Selective protection of 1,4,8,11-tetraazacyclotetradecane (cyclam) in position 1,4 with the phosphonothioyl group and synthesis of a cyclam-1,4-bis(methylphosphonic acid). Crystal structures of several cyclic phosphonothioamides

Article abstract of DOI:10.1135/cccc20060337

A new cyclam-based ligand, 1,4,8,11-tetraazacyclotetradecane-1,4- bis(methylphosphonic acid) (1,4-H₄te2p), was synthesized. Cyclam was protected by the reaction with PhP(S)Cl₂ to form exclusively five-membered cyclic phenylphosphonothioic diamide 2 in a moderate yield. The solid-state structures of 2 and several by-products were determined. Compound 2 was isolated as two stable conformers differing in a mutual position of benzene ring and sulfur atom with respect to the cyclam ring. Compound 2 was used for the synthesis of 1,4-dibenzylcyclam. However, the deprotection of the thiophosphoryl-protected bis(methyl-phosphonate diester) with aqueous HCl under non-optimized conditions led to a mixture of cyclam derivatives differently substituted with methylphosphonic acid groups. The crystal structures of the target product, 1,4-H₄te2p, and also 1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetrakis(methylphosphonic acid) (H ₈tetp) were determined. A similar reaction with cyclen (1,4,7,10-tetraazacyclododecane) led only to hardly purifiable mixtures.

Full text of DOI:10.1135/cccc20060337

Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
337
SELECTIVE PROTECTION OF 1,4,8,11-TETRAAZACYCLOTETRADECANE
(CYCLAM) IN POSITION 1,4 WITH THE PHOSPHONOTHIOYL GROUP
AND SYNTHESIS OF A CYCLAM-1,4-BIS(METHYLPHOSPHONIC ACID).
CRYSTAL STRUCTURES OF SEVERAL CYCLIC PHOSPHONOTHIOAMIDES
1
2
3
4
Tomáš VITHA , Jan KOTEK , Jakub RUDOVSKÝ , Vojtěch KUBÍČEK ,
5
6,
7
Ivana CÍSAŘOVÁ , Petr HERMANN * and Ivan LUKEŠ
Department of Inorganic Chemistry, Charles University,
1
Hlavova 2030, 128 40 Prague 2, Czech Republic; e-mail: vitha@seznam.cz,
2
5
3
4
modrej@natur.cuni.cz, rudovsky@natur.cuni.cz, vvvojta@seznam.cz,
6
7
cisarova@natur.cuni.cz, petrh@natur.cuni.cz, lukes@natur.cuni.cz
Received Novem ber 9, 2005
Accepted Jan uary 24, 2006
Dedicated to Professor Jaroslav Podlaha, who introduced organophosphorus ligands and their
coordination chemistry in our Department, on the occasion of his 70th birthday.
A n ew cyclam -based ligan d, 1,4,8,11-tetraazacyclotetradecan e-1,4-bis(m eth ylph osph on ic
acid) (1,4-H4te2p), was syn th esized. Cyclam was protected by th e reaction with Ph P(S)Cl2 to
form exclusively five-m em bered cyclic ph en ylph osph on oth ioic diam ide 2 in a m oderate
yield. Th e solid-state structures of 2 an d several by-products were determ in ed. Com poun d 2
was isolated as two stable con form ers differin g in a m utual position of ben zen e rin g an d
sulfur atom with respect to th e cyclam rin g. Com poun d 2 was used for th e syn th esis of
1,4-diben zylcyclam . However, th e deprotection of th e th ioph osph oryl-protected bis(m eth yl-
ph osph on ate diester) with aqueous HCl un der n on -optim ized con dition s led to a m ixture of
cyclam derivatives differen tly substituted with m eth ylph osph on ic acid groups. Th e crystal
structures of th e target product, 1,4-H4te2p, an d also 1,4,8,11-tetraazacyclotetradecan e-
1,4,8,11-tetrakis(m eth ylph osph on ic acid) (H8tetp) were determ in ed. A sim ilar reaction with
cyclen (1,4,7,10-tetraazacyclododecan e) led on ly to h ardly purifiable m ixtures.
Keyw ord s: Am in oph osph on ic acids; Azacycle; Azacrown ; Cyclam cis-protection ; Cyclam ;
Cyclen ; Macrocyclic ligan ds; Ph osph on ate ligan ds; Crystal structure determ in ation ; TETP;
Th ioph osph on ic am ides; Radioph arm aceuticals.
Tetraazam acrocycles an d th eir derivatives h ave been widely in vestigated
over years as th ey form very stable com plexes with m ost m etal cation s. In -
vestigation s h ave led to a n um ber of practical application s of th e ligan ds
an d th eir com plexes, such as production of MRI con trast agen ts based on
trivalen t gadolin ium 1, adm in istration of im agin g an d/or th erapeutic radio-
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 3, pp. 337–367
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20060337

338
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
ph arm aceuticals with a ran ge of radiom etal isotopes2, developm en t of lum i-
n escen t probes based on trivalen t lan th an ides3 or preparation of m etal-
based catalysts for th e artificial h ydrolysis of RNA or DNA 4. Th e ligan ds
used in th e com plexes are m ostly derivatives of two well-kn own cyclic
tetraam in es, 1,4,7,10-tetraazacyclododecan e (cyclen ) an d 1,4,8,11-tetraaza-
cyclotetradecan e (cyclam ), substituted on n itrogen atom s with four coordi-
n atin g groups (leadin g to octaden tate ligan ds) such as acetates, acetam ides,
alkylam in es, ph osph orus acid derivatives, h ydroxyalkyl derivatives, etc.
Represen tatives of polyden tate m acrocycles are H4dota an d H4teta (Ch art 1).
H4dota is a n on -selective ligan d form in g stron g com plexes with m ost diva-
len t an d trivalen t m etal ion s, wh ich is particularly suitable for th e com -
plexation of trivalen t lan th an ides. Th e H4teta h avin g a larger fourteen -
m em bered rin g form s exception ally stable com plexes with ion s of m etals
from th e first tran sition row. However, th e m etal ion s often require th e
octah edral coordin ation sph ere an d octaden tate H4teta (or its ph osph on ic
acid derivative H8tetp; Ch art 1) h ave m ore coordin atin g atom s th an n eces-
sary. To fulfil th e requirem en t for six coordin ation sites, several disub-
stituted derivatives of cyclam h ave been syn th esized an d th eir com plexin g
properties h ave been in vestigated5–8. Th e ligan ds are m ostly 1,8-substituted
derivatives of cyclam (den oted “trans”) as th ey are n owadays relatively
easily available9,10. Much less is kn own about properties of ligan ds an d
th eir com plexes based on oth er 1,4- or 1,11-disubstituted cyclam deriva-
tives (den oted “cis”). Th e m ain reason is th at th ere is n o reliable procedure
for th eir syn th esis.
