
Th e syn-bisTBs em body m olecular tweezers. TB derivatives1, can isom erize in
acidic m edia, th ereby allowin g, in con trast to com m on m olecular tweezers,
th e possibility of switch in g between a tweezer an d n on -tweezer form 2,3b,3c,4
.
In addition , Len ev at al.5 recen tly reported th at th e isom erization of TB de-
rivatives, i.e. th e stability of TB derivatives in acidic con dition , could be ef-
fectively tun ed by th e judicious ch oice of m oieties proxim al to n itrogen .
Th e in h eren t ch irality of TB derivatives1 also bolsters in terest in bisTB m o-
lecular arch itectures.
Gen eral m eth ods for bisTB preparation are lackin g. On e syn th etic strat-
egy is based on th e preparation of each TB un it in discreet steps2a,2b,2d,3b,4
.
Th e m ost direct route to bisTBs is a on e-pot preparation , i.e., th e m ixed
“troegeration ” of an arom atic am in e an d diam in e3b,3c. Th e low yield an d
un con trollable regioselectivity are restriction s of th is approach . Th us, n ew
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 392–402
© 2007 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20070392

Bis-Tröger’s Bases
393
approach es, in cludin g th e preparation of useful in term ediates, are of in ter-
est2c,3a,3c,3d
.
In a previous in vestigation , th e reduction of am ides 2 to tetraam in es 3
(th e precursors for fin al “troegeration ”) (Sch em e 1) h ad un expected lim ita-
tion s. In th e cases of aryls such as an th racen e, fluoren e an d pyren e, th e re-
duction was troublesom e3d
.
SCHEME 1
Th e critical step in am ide protocol of bisTB preparation
As an altern ative route to tetraam in es 3 we started from din itroxylen e 4
(Sch em e 2). Brom ation afforded 5, wh ich , after treatm en t with excess of
arylam in es 6, gave din itrodiam in es 7 in yields of about 90%. Un fortu-
n ately, attem pts6 at n itro group reduction to th e expected tetraaam in es 3
led to CH2–NHAryl cleavage. Arylam in es 6 were form ed as th e m ain prod-
ucts. Th us, th e problem s with am ide reduction are a result of th e low stabil-
ity of targeted tetraam in es 3 again st reducin g agen ts an d n ot due to th e
am ide carbon yls as reported previously7.
(i) NBS, 5 (20%); (ii) arylam in e 6 (series: a n aph th -2-yl, b an th racen -2-yl, c fluoren -2-yl, d
pyren -1-yl, e an th racen -1-yl), 7b (83%), 7c (87%), 7d (98%); (iii) reduction caused decom po-
sition 6
SCHEME 2
Nitrobrom ide syn th etic path way to bisTB.
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Havlík, Král, Dolenský:
To bypass th e reduction step, th e n itro groups of din itroxylen e 4 are re-
duced in itially to am in o groups, wh ich are protected by reaction with
Boc2O to give diam in e 8 (Sch em e 3). Th e protectin g was perform ed to pre-
clude poten tial com plication s with reactivity an d selectivity in th e follow-
in g reaction s. Th e bocylation after reduction gave better yields th an
bocylation durin g th e reduction . Th e bocyl was ch osen due to its rem ovin g
in acidic con dition an d un in terferin g byproducts, th us, in situ deprotection
durin g th e “troegeration ” can be ach ieved. Brom in ation of 8 furn ish ed
diam in odibrom ide 9 in good yield. Th e purification of 9 by ch rom atogra-
ph y led to decom position . Th us 9 was used crude (purity 80–90% by NMR)
in th e n ext reaction . Th e treatm en t of 9 with excess 6 gave correspon din g
tetraam in es 10 in m oderate yields. Dissolvin g tetraam in es 10 in trifluoro-
acetic acid (TFA) gave desired tetraam in es 3. Th e experim en t in NMR tube
sh own th at th e debocylation of tetram in e 10d in TFA-d1 is fin ish ed in
about 5 m in at 23 °C, an d form ed tetraam in e 3d in TFA-d1 is stable for
at least 24 h . Addition of paraform aldeh yde started th e “troegeration ” pro-
cess. Th is gave expected bisTBs in excellen t yields n ot on ly in th e case of
n aph th alen e-2-am in e derived bisTB 1a (isolated 41% of isom er 1a-A an d
53% of isom er 1a-B), wh ich was prepared also by th e am ide-based proto-
col3d (7%; so low yield can n ot be explain ed by th e sm all con tam in ation of
th e startin g tetram in e 3a with n aph th alen e-2-am in e), but also in th e case
of an th racen e-2-am in e derived bisTB 1b (isolated 36% of isom er 1b-A an d
(i) Pd/C, H2, Boc2O, 84%; (ii) NBS, 82%; (iii) arylam in e 6 (see footn ote of Sch em e 2), 10a
(48%), 10b (30%), 10c (43%), 10d (16%), 10e (11%); (iv) paraform aldeh yde, TFA, 1a (94%),
1b (76%), 1c (82%), 1d (~0%), 1e (~0%)
SCHEME 3
Am in obrom ide syn th etic path way to bisTB
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Bis-Tröger’s Bases
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40% of isom er 1b-B) an d fluoren e-2-am in e derived bisTB 1c (isolated 44%
of isom er 1c-A an d 38% of isom er 1c-B), wh ich are can n ot be readily pre-
pared via th e correspon din g am ides3d. It sh ould be n oted both diastereo-
isom ers of bisTBs were isolated an d separated, h owever, th e determ in ation
of th e relative con figuration is due to sym m etry im possible base on NMR,
th us, th e X-ray diffraction an alyses will be n ecessary. Un fortun ately, pyren e-
1-am in e derived bisTB 1d an d an th racen e-1-am in e derived bisTB 1e were
n ot isolated (see Experim en tal) from th e correspon din g tetraam in es 10 via
our n ew m eth odology.