CHART 1
Structures of th e com poun ds m en tion ed in text
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
339
For som e years, we h ave been en gaged in study of coordin ation proper-
ties of am in oph osph on ic acids an d m acrocycles with ph osph orus acid pen -
dan t arm s11. Recen tly, we h ave foun d th at 1,8-bis(m eth ylph osph on ic acid)
derivative12 (1,8-H4te2p, Ch art 1) of cyclam is an appropriate ligan d for di-
valen t tran sition m etal ion s13–15. Th e ligan d form s th erm odyn am ically very
stable com plexes15,16 exh ibitin g two isom eric form s13–15. It is particularly
selective for divalen t copper17 an d both th e isom ers of Cu2+ com plex are
h igh ly kin etically in ert. However, we h ave n ot been able to fully explain
th e suitable com plexin g properties of th e ligan d. Th e trans arran gem en t of
th e pen dan t arm s m ay be respon sible for th e perform an ce of th e ligan d. As
two oth er (1,4 an d 1,11) regioisom ers of bis(m eth ylph osph on ic acid) deriv-
atives of cyclam are possible, we decided to syn th esize th e isom ers an d in -
vestigate th eir com plexin g properties to th row m ore ligh t on coordin ation
ch em istry of such ligan ds. In th is paper, we focus on th e syn th esis of the
1,4-bis(m ethylphosphonic acid) derivative (1,4-H4te2p, Chart 1).
Th e 1,4-protection of cyclam is rath er un usual an d syn th eses of on ly
several cyclam 1,4 derivatives h ave been described. Th e 1,4-diben zylcyclam
was prepared by Ni2+-tem plate syn th esis18 but th e procedure requires a se-
lectively substituted startin g am in e (5,8-diben zyl-1,5,8,12-tetraazadodecan e),
which is not easily available. Another possibility is 2,3-dioxocyclam (Chart 1)
accessible th rough h igh -dilution syn th esis19. Un fortun ately, th e h igh -
dilution syn th etic m eth ods give, in gen eral, rath er low yields an d reduction
of m acrocyclic am ides is often com plicated. More successful was th e use of
oxalyl protection 20 (Ch art 1). However, th e deprotection requires very h arsh
con dition s (h eatin g in con cen trated alkalin e h ydroxide)20,21. A tem plate
syn th esis with form ation of cobalt(III) com plex of cyclam -1,4-diacetic acid
followed by reduction to cobalt(II) com plex an d dem etallation led to syn -
th esis of th e free ligan d7a. Som e years ago, Majoral et al. used ph osph oro-
th ioic diam ides of cyclam (in 1,4-position ) for syn th esis of ph osph orus-
based den drim ers22. On th e basis of th is paper, we decided to test a syn -
th etic route em ployin g easily available ph en ylph osph on oth ioic dich loride
for 1,4-protection of cyclam as ph osph orus acid am ides are usually rath er
easily h ydrolyzable.
RESULTS
Cyclam Protection
Th e target product 2 was isolated from th e reaction of cyclam 1 with an
equivalen t am oun t of ph en ylph osph on oth ioic dich loride in ch loroform in
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340
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
th e presen ce of trieth ylam in e as a base. Th e yields were on ly m oderate
(40–50% after colum n ch rom atograph y) an d two oth er by-products were
isolated an d iden tified (Sch em e 1). Surprisin gly, th e target product 2 was
foun d to form two ch rom atograph ically separable isom ers 2a an d 2b. Th e
isom er 2a (δP ~ 77 ppm ) is form ed predom in an tly durin g th e protectin g
reaction an d it was fully ch aracterized by spectroscopic m eth ods (m ulti-
n uclear NMR, MS). A n ew peak aroun d 81 ppm wh ich appeared in 31P NMR
spectra of som e aged solution s after ch rom atograph ic purification of reac-
tion m ixtures was assign ed to th e secon d isom er 2b. Th is com poun d was
obtain ed in pure state after colum n ch rom atograph y of th e solution s.
Lately, isom er 2b was iden tified as th e on ly isom er of 2 presen t in alkalin e
aqueous solution of com poun d 2. Th e structures of both isom ers were un -
am biguously con firm ed by sin gle-crystal X-ray determ in ation (see below).
Th e m ain by-product was isolated by colum n ch rom atograph y an d iden -
tified as a bis-substituted cyclam 3. Th is com poun d was obtain ed in a yield
of ~10%. Th e 2:1 in ten sity ratio of sign als of arom atic an d aliph atic h ydro-
gen atom s, δP ~ 80 ppm fallin g in th e region of ph osph on oth ioic diam ides23
an d m olecular m ass suggested th at th e product is 2:1 adduct of cyclam an d
Ph P(S)Cl2. Com poun d 3 was also isolated as a m ixture of isom ers as it was
eviden ced by com plexity of 31P an d 1H NMR spectra of th e ch rom atog-
raph ically pure product. Fin ally, on e stereoisom er (3a) crystallized in pure
form from solution of th e isom ers an d its crystal structure was determ in ed
(see below).
In som e reaction batch es, traces of an oth er by-product were iden tified by
TLC. Th e com poun d was con cen trated in th e late fraction s from colum n
ch rom atograph ies used for isolation of m ain products 2 an d 3 an d, fin ally,
1
it was purified an d isolated from th e com bin ed late fraction s. H NMR spec-
trum of th e product sh owed a full n on -equivalen ce of all rin g proton s an d
in tegration of th e spectrum revealed th e 1:1 ph en yl-to-m acrocycle ratio. In
31P NMR spectrum , th e com poun d exh ibited a sin gle broad peak at 71 ppm
SCHEME 1
Products of th e reaction of cyclam with ph en ylph osph on oth ioic dich loride
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
341
correspon din g to a ran ge of ph osph on oth ioic acid m on oam ides23. Th ere-
fore, cyclam derivative 4 with on e substituted n itrogen atom was suggested
(Sch em e 1). Th is h ypoth esis was un am biguously con firm ed by X-ray struc-
ture determ in ation (see below). Th e occurren ce of th is product can be attri-
buted to th e presen ce of a trace am oun t of water in th e reaction m ixtures.
Crystal Structures of Cyclam Phenylphosphonothioic Amides
We were able to grow sin gle crystals of several ph osph on oth ioic am ides an d
th e determ in ation of th eir structures in th e solid state un am biguously con -
firm ed m olecular structures of th e com poun ds.
Crystal structure of isom er 2a con sists of two in depen den t m olecules;
h owever, both un its adopt virtually iden tical con form ation s an d, th us,
on ly on e of th em is depicted in Fig. 1. Two adjacen t cyclam 1,4-n itrogen
atom s are bridged by ph osph on oth ioic group, form in g a five-m em bered
C2N2P h eterocycle (diazaph osph olidin e rin g). Th e ben zen e rin g is directed
above th e h eterocycle, an d th e sulfur atom poin ts above th e plan e form ed
by th e rest of th e cyclam rin g. Th e five-m em bered h eterocycle is in an en -
velope con form ation , with th e N4 atom turn ed out from th e plan e defin ed
by P1, N1, C2 an d C3 atom s. Both am ide n itrogen atom s sign ifican tly sh are
th eir lon e electron pairs with ph osph orus atom ; it is apparen t from th e pla-
FIG. 1
Molecular structure of 2a. Hydrogen atom s (except th ose attach ed to n itrogen atom s) are
om itted for clarity
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342
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
n arity of th eir n eigh borin g atom s (sum of valen ce an gles on am ide n itro-
gen atom s is 358.3 an d 359.4° on N1 atom s an d 347.9 an d 352.1° on N4
atom s in both in depen den t m olecules, respectively). Th e h igh er distortion
from plan arity foun d for N4 n itrogen atom s is a con sequen ce of th e in tra-
m olecular h ydrogen bon d to th e n itrogen atom N8 (d(N8···N4) = 3.03 an d
3.06 Å in both in depen den t m olecules, respectively). Furth erm ore, n itrogen
atom N11 is also in volved in h ydrogen bon din g to N8 (d(N8···N11) = 2.89
an d 2.91 Å), stabilizin g an en doden tate an gular con form ation typical of
n on -proton ated cyclam rin g24. Th e relevan t bon d len gth s an d an gles are
collected in Tables I an d II.
In addition to th e structure of free base 2a, crystal structure of its proton -
ated form (H2a)+ was also determ in ed. Several sin gle crystals of sulfate of
th is cation crystallized from ch loroform solution s used for NMR ch aracter-
ization . Th e in depen den t un it in th is crystal structure con sists of two
m on oproton ated m olecules (H2a)+ (Fig. 2), on e sulfate dian ion an d som e
water m olecules. Th e best refin em en t of th e crystal data was obtain ed with
th e assum ption of two fully occupied water m olecules, an d two oth ers with
occupan cies of 0.5 an d 0.25. Th e structure of both in depen den t m acro-
cyclic ion s is alm ost iden tical (Tables I an d II) an d th e con form ation of th e
m acrorin g of proton ated (H2a)+ is essen tially th e sam e as th at foun d in th e
structure of n on -proton ated 2a (an alogous in tram olecular h ydrogen bon ds
(d(N8···N4) = 2.96 an d 3.02 Å, an d d(N8···N11) = 2.79 an d 2.81 Å in both
FIG. 2
Molecular structure of (H2a)+ (left) an d (H2b)+ (righ t) cation s in th e crystal structures of
2a·0.5H2SO4·1.375H2O an d 2b·0.5H2SO4·3H2O. Hydrogen atom s (except for th ose attach ed to
th e n itrogen atom s) are om itted for clarity
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
343
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Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
345
th e in depen den t m olecules of (H2a)+, respectively). We were surprised th at
th e sin gle crystals con tain th e sulfate an ion s as th e sam ple h ad n o con tact
with an y sulfates. Very probably, th ese an ion s origin ate from th e silica gel
used for colum n ch rom atograph y due to elution with basic eluen t con tain -
in g am m on ia.
Th e sin gle crystal con tain in g cation (H2b)+ was also isolated as a sulfate
salt from th e sam ple used for NMR ch aracterization , sim ilarly to th e previ-
ous case (th e origin of th e sulfate an ion is also th e sam e). Th e com poun ds
2a an d 2b (or (H2a)+ an d (H2b)+ ion s) differ in th e m utual position of
ph en yl an d sulfur atom on ph osph orus atom in respect to th e cyclam rin g.
In th e case of 2b, th e sulfur atom is directed above th e five-m em bered
C2N2P h eterocycle. Hen ce, com poun d 2b is a “frozen ” con form er of com -
poun d 2a. Th e in depen den t un it of 2b·0.5H2SO4·3H2O con sists of a m on o-
proton ated (H2b)+ ion (Fig. 2), on e h alf of th e sulfate an ion (with sulfur
an d two oxygen atom s lyin g in special position s with h alf-occupan cy) an d
two fully-occupied an d two h alf-occupied water m olecules. Th e m acrocycle
con form ation in (H2b)+ is very sim ilar to th at foun d for 2a an d (H2a)+,
except th at th e proton attach ed to n itrogen N11 poin ts to th e opposite
direction . Th erefore, torsion an gles alon g C9–C10 an d C12–C13 bon ds are
differen t as well an d h ave th e opposite sign . Sim ilarly to th e previous cases,
m olecule of (H2b)+ is also stabilized in en doden tate con form ation by in tra-
m olecular h ydrogen bon ds (d(N8···N4) = 2.82 Å an d d(N8···N11) = 2.79 Å).
Com parison of both proton ated isom eric species (H2a)+ an d (H2b)+ is given
in Fig. 2, bon d len gth s an d an gles are collected in Tables I an d II.
We were also able to determ in e crystal structures of th e isolated by-
products 3a an d 4. Th e m olecular structure of com poun d 3a (on e of several
possible con form ers of 3) is sh own in Fig. 3 an d selected bon d len gth s an d
an gles are given in Tables I an d II. Th e m olecule of 3a is cen trosym m etric.
Th e P–S vectors are orien ted above th e cyclam m acrocycle an d th e ben zen e
rin gs poin t above th e C2N2P h eterocycle sim ilarly as in th e previous case of
2a. Th e iden tity of com poun d 4 was un am biguously con firm ed by th e de-
term in ation of its crystal structure (Fig. 4, Tables I an d II). However, th e
data quality was rath er poor in th is case an d th e fin al R-factor is h igh
(7.71%), m ain ly due to a h uge disorder in th e cyclam m acrocyclic un it.
Th erefore, th e exact proton ation site of th e com poun d can n ot be assign ed,
but th e proton is rem oved from th e ph osph on oth ioic m oiety as eviden ced
by relatively sh ort P–O distan ce (Table I) an d, th us, th e proton sh ould be
located on an am in o group of th e cyclam rin g.