Relatively sim pler Tröger’s base derivatives1 are readily form ed from pre-
cursors such as n aph th alen e-2-am in e (67% yield)8 or an th racen e-2-am in e
(30% yield); addition ally, th e tetraam in es 10a an d 10b give th e expected
bisTBs 1a an d 1b, respectively. In con trast, “un troegerable” arylam in es, such
CHART 1
BisTB derivatives
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Havlík, Král, Dolenský:
as n aph th alen e-1-am in e, an th racen e-1-am in e or pyren e-1-am in e, do n ot
afford TB derivatives. Th us, it is n ot surprisin g bisTB derivatives are n ot
form ed from th e correspon din g tetraam in es 10d an d 10e (Ch art 1).
In con clusion , we h ave presen ted a n ew am in obrom ide-based protocol,
wh ich overcom es th e reduction issues in h eren t in prior m eth odology. It en -
ables th e preparation of derivatives, wh ich are n ot accessible via previous
protocols. Th us, th e first preparation s of bisTB derivatives with sidewalls as
large as an th racen e are presen ted. Th e am in obrom ide protocol appears use-
ful at least for bisTB derivatives with “troegerable” arylam in es as sidewalls.
Th e syn th etic m eth ods described h erein sh ould be readily applicable to
an alogous arch itectures beyon d th ose wh erein th e cen tral buildin g block is
ben zen e.
EXPERIMENTAL
Com m ercial solven ts for ch rom atograph y were purified by distillation . NMR spectra were
obtain ed with Varian Gem in i 300 HC (300.077 MHz for 1H an d 75.460 MHz for 13C) at 23 °C
in deuterioch loroform CDCl3 or deuterated dim eth yl sulfoxide DMSO-d6. Ch em ical sh ifts δ
are presen ted in ppm , couplin g con stan ts J in Hz. Mass spectra were obtain ed by fast atom
bom bardm en t (FAB) with a VG An alytical ZAB-EQ spectrom eter. Th in -layer ch rom atograph y
was perform ed on TLC-sh eet (Merck) with UV detection at 254 n m .
Preparation of Dibrom ide 5
1,3-Dim eth yl-4,6-din itroben zen e (2.0 g, 10.2 m m ol) was treated with N-brom osuccin im ide
(NBS, 3.8 g, 21.4 m m ol) an d diben zoyl peroxide (DBP, 0.02 g, 83 µm ol) in CCl4 (200 m l) at
reflux for 4 h . Th en n ext portion s of NBS (3.8 g) an d DBP (0.02 g) were added an d th e reac-
tion m ixture was kept at reflux overn igh t. Precipitated solid was filtered off an d wash ed
with CCl4. Th e filtrate was evaporated to dryn ess in vacuo an d dibrom ide 5 (0.71 g, 20%)
an d m on obrom ide 13 (0.48 g, 17%) were isolated by colum n ch rom atograph y (CHCl3–
h exan e 2:1).
1,5-Bis(bromomethyl)-2,4-dinitrobenzene (5): 1H NMR (CDCl3): 8.69 s, 1 H; 7.80 s, 1 H; 4.80 s,
4 H. 13C APT NMR (CDCl3): 146.83 (C), 138.33 (C), 136.97 (CH), 123.09 (CH), 26.76 (CH2).
HRMS (EI+): for C8H6Br2N2O4 [M+] calculated: 351.8694, 353.8671, 355.8653; foun d:
351.8681, 353.8675, 355.8637.