Th e geom etry aroun d th e ph osph orus atom in th e ph en ylph osph on o-
th ioic m oiety in cyclam derivatives 2a, (H2a)+, (H2b)+ an d 3a is very sim ilar
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346
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
(Table I). Bon d distan ces are in th e ran ge expected for th is m oiety22,25. Th e
bon d an gles are h igh ly affected by th e form ation of th e five-m em bered
C2N2P h eterocycle with a relatively sm all N1–P1–N4 an gle (93–94°). Th e
oth er bon d an gles are correspon din gly larger th an th e th eoretical tetrah e-
dral on es (Table I). In th e case of sterically n on -con strain ed m on oam ide 4,
FIG. 3
Molecular structure of 3a. Hydrogen atom s are om itted for clarity
FIG. 4
Molecular structure of 4 in th e crystal structure of 4·H2O. Th e disordered m acrorin g is sh own
in a m ore abun dan t position an d h ydrogen atom s are om itted for clarity
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
347
th e atom s aroun d th e ph osph orus atom form alm ost a regular tetrah edron .
Five-m em bered C2N2P h eterocycle is in th e en velope con form ation in all
cases, with N4 n itrogen atom (n itrogen atom s in all th e structures are la-
belled con sisten tly in th is way) turn ed away from th e plan e of th e rem ain -
in g atom s. An exception was foun d on ly in th e m olecule A in th e structure
of 2a·0.5H2SO4·1.375H2O, wh ere C3 carbon atom is th e out-of-plan e atom
of th e five-m em bered C2N2P h eterocycle. Com parin g values of torsion an -
gles alon g th e N1–P1 an d N4–P1 bon ds, it is clear th at th e structure of
2b·0.5H2SO4·3H2O rem arkably differs from th e oth er as a con sequen ce of
differen t P–S an d P–Ph vector orien tation s in space (Table II).
Cleavage of the Phenylphosphonothioic Moiety
First, we wan ted to get som e in form ation about stability of th e ph en ylph os-
ph on oth ioic m oiety in 2 an d, th erefore, we tested several deprotection pro-
tocols wh ich can be later used for rem oval of th e group.
To follow acid h ydrolysis of th e ph en ylh osph on oth ioic diam ide m oiety,
com poun d 2a was dissolved in aqueous 6 M h ydroch loric acid an d h eated
at 70 °C. Th e course of th e reaction was m on itored by 31P NMR spectrum ;
th e sign al of th e startin g com poun d at 76 ppm disappeared wh ile th e sign al
of ph en ylph osph on ic acid (21 ppm ) rose. No oth er ph osph orus-con tain in g
com poun ds were iden tified in th e reaction m ixture. From th e expon en tial
depen den ce of th e in tegral in ten sity of th e startin g com poun d sign al, th e
h alf-life tim e of deprotection was calculated to be ~45 m in . It is com parable
with th e literature data reported for oth er m acrocyclic ph osph orus am ides26.
No reaction was observed at room tem perature. Th e assign m en t of sign al of
th e released Ph PO3H2 was con firm ed by addition of th e com poun d to th e
reaction m ixture.
A sam ple of 2a was dissolved in th e borate buffer (pH 11.0) an d h eated
at 70 °C as in th e previous case. 31P NMR spectroscopy revealed a fast con -
version of 2a to 2b as th e sign al of 2a at 77 ppm h ad on ly about 1% in ten -
sity after dissolution ; in th e spectra, th e m ajor sign al of 2b was observed at
81 ppm . Durin g th e reaction , a n ew sign al assign ed to ph en ylph osph on o-
th ioic acid at 72 ppm appeared, but th e h ydrolysis led to a con version of
on ly ca. 10% after 12 h . Th e assign m en ts of all th e sign als were again con -
firm ed by addition of th e stan dard to th e reaction m ixture.
From th e attem pts to purify th e reaction in term ediates from th e Man n ich
reaction of 2a with CH2O an d a ph osph orus com pon en t (see below), fol-
lowed th at th e ph en ylph osph on oth ioic diam ide 2a could be h ydrolyzed in
th e presen ce of a stron g cation exch an ge resin . To illustrate th is process, we
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Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
loaded eth an olic solution of 2a on to a colum n of stron g sulfon ic cation
acid exch an ger (Dowex 50) in H+-form . Th e colum n was eluted with water,
an d th e eluate was con cen trated by vacuum evaporation . 31P NMR spectros-
copy revealed th e presen ce of ph en ylph osph on oth ioic acid as a m ajor com -
pon en t an d ph en ylph osph on ic acid as a m in or on e. Wh en th e eluate was
n eutral, th e colum n was wash ed with 6 M h ydroch loric acid. After evapora-
tion of th e HCl eluate, th e solid product was iden tified as cyclam h ydro-
ch loride (1H an d 13C NMR) with n o ph osph orus-con tain in g adm ixture (n o
sign al in 31P NMR spectrum ).
Syntheses of Selected 1,4-Derivatives
To dem on strate th e suitability of th e n ew protectin g reagen t, we used th is
approach in preparation of 1,4-substituted cyclam s. First, we prepared
kn own 1,4-diben zylcyclam by th e reaction of com poun d 2a with a sligh t
excess of ben zyl brom ide in aceton itrile. After h ydrolysis (6 M HCl, 12 h re-
flux), colum n ch rom atograph y an d crystallization , th e 1,4-diben zylcyclam
was isolated in 65% yield.
Th e prim ary aim of th e work was th e syn th esis of a n ovel ligan d with two
m eth ylph osph on ic acid pen dan t arm s, 1,4-H4te2p (Ch art 1), as th e previ-
ous studies of its 1,8-isom er revealed a h igh poten tial of such ligan d class in
coordin ation ch em istry12–16. First, th is ligan d was prepared by a Man n ich -
type reaction (Sch em e 2) between 2a, trieth yl ph osph ite an d paraform -
aldeh yde followed (with out purification ) by acid h ydrolysis of 5 (6 M HCl,
4 days reflux; th e lon g tim e was n ecessary to ach ieve a full h ydrolysis of th e
SCHEME 2
Syn th esis of 1,4-H4te2p
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
349
diesters) an d ch rom atograph ic separation on cation -exch an ge colum n s.
Th e target ligan d was isolated as a tetrah ydrate in 42% yield togeth er with
trisubstituted H6te3p (12%, Sch em e 2) an d recen tly reported27 m on osubsti-
tuted H2te1p (5%, Sch em e 2). Fortun ately, all th ree com poun ds can be eas-
ily separated on a weak cation exch an ger as th ey sign ifican tly differ in th eir
acid-base properties. Wh en th e reaction m ixture after th e Man n ich reaction
was purified by silica gel ch rom atograph y to obtain pure tetraester 5, its
acid h ydrolysis un der th e con dition s given above was surprisin gly faster
(24 h ). Th e isolated yield of 1,4-H4te2p was im proved to 73%.