1-(Bromomethyl)-5-methyl-2,4-dinitrobenzene (13): 1H NMR (CDCl3): 8.64 s, 1 H; 7.56 s, 1 H;
4.78 s, 2 H; 2.65 s, 3 H. 13C APT NMR (CDCl3): 147.99 (C), 145.38 (C), 139.98 (C), 137.35
(C), 137.14 (CH), 122.36 (CH), 27.25 (CH2), 20.50 (CH3). HRMS (EI+): for C8H7BrN2O4 [M+]
calculated: 273.9589, 275.9569; foun d: 273.9584, 275.9554.
Preparation of Diam in es 7. Gen eral Procedure
Dibrom ide 5 was treated with arylam in e 6 in EtOH (150 m l) at 80 °C overn igh t. Precipitated
solid filtered off an d wash ed with EtOH, con cen trated NH3 an d water, dried in vacuo to give
correspon din g diam in e 7.
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N-(5-((Anthracen-2-ylamino)methyl)-2,4-dinitrobenzyl)anthracene-2-amine (7b): Dibrom ide 5
(0.20 g, 0.57 m m ol) an d an th racen e-2-am in e (1.09 g, 5.67 m m ol) gave 0.27 g (83%) of 7b.
1H NMR (DMSO-d6): 8.82 s, 1 H; 8.14 s, 1 H; 8.04 s, 2 H; 7.85 m , 2 H; 7.75 s, 2 H; 7.59 m , 2 H;
7.50 d, 2 H, J = 9.2; 7.29 m , 4 H; 6.89 dd, 2 H, J = 9.1, J = 1.8; 6.73 t, 2 H, J = 5.7; 6.52 s,
2 H; 4.78 d, 4 H, J = 5.7. 13C APT NMR (DMSO-d6): 146.51 (C), 144.82 (C), 141.23 (C),
133.13 (C), 131.70 (C), 130.38 (CH), 128.78 (CH), 128.57 (C), 127.97 (CH), 126.95 (CH),
126.77 (C), 125.58 (CH), 125.03 (CH), 123.22 (CH), 122.24 (CH), 121.65 (CH), 120.01 (CH),
100.05 (CH), 44.31 (CH2). HRMS (FAB+): for C36H27N4O4 [MH+] calculated: 579.2032; foun d:
579.2014.
N-(5-((9H-Fluoren-2-ylamino)methyl)-2,4-dinitrobenzyl)-9H-fluorene-2-amine (7c). Dibrom ide 5
(0.20 g, 0.57 m m ol), fluoren e-2-am in e (1.03 g, 5.66 m m ol) gave 0.27 g (87%) of 7c. 1H NMR
(DMSO-d6): 8.74 s, 1 H; 8.06 s, 1 H; 7.40 d, 2 H, J = 7.5; 7.26 m , 6 H; 7.08 m , 2 H; 6.61 s,
2 H; 6.41 m , 4 H; 4.68 d, 4 H, J = 6.2; 3.51 s, 4 H. 13C APT NMR (DMSO-d6): 147.44 (C),
146.37 (C), 144.44 (C), 141.80 (C), 141.68 (C), 141.57 (C), 130.86 (CH), 130.48 (C), 126.37
(CH), 124.58 (CH), 124.40 (CH), 122.13 (CH), 120.26 (CH), 118.04 (CH), 111.16 (CH),
108.58 (CH), 44.68 (CH2), 36.14 (CH2). HRMS (FAB+): for C34H27N4O4 [MH+] calculated:
555.2032; foun d: 555.2042.
N-{5[(Pyren-1-ylamino)methyl]-2,4-dinitrobenzyl}pyrene-1-amine (7d ). Dibrom ide 5 (0.15 g,
0.43 m m ol) an d pyren e-1-am in e (0.94 g, 4.32 m m ol) gave 0.27 g (98%) of 7d . 1H NMR
(DMSO-d6): 8.89 s, 1 H; 8.13 s, 1 H; 7.94 d, 2 H, J = 7.6; 7.87 t, 2 H, J = 7.6; 7.70 m , 4 H;
7.54 s, 4 H; 7.53 d, 2 H, J = 6.5; 7.24 d, 2 H, J = 9.4; 7.12 t, 2 H, J = 5.6; 6.79 d, 2 H, J = 8.5;
4.94 d, 4 H, J = 5.3. 13C APT NMR (DMSO-d6): 146.37 (C), 141.63 (C), 141.57 (C), 131.66
(C), 131.00 (C), 129.70 (CH), 127.17 (CH), 125.91 (CH), 125.62 (CH), 124.97 (C), 124.60 (C),
124.28 (CH), 123.06 (CH), 122.64 (CH), 122.47 (CH), 122.22 (CH), 121.69 (C), 120.30 (CH),
115.54 (C), 108.15 (CH), 44.31 (CH2). HRMS (ES+): for C40H26N4O4 [M+• ] calculated:
626.1954; foun d: 626.1726.
Preparation of Dibrom ide 9
1,3-Dim eth yl-4,6-din itroben zen e (2.0 g, 10.2 m m ol) was dissolved in 50 m l of m eth an ol,
an d catalyst (5% Pd/C, 0.2 g) was added. Th e reaction m ixture was stirred un der h ydrogen
atm osph ere for 2 days. Th e catalyst was filtered off, an d th e filtrate was evaporated to dry-
n ess in vacuo to give 1.3 g (94%) of 4,6-dim eth ylben zen e-1,3-diam in e (14). Obtain ed
diam in e 14 (1.0 g, 7.34 m m ol) was treated with Boc2O (3.4 g, 15.6 m m ol) in 150 m l of
MeOH at room tem perature for 3 h . Reaction m ixture was evaporated to dryn ess in vacuo,
an d th e residue was separated by colum n ch rom atograph y (MeOH–CHCl3 975:25) to give
2.2 g (89%) of bocylam in e 8. Obtain ed bocylam in e 8 (1.0 g, 3.0 m m ol) was treated with
N-brom osuccin im ide (NBS, 1.1 g, 6.0 m m ol) an d α,α′-azo-bis(isobutyron itrile) (AIBN, 0.1 g,
0.6 m m ol) in CCl4 (150 m l) un der irradiation by th e IR lam p for 1.5 h . Precipitated solid
was filtered off an d wash ed with CCl4. Th e filtrate was extracted with 2% aqueous am m on i-
um an d th en with water. Th e organ ic layer was dried over Na2SO4 an d evaporated to dry-
n ess in vacuo, dissolved in Et2O an d th e precipitated solid was filtered off. Th e filtrate was
evaporated to dryn ess in vacuo to give brom ide 9 (1.2 g, 82%).
4,6-Dimethylbenzene-1,3-diamine (14): 1H NMR (CDCl3): 6.64 s, 1 H; 5.98 s, 1 H; 3.33 bs,
4 H; 1.98 s, 6 H. 13C APT NMR (CDCl3): 143.13 (C), 132.24 (CH), 112.86 (C), 102.37 (CH),
16.26 (CH3). HRMS (EI+): for C8H12N2 [M+] calculated: 136.1000; foun d: 136.0999. Kn own
com poun d9.
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Havlík, Král, Dolenský:
4,6-Dimethylbenzene-N1,N3-bis(tert-butoxycarbonyl)-1,3-diamine (8): 1H NMR (CDCl3): 7.94 s,
1 H; 6.86 s, 1 H; 6.08 bs, 2 H; 2.10 s, 6 H; 1.44 s, 18 H. 13C APT NMR (CDCl3): 153.11 (C),
134.39 (C), 131.96 (CH), 124.33 (C), 115.63 (CH), 80.24 (C), 28.34 (CH3), 17.13 (CH3).
HRMS (EI+): for C18H28N2O4 [M+] calculated: 336.2049; foun d: 336.2059.
4,6-Bis(bromomethyl)-N1,N3-bis(tert-butoxycarbonyl)benzene-1,3-diamine (9): 1H NMR (CDCl3):
8.35 s, 1 H; 7.20 s, 1 H; 6.68 s, 2 H; 4.44 s, 4 H; 1.53 s, 18 H. 13C APT NMR (CDCl3): 152.44
(C), 138.57 (C), 131.61 (CH), 122.29 (C), 116.25 (CH), 81.30 (C), 30.73 (CH2), 28.26 (CH3).
HRMS: n o ion ization tech n iques (EI+, FAB+, ESI+) gave m olecular ion .
Preparation s of Diam in es 10. Gen eral Procedure
Dibrom ide 9 was treated with arylam in e 6 an d K2CO3 in DMF at 70 °C for 5 h . Th e reaction
m ixture was evaporated to dryn ess in vacuo an d tetraam in e 10 was obtain ed by colum n
ch rom atograph y to give pure tetram in e 10.
N1,N3-Bis(tert-butoxycarbonyl)-4,6-bis((naphthalen-2-ylamino)methyl)benzene-1,3-diamine (10a):
Naph th alen e-2-am in e 6a (2.90 g, 20.2 m m ol), dibrom ide 9 (1.00 g, 2.0 m m ol), K2CO3 (0.28 g,
2.0 m m ol), 100 m l of DMF; th e first colum n ch rom atograph y (toluen e–EtOAc–Et3N 500:100:1)
gave crude product, wh ich was purified by n ext colum n ch rom atograph y (CH2Cl2) to give
pure 0.60 g (48%) of diam in e 10a. 1H NMR (CDCl3): 8.29 s, 1 H; 7.63 d, 2 H, J = 8.2; 7.60 d,
2 H, J = 8.2; 7.57 d, 2 H, J = 6.7; 7.31 m , 4 H; 7.21 m , 3 H; 6.90 m , 4 H; 4.25 s, 4 H; 3.91 bs,
2 H; 1.41 s, 18 H. 13C APT NMR (CDCl3): 153.24 (C), 145.55 (C), 137.64 (C), 134.86 (C),
130.71 (CH), 128.99 (CH), 128.18 (C), 127.65 (CH), 126.46 (CH), 126.21 (CH), 123.78 (C),
122.71 (CH), 118,44 (CH), 115.68 (CH), 106.44 (CH), 80.68 (C), 46.7 (CH2), 28.31 (CH3).