Th e structure of th e target ligan d, 1,4-H4te2p, was con firm ed by th e X-ray
structure determ in ation . Sin gle crystals of 1,4-H4te2p tetrah ydrate were
form ed by slow crystallization of its aqueous solution with diffusion of ace-
ton e vapours. Th e m olecular structure of th e ligan d is sh own in Fig. 5. Th e
relevan t bon d len gth s an d an gles are collected in Table III. Th e in depen d-
en t un it con sists of on e ligan d an d four solvate water m olecules. Each ph os-
ph on ate pen dan t is m on oproton ated an d th e oth er proton s are boun d to
both secon dary am in o groups in th e rin g. Th e geom etries aroun d th e ph os-
ph orus atom s are rough ly tetrah edral, with sign ifican tly lon ger P–O bon ds
to th e proton ated oxygen atom s O11 an d O21 (Table III). Th e m acrocycle is
in an en doden tate con form ation typical of a n on -fully proton ated cyclam
rin g24. Th e m olecular structure is stabilized by rath er stron g in tram olecular
FIG. 5
Molecular structure of 1,4-H4te2p in th e crystal structure of 1,4-H4te2p·4H2O. Hydrogen atom s
(except for th ose attach ed to th e n itrogen an d oxygen atom s) are om itted for clarity.
In tram olecular h ydrogen bon ds are sh own as dash ed lin es
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
351
h ydrogen bon ds (d(N8···O12) = 2.72 Å, d(N11···O22) = 2.70, d(N8···N4) =
+
2.79 an d d(N11···N1) = 2.76 Å, Fig. 5). Sim ilarly stron g N–H···O– h ydrogen
bon ds were observed in 1,8-H4te2p an d its derivatives12. Except for th ese in -
teraction s, th e wh ole crystal structure is stabilized by an exten ded h ydro-
gen bon d n etwork between th e ph osph on ate oxygen atom s an d th e h ydrate
water m olecules (O···O distan ces in th e ran ge 2.56–2.87 Å).
On stan din g of th e acidic reaction m ixture from h ydrolysis of on e batch
of ester 5 in an NMR tube for on e week, several sm all colourless prism atic
crystals appeared. Th e X-ray diffraction study revealed th ese crystals are th e
well-kn own tetraph osph on ic acid derivative of cyclam 28, H8tetp (Ch art 1
an d Fig. 6), wh ich is alm ost in soluble in acid solution s. Th e relevan t bon d
len gth s an d an gles are given in Table III. Th e in depen den t un it is form ed
by on e h alf of m olecule of th e ligan d an d five addition al h ydrate water
m olecules. Each ph osph on ate pen dan t group is m on oproton ated an d, cor-
respon din gly, all m acrocycle n itrogen atom s are proton ated. Th e geom e-
tries aroun d ph osph orus atom s are rough ly tetrah edral, with sign ifican tly
lon ger P–O bon ds to proton ated oxygen atom s O11 an d O21 (Table III).
Th e m acrocycle adopts (3,4,3,4)-A con form ation typical of fully proton ated
cyclam s24. Th e sam e con form ation of th e cyclam rin g was also observed for
trih ydrobrom ide of H2te1p (ref.27). All pen dan t ph osph on ate m oieties are
turn ed away from th e m acrocycle an d are con n ected with th e n eigh borin g
ligan d m olecules an d th e solvate water m olecules via an exten ded h ydro-
gen bon d n etwork.
FIG. 6
Molecular structure of H8tetp in th e crystal structure of H8tetp·10H2O. Hydrogen atom s
(except for th ose attach ed to n itrogen an d oxygen atom s) are om itted for clarity
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Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
Attempts to Protect Cyclen
We tried to apply the m ethod of protection to the cyclen skeleton (Schem e 3).
Alth ough th e required product 2′ was foun d in th e reaction m ixture (NMR
an d MS), all attem pts to fin d an efficien t separation m eth od failed. After
repeated ch rom atograph ies, pure 2′ was isolated as an oil an d in a low yield
(~20%). Com poun d 2′ is presen t as a m ixture of isom ers. Th is was evi-
den ced by com plexity of 31P an d 1H NMR spectra. However, by stan din g
of its ch loroform solution used for NMR ch aracterization for som e tim e,
several sin gle crystals appeared. Th ey were foun d to be 2a′·0.5H2SO4·3H2O
(Fig. 7; th e source of sulfate an ion is silica gel used for ch rom atograph y).
Th e orien tation of th e sulfur atom an d ph en yl substituen t is an alogous to
th at in th e cyclam product 2a, i.e. with th e ben zen e rin g located above th e
five-m em bered C2N2P h eterocycle an d sulfur atom directed above th e rest
of th e m acrocycle. Th e in depen den t un it con sists of two m on oproton ated
m acrocycles (H2a′)+, on e sulfate an ion an d six water m olecules. However,
both th e m acrocyclic ion s are alm ost iden tical an d, th us, on ly on e of th em
is presen ted in Fig. 7. Th e m on oproton ated cyclen rin g is stabilized in
en doden tate con form ation by in tram olecular h ydrogen bon d between
proton ated am in e n itrogen atom N7, un proton ated am in e N10 an d am ide
N4 (d(N7···N4) = 2.99 an d 3.01 Å, an d d(N7···N10) = 2.71 an d 2.72 Å in
both in depen den t m olecules). Th e relevan t bon d len gth s an d an gles are
given in Table IV.