HRMS (FAB+): for C38H43N4O4 [MH+] calculated: 619.3284; foun d: 619.3275.
4,6-Bis((anthracen-2-ylamino)methyl)-N1,N3-bis(tert-butoxycarbonyl)-1,3-diamine
(10b ):
An th racen e-2-am in e 6b (3.90 g, 20.2 m m ol), dibrom ide 9 (1.00 g, 2.0 m m ol), K2CO3 (0.31 g,
2.2 m m ol), 50 m l of DMF, colum n ch rom atograph y (toluen –EtOAc–Et3N 833:167:1), 0.43 g
(30%) of diam in e 10b. 1H NMR (DMSO-d6): 8.76 s, 2 H; 8.20 s, 2 H; 7.90 s, 2 H; 7.89 d, 2 H,
J = 8.1; 7.74 d, 2 H, J = 8.1; 7.69 d, 2 H, J = 8.8; 7.54 s, 1 H; 7.48 s, 1 H; 7.31 m , 4 H;
7.02 dd, 2 H, J = 9.2, J = 1.8; 6.59 s, 2 H; 6.51 t, 2 H, J = 5.5; 4.27 d, 4 H, J = 5.5; 1.47 s,
18 H. 13C APT NMR (DMSO-d6): 153.67 (C), 145.74 (C), 135.02 (C), 133.46 (C), 131.84 (C),
129.09 (C), 128.58 (CH), 128.50 (C), 128.01 (CH), 127.25 (CH), 126.91 (CH), 126.74 (C),
125.66 (CH), 125.13 (CH), 123.15 (CH), 121.42 (CH), 120.97 (CH), 120.78 (CH), 99.84 (CH),
78.97 (C), 43.11 (CH2), 28.10 (CH3). HRMS (FAB+): for C46H46N4O4 [M+] calculated:
718.3519; foun d: 718.3508.
4,6-Bis((9H-fluoren-2-ylamino)methyl)-N1,N3-bis(tert-butoxycarbonyl)benzene-1,3-diamine (10c):
Fluoren e-2-am in e 6c (3.67 g, 20.2 m m ol), dibrom ide 9 (1.00 g, 2.0 m m ol), K2CO3 (0.31 g,
2.2 m m ol), 45 m l of DMF, colum n ch rom atograph y (toluen –EtOAc–Et3N 833:167:1), 0.60 g
(43%) of diam in e 10c. 1H NMR (DMSO-d6): 8.68 s, 2 H; 7.51 s, 1 H; 7.49 d, 2 H, J = 7.9;
7.40 d, 2 H, J = 8.2; 7.38 s, 1 H; 7.32 d, 2 H, J = 7.3; 7.23 t, 2 H, J = 7.3; 7.08 m , 2 H; 6.68 s,
2 H; 6.49 dd, 2 H, J = 8.2, J = 1.8; 6.18 t, 2 H, J = 5.6; 4.19 d, 4 H, J = 5.3; 3.61 s, 4 H; 1.46 s,
18 H. 13C APT NMR (DMSO-d6): 153.52 (C), 148.41 (C), 144.37 (C), 142.00 (C), 141.55 (C),
134.83 (C), 130.00 (C), 129.10 (C), 127.26 (CH), 126.42 (CH), 124.60 (CH), 124.30 (CH),
120.29 (2 × CH), 117.98 (CH), 111.59 (CH), 108.76 (CH), 78.94 (C), 43.64 (CH2), 36.21
(CH2), 28.10 (CH3). HRMS (FAB+): for C44H46N4O4 [M+] calculated: 694.3519; foun d:
694.3492.
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N1,N3-Bis(tert-butoxycarbonyl)-4,6-bis((pyren-1-ylamino)methyl)benzene-1,3-diamine (10d ):
Pyren e-1-am in e 6d (1.4 g, 6.4 m m ol), dibrom ide 9 (0.8 g, 1.6 m m ol), K2CO3 (0.2 g, 1.6 m m ol),
50 m l of DMF; th e first colum n ch rom atograph y (toluen e–EtOH–Et3N 800:200:1) gave crude
product, wh ich was purified by n ext colum n ch rom atograph y (CH2Cl2) to give pure 0.2 g
(16%) of diam in e 10d . 1H NMR (DMSO-d6): 8.90 s, 2 H; 8.08 d, 2 H, J = 9.4; 7.94 m , 6 H;
7.61 m , 8 H; 7.48 d, 2 H, J = 7.6; 7.16 bs, 2 H; 6.82 d, 2 H, J = 8.2; 4.44 s, 4 H; 1.47 s, 18 H.
13C APT NMR (DMSO-d6): 153.72 (C), 142.88 (C), 134.74 (C), 131.92 (C), 131.35 (C), 129.42
(C), 127.53 (CH), 126.20 (CH), 126.11 (CH), 125.83 (CH), 125.24 (C), 124.92 (C), 124.43
(CH), 123.00 (CH), 122.55 (CH), 121.96 (CH), 121.24 (C), 121.00 (2 × CH), 115.62 (C),
108.58 (CH), 78.94 (C), 42.98 (CH2), 28.10 (CH3). HRMS (FAB+): for C50H47N4O4 [MH+] cal-
culated: 767.3597; foun d: 767.3617.
4,6-Bis((anthracen-1-ylamino)methyl)-N1,N3-bis(tert-butoxycarbonyl)benzene-1,3-diamine (10e):
An th racen e-1-am in e 6e (0.97 m g, 5.0 m m ol), dibrom ide 9 (0.50 m g, 1.0 m m ol), K2CO3
(0.14 m g, 1.0 m m ol), 50 m l of DMF; th e first colum n ch rom atograph y (toluen e–CH2Cl2–Et3N
100:900:1) gave crude product, wh ich was purified by n ext colum n ch rom atograph y
(CH2Cl2) to give pure 80 m g (11%) of diam in e 10e. 1H NMR (CDCl3): 8.43 s, 1 H; 8.31 s,
4 H; 7.91 m , 4 H; 7.55 s, 2 H; 7.44 d, 2 H, J = 8.5; 7.38 m , 5 H; 7.29 m , 2 H; 6.63 d, 2 H, J =
7.3; 4.56 bs, 2 H; 4.40 s, 4 H; 1.36 s, 18 H. 13C APT NMR (CDCl3): 153.48 (C), 142.74 (C),
138.12 (C), 132.29 (C), 131.64 (C), 131.48 (CH), 131.10 (C), 128.41 (CH), 127.78 (CH),
126.72 (CH), 125.79 (CH), 125.65 (CH), 125.30 (CH), 124.12 (C), 123.91 (C), 119.36 (CH),
118.88 (CH), 116.05 (CH), 104.21 (CH), 80.75 (C), 46.82 (CH2), 28.27 (CH3). HRMS (FAB+):
for C46H46N4O4 [M+] calculated: 718.3519; foun d: 718.3526.
Preparation of Tröger’s Bases 1. Gen eral Procedure
Diam in e 10 was dissolved in of TFA an d paraform aldeh yde (37 m g) was added. Th e reaction
m ixture was stirred at room tem perature for 1 h . Th e m ixture was diluted with ice water,
an d alkalin ized by con cen trated aqueous am m on ia. Th e product was extracted in to CHCl3
or CH2Cl2, wash ed with water, with brin e, dried over Na2SO4, an d evaporated to dryn ess in
vacuo. Th e residue was separated by ch rom atograph y to obtain correspon din g bisTB 1,
wh erein th e diastereoisom er eluted as th e first on e is m arked as 1-A wh ile th e slower on e is
m arked as 1-B.
Naphthalene-2-amine derived bisTB 1a: Diam in e 10a (80 m g, 0.13 m m ol), 10 m l of TFA, 37 m g
(0.77 m m ol of CH2O equiv.) of paraform aldeh yde; by preparation TLC (CH2Cl2–CH3OH
95:5) were obtain ed 25 m g (41%) of 1a-A an d 32 m g (53%) of 1a-B. Th e NMR ch aracteristics
was iden tical with th e on es observed previously3d
.
Anthracene-2-amine derived bisTB 1b: Diam in e 10b (250 m g, 0.35 m m ol), 25 m l of TFA,
134 m g (2.79 m m ol of CH2O equiv.) of paraform aldeh yde; by colum n ch rom atograph y
(CH2Cl2–CH3OH 97:3) were obtain ed 71 m g (36%) of 1b-A an d 79 m g (40%) of 1b-B.