In addition , colorless crystals were form ed in aqueous eth an ol durin g
th e work-up. Th e com poun d was alm ost in soluble in all th e tested organ ic
solven ts (EtOH, aceton e, MeCN, toluen e, CHCl3, DMSO, DMF) wh ich pre-
ven ts its spectral ch aracterization . Fortun ately, sin gle crystals were form ed
in several batch es an d th e structure was solved by X-ray diffraction an aly-
sis. Surprisin gly, th e product was iden tified as com poun d 6 with th e
th ioph osph oryl–cyclen ratio 3:1 (Fig. 8 an d Table IV). Th e isolated yields of
th is com poun d were relatively h igh (~10%), even from equim olar
Ph P(S)Cl2–cyclen m ixtures. Th e geom etry of th e five-m em bered C2N2P
h eterocycle is sim ilar to th at foun d for th e cyclam derivatives (Tables I
SCHEME 3
Isolated products from reaction of cyclen an d Ph P(S)Cl2
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
353
FIG. 7
Molecular structure of (H2a′)+ cation in th e crystal structure of 2a′·0.5H2SO4·3H2O. Hydrogen
atom s (except for th ose attach ed to th e n itrogen atom s) are om itted for clarity
FIG. 8
Molecular structure of 6. Hydrogen atom s are om itted for th e clarity
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
355
an d IV). However, in th e seven -m em bered h eterocycle C2N2P2O (h exa-
h ydrooxadiazaph osph epin e rin g), un usually lon g P–O bon ds (1.62 Å) an d
a very large oxygen valen ce an gle P2–O1–P3 (~140°) were foun d. To our
kn owledge, it is th e first exam ple of th e seven -m em bered C2N2P2O h etero-
cycle structurally ch aracterized.
From th e reaction m ixture, an oth er TLC pure com poun d was also sepa-
rated. A cluster of peaks in 31P NMR spectrum aroun d 80 ppm , 2:1 in tegral
ratio of arom atic/aliph atic proton s in 1H NMR spectrum an d m ass spectrum
th e suggest structure of 3′ (Sch em e 3). Again , th e com plexity of th e NMR
spectra is due to th e presen ce of a n um ber of isom ers.
DISCUSSION
Th e target 1,4-protected cyclam 2 was obtain ed in a m oderate yield of
40–50% em ployin g easily available Ph P(S)Cl2. As foun d, th e 2a isom er is
obtain ed alm ost exclusively in th e protectin g reaction an d th is com poun d
2a was used in all subsequen t tran sform ation s. Th e m in or isom er 2b is
form ed from 2a on ly un der basic con dition s an d in polar solven t as th e iso-
m er 2a is fully stable in ch loroform , ch loroform –DABCO m ixture or MeOH
even un der reflux. Form ation of 2b was observed on ly in MeOH–water m ix-
tures or in water at pH > 10 an d at elevated tem perature. Th e rearran ge-
m en t is irreversible. It was also observed durin g attem pts of alkalin e
h ydrolysis of th e protectin g m oiety (see above). Th erefore, th e origin of
com poun d 2b in th e oily ch rom atograph ic fraction s after purification of
com poun d 2a (stan din g at room tem perature for several h ours) can be ex-
plain ed by a presen ce of am m on ia in th e eluen t; am m on ia was n ot com -
pletely rem oved by evaporation of th e fraction s.
Th us, both com poun ds 2a an d 2b are form ally “frozen ” con form ers.
Obviously, pen etration of th e eth ylen e bridge (as it is a less sterically
con strain ed group th an ph en yl) th rough th e rest of th e m acrocycle m ust
occur durin g th e 2a→2b rearran gem en t (Sch em e 4). Th e kin etic isom er 2a
SCHEME 4
Rearran gem en t of isom ers of 2
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356
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
is m ore stable in n eutral an d acid solution s, probably due to stabilization
th rough th e h ydrogen bon d between proton ated am in es an d th e sulfur
atom . In polar solven t, presen ce of water, h igh pH an d at elevated tem pera-
ture, th e h ydrogen bon d an d th e in tram olecular h ydrogen bon d between
am in e an d am ide n itrogen atom s are cleaved an d, con sequen tly, th e th er-
m odyn am ic isom er 2b is form ed (possibly th rough a pen tacoordin ated
ph osph orus in term ediate with participation of h ydroxide an ion ).
By-product 3 (as a m ixture of isom ers) apparen tly arose from a furth er
substitution of eith er isom er 2 with Ph P(S)Cl2. Th e reaction rate of th is sec-
on d substitution is com parable with th at of th e first step as com poun d 3
was always presen t in th e reaction m ixtures, even at th e begin n in g of th e
reaction or wh en a large excess of cyclam was em ployed. Accordin g to th ese
fin din gs, we em ployed a large excess of trieth ylam in e (up to usin g it as a
solven t) or bases such as DBU or Bu4NOH. However, on ly a sligh tly reduced
am oun t of by-product 3 in th e reaction m ixtures resulted. Even lowerin g
tem perature (down to –20 °C) did n ot lead to better yields of 2. In th e origi-
n al report22, K2CO3 was em ployed as a base. However, th e use of carbon ates
in stead of NEt3 led to m uch lower yields of 2. Th e occurren ce of traces of
th e ph osph on oth ioic m on oam ide by-product 4 can be attributed to th e
presen ce of trace am oun ts of water in th e reaction m ixtures. Un der th e
optim ized con dition s, th e target protected cyclam could be isolated in
40–50% yields.
Th e protection route was also tested in protection of cyclen . However, we
foun d th at th e reaction is m uch less clear th an th at with cyclam . Th e target
product 2′ was isolated on ly after exten sive ch rom atograph ic purification
as a m ixture of two isom ers (on e isom er 2a′ was ch aracterized structurally).
Th e oth er two by-products 3′ an d 6 were also isolated. Th e form ation of th e
peculiar h eterocyclic com poun d 6 m ay be explain ed by m on osubstitution
of two Ph P(S)Cl2 m olecules with adjacen t am in o groups leadin g to th e for-
m ation of a very un usual seven -m em bered h eterocycle after partial h ydro-
lysis an d con den sation of two P–OH groups. Th erefore, on e can suggest
th at th e substitution reaction on cyclen is probably faster an d m ore n on -
selective th an th at on cyclam an d substitution on several n itrogen atom s
can proceed in depen den tly. Accordin g to th ese fin din gs, th e reaction of
ph en ylph osph on oth ioic dich loride with cyclen can be sum m arized in
Sch em e 3.
We also tried to em ploy com m ercially available ph en ylph osph on ic
dich loride in th e reaction with cyclam an d cyclen . However, TLC an d
31P NMR spectroscopy sh owed th at on ly very com plex m ixtures were pro-
duced in th ese reaction s. Probably, th e reaction between ph en ylph os-
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
357
ph on ic dich loride an d th e cyclic polyam in es is fast, with n o preferen ce for
th e form ation of adducts with a sim ple stoich iom etry.
Th e crystal structures h elped to un am biguously determ in e m olecular
structures of th e isolated com poun ds as spectral ch aracterization of
ch rom atograph ically pure products was rath er difficult. Th ere h ave been
on ly several exam ples of five-m em bered C2N2P h eterocycles presen ted in
literature. Prevote et al.22 determ in ed crystal structures of sim ilar m acro-
cyclic ph osph oroth ioic triam ides h avin g th e sam e five-m em bered C2N2P
h eterocyclic rin g but th eir com poun ds were diproton ated on th e rem ain -
in g am in e n itrogen atom s. Th e orien tation of sulfur atom s in th eir five-
m em bered h eterocycles correspon ds to th at in 2a, (H2a)+, 3a, 2a′ an d 6
wh ere th e sulfur is localized above th e am in e n itrogen atom s of th e rest of
m acrocycle. Bon d distan ces an d an gles in all h eterocycles are sim ilar. Th e
sulfate an ion foun d in som e sin gle crystals used for X-ray structure determ i-
n ation obviously cam e from silica gel used for colum n ch rom atograph y.
Sulfates were detected in eluates from wash in g of th e silica gel colum n with
th e am m on ia-con tain in g eluen ts un der th e con dition s used in th e prepara-
tive work.
We tested som e selected con dition s of rem oval of th e ph osph on oth ioic
protectin g group. Acid h ydrolysis was foun d to be m ore effective th an th e
alkalin e on e in accordan ce with literature data26. Deprotection with a
stron g cation exch an ge resin m ay be used for a selective rem oval of th e pro-
tectin g group. However, th e protectin g strategy was n ot a prim ary aim of
th e work an d it was n ot com pletely explored. Th e protectin g m oiety could
be easily rem oved by acid h ydrolysis. For our purposes, acid h ydrolysis is
con ven ien t as eth yl ph osph on ates are also h ydrolyzed un der th ese con di-
tion s.
Th e 1,4-diben zylcyclam was syn th esized startin g from 2a. More im por-
tan tly, 1,4-bis(m eth ylph osph on ate) derivative 5 was easily form ed by th e
Man n ich reaction . Direct acid h ydrolysis of un purified ester 5 led to a m ix-
ture of several m eth ylph osph on ic acid derivatives of cyclam (Sch em e 3).
Th e presen ce of th ese by-products can be attributed to a m ech an ism of th e
Man n ich reaction of th is kin d as it is, in gen eral, reversible. Th e trace
am oun ts of form aldeh yde an d ph osph ite (in com pletely rem oved by filtra-
tion an d evaporation ) can react durin g th e h ydrolysis with com poun d(s)
a risin g in th e reverse Man n ich reaction . Purified ester 5 gave th e target
ligan d 1,4-te2p in a h igh yield. Several H8tetp crystals were form ed on
stan din g of an acid reaction batch . Th e com poun d m ust h ave arisen from
a trace am oun t of cyclam in th e 2a used for th e particular syn th etic batch
of ester 5. Probably, a very low con cen tration of th e com poun d (n on -
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358
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
detectable in 31P NMR spectra of th e batch ) led to slow crystallization of
th is ligan d in th e form suitable for th e X-ray diffraction study. Th e stron g
in tram olecular h ydrogen bon ds in 1,4-te2p are very sim ilar to th ose presen t
in th e structure of 1,8-te2p (ref.12) an d are respon sible for a h igh basicity of
th e am in e n itrogen atom s in 1,4-te2p (ref.29).
CONCLUSIONS
We syn th esized a 1,4-protected cyclam usin g Ph P(S)Cl2. Th e solid-state
structures of th e target 1,4-protected cyclam an d several by-products were
determ in ed by th e sin gle-crystal X-ray diffraction . Th e m eth od is useful for
th e syn th esis of 1,4-substituted cyclam derivatives as it is sim ple an d th e
ph osph on oth ioic m oiety m ay be rem oved un der m ilder con dition th an th e
oxalate group used previously. Th e protected cyclam 2a was successfully
used for th e syn th esis of a n ew m acrocyclic ph osph on ate ligan d, 1,4,8,11-
tetraazacyclotetradecan e-1,4-bis(m eth ylph osph on ic acid). Th e crystal struc-
ture of th e ligan d sh owed th e presen ce of stron g in tram olecular h ydrogen
bon ds wh ich are probably respon sible for its h igh basicity. Th e crystal
structure of H8tetp was also determ in ed. Despite th e on ly m oderate yield
of th e 1,4-protected cyclam , th e m eth od is a reason able altern ative to th e
existin g procedures.
Un fortun ately, th e m eth od is on ly partly useful for th e syn th esis of
1,4-protected cyclen as it led to rath er com plex m ixtures. From th e m ix-
tures, th e target cyclen derivative was isolated in a low yield togeth er with a
cyclen ph osph on oth ioic tetraam ide con tain in g a very un usual seven -
m em bered C2N2OP2 h eterocycle; it is th e first exam ple of such h eterocycle
wh ich was structurally ch aracterized.
EXPERIMENTAL
Gen eral
Cyclam 30 (1) an d ph en ylph osph on oth ioic dich loride31 were syn th esized followin g th e litera-
ture procedures. Paraform aldeh yde was obtain ed by filtration of aged form aldeh yde solu-
tion s. Oth er ch em icals were available from com m ercial sources (Lach em a, Fluka, Aldrich ,
Merck, Acros or Bracco SpA). Solven ts were dried by establish ed procedures32. Colum n
ch rom atograph y was perform ed on silica gel (60–230 m esh , Merck). TLC was perform ed on
silica gel sh eets (Merck TLC alum in ium sh eets silica gel 60 F254
) in th e m ixtures:
(A) propan -2-ol–25% aqueous NH3 6:1, (B) propan -2-ol–25% aqueous NH3–water 10:2:7,
(C) propan -2-ol–EtOAc 25:1, (D) eth an ol–25% aqueous NH3 1:1, (E) eth an ol–25% aqueous
NH3 15:1, detection with aqueous solution of CuSO4 or Draggen dorf reagen t. Elem en tal
an alyses were m ade in th e In stitute of Macrom olecular Ch em istry, Academ y of Scien ces of
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
359
th e Czech Republic. Meltin g poin ts were determ in ed usin g a Kofler h ot-stage apparatus
(Boetius) an d are un corrected. NMR spectra (δ, ppm ; J, Hz) were recorded on a Varian Un ity
In ova 400 at 399.95 MHz for 1H, 100.58 MHz for 13C an d 161.9 MHz for 31P. In tern al refer-
en ces for 1H NMR: TMS (δ 0.00 ppm ) for CDCl3 solution s, t-BuOH (δ 1.25 ppm ) for D2O
solution s an d CHD2OD (δ 3.31 ppm ) for CD3OD solution s. In tern al referen ces for 13C NMR:
CDCl3 (δ 77.0 ppm ) for CDCl3 solution s, t-BuOH (δ 32.8 ppm ) for D2O solution s an d
CD3OD (δ 39.3 ppm ) for CD3OD solution s. Extern al referen ce for 31P NMR: 85% H3PO4 (δ
0.0 ppm ). ESI/MS spectra were recorded on a Bruker Esquire 3000 with an ion -trap detector.