BisTB 1b-A: 1H NMR (CDCl3): 8.21 s, 2 H; 8.07 s, 2 H; 7.89 d, 2 H, J = 8.9; 7.86 d, 2 H, J =
8.9; 7.73 d, 2 H, J = 9.1; 7.38 m , 4 H; 7.11 d, 2 H, J = 9.1; 7.09 s, 1 H; 6.40 s, 1 H; 4.99 d,
2 H, J = 16.6; 4.71 d, 2 H, J = 16.6; 4.46 d, 2 H, J = 16.6; 4.31 d, 2 H, J = 12.5; 4.18 d, 2 H,
J = 12.5; 4.17 d, 2 H, J = 16.6. 13C APT NMR (CDCl3): 147.56 (C), 144.13 (C), 131.96 (C),
130.81 (C), 129.77 (C), 129.57 (C), 128.29 (CH), 128.04 (CH), 127.97 (CH), 126.98 (CH),
125.74 (CH), 125.24 (CH), 125.04 (CH), 124.64 (CH), 123.83 (C), 121.07 (CH), 120.40 (C),
119.31 (CH), 66.73 (CH2), 57.30 (CH2), 56.34 (CH2). HRMS (FAB+): for C40H31N4 [MH+] cal-
culated: 567.2549; foun d: 567.2563.
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Havlík, Král, Dolenský:
BisTB 1b-B: 1H NMR (CDCl3): 8.06 s, 2 H; 7.98 s, 2 H; 7.79 d, 2 H, J = 8.0; 7.71 d, 2 H, J =
8.0; 7.60 d, 2 H, J = 9.0; 7.25 m , 4 H; 7.06 d, 2 H, J = 9.0; 7.05 s, 1 H; 6.48 s, 1 H; 5.02 d,
2 H, J = 16.7; 4.58 d, 2 H, J = 16.7; 4.47 d, 2 H, J = 16.7; 4.33 d, 2 H, J = 12.9; 4.32 d, 2 H,
J = 12.9; 4.19 d, 2 H, J = 16.7. 13C APT NMR (CDCl3): 147.74 (C), 144.21 (C), 131.80 (C),
130.67 (C), 129.63 (C), 129.42 (C), 128.10 (CH), 127.92 (CH), 127.84 (CH), 126.84 (CH),
125.56 (CH), 125.09 (CH), 124.83 (CH), 124.54 (CH), 124.06 (C), 121.65 (CH), 120.21 (C),
119.20 (CH), 66.84 (CH2), 56.91 (CH2), 56.21 (CH2). HRMS (FAB+): for C40H31N4 [MH+] cal-
culated: 567.2549; foun d: 567.2570.
Fluorene-2-amine derived bisTB 1c: Diam in e 10c (0.50 g, 0.35 m m ol), 50 m l of TFA, 275 m g
(5.72 m m ol of CH2O equiv.) of paraform aldeh yde; by colum n ch rom atograph y (CH2Cl2–
CH3OH 97:3) were obtain ed 173 m g (44%) of 1c-A an d 146 m g (38%) of 1c-B.
BisTB 1c-A: 1H NMR (CDCl3): 7.56 d, 2 H, J = 7.3; 7.40 d, 2 H, J = 7.3; 7.24 s, 2 H; 7.24 td,
2 H, J = 7.3, J = 1.1; 7.19 s, 2 H; 7.16 td, 2 H, J = 7.3, J = 1.1; 6.93 s, 1 H; 6.39 s, 1 H; 4.73 d,
2 H, J = 16.5; 4.50 d, 2 H, J = 16.5; 4.27 d, 2 H, J = 16.5; 4.24 d, 2 H, J = 12.5; 4.16 d, 2 H,
J = 12.5; 4.07 d, 2 H, J = 16.5; 3.80 d, 2 H; 21.7, 3.70 d, 2 H, J = 21.7. 13C APT NMR (CDCl3):
147.27 (C), 146.92 (C), 143.04 (C), 142.54 (C), 141.28 (C), 138.07 (C), 126.72 (CH), 126.25
(CH), 126.14 (C), 125.03 (CH), 124.89 (CH), 123.87 (C), 121.47 (CH), 120.84 (CH), 119.43
(CH), 117.88 (CH), 66.93 (CH2), 59.44 (CH2), 58.63 (CH2), 36.60 (CH2). HRMS (FAB+): for
C
38H31N4 [MH+] calculated: 543.2549; foun d: 543.2542.
BisTB 1c-B: 1H NMR (CDCl3): 7.46 d, 2 H, J = 7.3; 7.30 d, 2 H, J = 7.3; 7.17 s, 2 H; 7.15 td,
2 H, J = 7.3, J = 1.2; 7.13 s, 2 H; 7.06 td, 2 H, J = 7.3, J = 1.2; 6.87 s, 1 H; 6.37 s, 1 H; 4.71 d,
2 H, J = 16.6; 4.57 d, 2 H, J = 16.6; 4.25 d, 2 H, J = 12.5; 4.23 d, 2 H, J = 12.5; 4.12 d, 2 H,
J = 16.6; 4.03 d, 2 H, J = 16.5; 3.71 d, 2 H, J = 21.7; 3.58 d, 2 H, J = 21.7. 13C APT NMR
(CDCl3): 147.53 (C), 146.96 (C), 142.95 (C), 142.40 (C), 141.13 (C), 137.89 (C), 126.56 (CH),
126.13 (CH), 126.09 (C), 124.87 (CH), 124.79 (CH), 123.99 (C), 121.41 (CH), 120.87 (CH),
119.27 (CH), 117.77 (CH), 66.90 (CH2), 59.15 (CH2), 58.52 (CH2), 36.47 (CH2). HRMS
(FAB+): for C38H31N4 [MH+] calculated: 543.2549; foun d: 543.2527.
Pyrene-1-amine derived bisTB 1d : Diam in e 10d (40 m g, 52 µm ol), 5 m l of TFA, 20 m g
(416 µm ol of CH2O equiv.) of paraform aldeh yde. 1H NMR spectrum of crude product con -
firm s a form ation of very com plex m ixture, in wh ich m ass spectroscopy foun d very low in -
ten sity of th e expected peak of 1d . HRMS (FAB+): for C44H31N4 [MH+] calculated: 615.2549;
foun d: 615.2574.
Anthracene-1-amine derived bisTB 1e: Diam in e 10e (20 m g, 28 µm ol), 2 m l of TFA, 8 m g
(167 µm ol of CH2O equiv.) of paraform aldeh yde. 1H NMR spectrum of crude product con -
firm s a form ation of very com plex m ixture, in wh ich m ass spectroscopy foun d very low in -
ten sity of th e expected peak of 1e. HRMS (FAB+): for C40H31N4 [MH+] calculated: 567.2549;
foun d: 567.2564.
Preparation s of Tröger’s Bases 11 from An th racen e-2-am in e
Th e flask was ch arged with 783 m g (4.05 m m ol) of an th racen e-2-am in e an d 400 m l of
m eth an ol. Th en 10 m l of form ol (37%) were added, followed by 10 m l of con cen trated
aqueous HCl. Th e m ixture was stirred at room tem perature for 3 days. Th e m ixture was
poured in to 1.3 l of water, alkalized by 30 m l of con cen trated aqueous NH3, an d extracted
by CH2Cl2. Th e organ ic parts were collected an d filtrated th rough 40 g of silica an d evapo-
rated to dryn ess. Th e obtain ed solid was m acerated with warm CHCl3 to obtain yellowish
solid com poun d 12 (98 m g) of un kn own structure, an d solution con tain in g expected
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 392–402

Bis-Tröger’s Bases
401
Tröger’s base 11. Th e solution was con cen trated in vacuo an d separated by colum n ch rom a-
tograph y (350 g, silica, CHCl3) to give 261 m g (30%) of Tröger’s base 11.
Tröger’s base 11: Th e ch em ical sh ifts were assign ed based on g-COSY, g-HMBC, g-HMQC,
1D NOEDIF NMR experim en ts an d geom etric data (dih edral an gles an d distan ces) from th e
com puter m odel (geom etry optim alized by PM3) of th e com poun d. 1H NMR (DMSO-d6):
8.39 s, 2 H (H-6); 8.35 s, 2 H (H-13); 8.04 d, 2 H, J = 8.2 (H-11); 7.96 d, 2 H, J = 8.0 (H-8);
7.86 d, 2 H, J = 9.1 (H-4); 7.47 dd, 2 H, J = 8.2, J = 6.3 (H-10); 7.42 dd, 2 H, J = 8.0, J = 6.3
(H-9); 7.40 d, 2 H, J = 9.1 (H-3); 5.06 d, 2 H, J = 17.0 (H-15b); 4.87 d, 2 H, J = 17.0 (H-15a);
4.53 s, 2 H (H-16). 13C NMR (DMSO-d6): 144.71 (C-2), 131.47 (C-12), 130.21 (C-7), 129.49
(C-14), 129.13 (C-5), 127.95 (C-11), 127.86 (C-8), 127.70 (C-4), 126.68 (C-6), 125.75 (C-10),
125.19 (C-3), 125.08 (C-9), 120.24 (C-1), 119.39 (C-13), 66.32 (C-16), 54.62 (C-15). HRMS
(FAB+): for C31H23N2 [MH+] calculated: 423.1861; foun d: 423.1868.
11
Compound 12: 1H NMR (DMSO-d6): 10.83 s, 1 H; 10.05 s, 2 H; 8.69 s, 2 H; 8.40 dd, 2 H,
J = 8.1, J = 1.0; 8.32 d, 2 H, J = 9.3; 8.24 dd, 2 H, J = 8.1, J = 1.0; 7.96 d 2 H, J = 9.3;
7.81–7.68 m , 4 H.
This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic
(MSM 6046137307 and LC06077), the Grant Agency of Czech Republic (203/03/D049), and EU
grant CIDNA (NMP4-CT-2003-505669).
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