Syn th eses
Phenylphosphonothioic dichloride. Th e com poun d was syn th esized accordin g to th e litera-
ture procedure31. Yield 95%. 1H NMR (CDCl3): 7.54–7.70 m , 3 H; 8.10–8.18 m , 2 H. 13C NMR
(CDCl3): 128.8 d, 2 C, 3J(P-C) = 18 (PCCHCH); 130.2 d, 2 C, 2J(P-C) = 14.5 (PCHCH);
133.8 d, 1 C, 4J(P-C) = 3.8 (PC(CH)2CH); 138.4 d, 1 C, 1J(P-C) = 117.9 (P–C). 31P NMR
(CDCl3): 76.3 t, 3J(P-H) = 19.1.
15-Phenyl-1,5,8,12-tetraaza-15λ5-phosphabicyclo[10.2.1]pentadecane-15-thione (2). Cyclam (1;
10.00 g, 50 m m ol) was dissolved in dry ch loroform (700 m l) an d dry trieth ylam in e (10.12 g,
100 m m ol) was added. To th is solution , ph en ylph osph on oth ioic dich loride (10.55 g,
50 m m ol) diluted with dry ch loroform (5 m l) was added dropwise durin g 12 h with stirrin g.
Th e m ixture was stirred at room tem perature for 3 days. Solven ts were evaporated on rotary
evaporator to give yellow oil. Four spots were detected by TLC (eluen t A, Draggen dorf detec-
tion ): th e m ain product 2a (RF 0.2), traces of its isom er 2b (RF 0.4), in separable m ixture of
isom ers of com poun d 3 (RF 1.0) an d a sm all am oun t of com poun d 4 (RF 0.15). Th e products
were separated by colum n ch rom atograph y. Because of a low solubility of th e reaction m ix-
ture in th e eluen ts, th e crude product was dissolved in a sm all am oun t of ch loroform an d
poured on to a colum n . Th e by-product 3 was separated from th e oth er com poun ds by gradi-
en t colum n ch rom atograph y on silica (25% aqueous NH3–MeOH from 1:6 to 1:3). Com -
poun ds 4 an d 2a were separated by an oth er colum n ch rom atograph y usin g eluen t B.
Com poun d 2a was obtain ed as a viscous yellow oil solidifyin g on stan din g. Yield 7.11 g
(42%). For C16H27N4PS (338.5) calculated: 56.78% C, 8.04% H, 16.55% N, 9.47% S; foun d:
56.55% C, 7.79% H, 16.13% N, 10.09% S. M.p. 102–107 °C. 1H NMR (CDCl3): 1.60–1.74 m ,
2 H (CH2CH2CH2); 1.81–1.95 m , 2 H (CH2CH2CH2); 2.64–2.70 m , 2 H (CH2NH); 2.74–2.77 m ,
2 H (CH2NH); 2.80–2.86 m , 4 H; 3.00–3.05 m , 4 H (CH2NH); 3.51–3.62 m , 2 H (PNCH2);
3.77–3.84 m , 2 H (PNCH2); 7.34–7.44 m , 4 H, aryl H); 7.57–7.63 m , 1 H (PCCH). 13C NMR
(CDCl3): 25.8 d, 2 C, 3J(P-C) = 3.0 (CH2CH2CH2); 42.8 d, 2 C, 2J(P-C) = 7.6 (PNCH2); 43.3 d,
2 C, 2J(P-C) = 6.4 (PNCH2); 47.6 s, 2 C (CH2NH); 48.4 s, 2 C (CH2NH); 128.1 d, 2 C,
3J(P-C) = 13.3 (PCCHCH); 129.6 d, 2 C, 2J(P-C) = 11.5 (PCCH); 130.5 d, 1 C, 4J(P-C) = 3.0
1
(PC(CH)2CH); 138.1 d, 1 C, 1J(P-C) = 112.5 (P-C). 31P{ H} NMR (CDCl3): 76.6 s. MS, m/z (%):
339.3 (100, M + H+).
Th e m ain by-product 3 was obtain ed as a m ixture of isom ers (yellowish oil, 2.35 g, 10%).
NMR spectra were very com plex, but th e in ten sity ratio arom atic/aliph atic h ydrogen s in
1H NMR agrees well with th e assum ption of 2:1 adduct of th e Ph P(S)Cl2 an d cyclam . Several
1
peaks were observed at about 80 ppm in 31P{ H} NMR spectrum , wh ich is in agreem en t with
th e proposed structure as well. Furth erm ore, on e of th e isom ers (3a) crystallized from th e
oily m ixture upon stan din g an d was iden tified by X-ray an alysis.
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360
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
Com poun d 4 was isolated in a m in ute yield. TLC (eluen t B, Draggen dorf detection ):
1
RF 0.6 (RF of both th e isom ers of 2 is 0.8 in th e eluen t). 31P{ H} NMR (D2O): 71.2 s.
Isom er 2b was isolated by ch rom atograph y (eluen t A) of com bin ed h igh ly en rich ed frac-
tion s from several syn th etic batch es as a ligh t yellow oil in a sm all yield. 1H NMR (CD3OD):
1.40–1.52 m , 2 H (CH2CH2CH2); 1.96–2.12 m , 2 H (CH2CH2CH2); 2.73 t, 2 H, 3J(H-H) = 11.4
(CH2NH); 2.85–3.06 m , 4 H (PNCH2); 2.96–3.00 m , 2 H (CH2NH); 3.06–3.16 m , 2 H
(CH2NH); 3.16–3.28 m , 4 H; 3.73–3.90 m , 2 H (PNCH2); 7.68–7.76 m , 2 H (PCCHCH);
7.71–7.76 m , 1 H (PC(CH)2CH); 8.06–8.18 m , 2 H (PCCH). 13C NMR (CD3OD): 26.0 d, 2 C,
3J(P-C) = 6.0 (CH2CH2CH2); 43.9 d, 2 C, 2J(P-C) = 6.5 (PNCH2); 44.8 s, 2 C (PNCH2); 47.4 s,
2 C (CH2NH); 49.4 s, 2 C (CH2NH); 130.0 d, 2 C, 3J(P-C) = 13.7 (PCCHCH); 130.8 d, 1 C,
1J(P-C) = 117.9 (P-C); 134.1 d, 2 C, 2J(P-C) = 11.5 (PCHCH); 134.5 s, 1 C (PC(CH)2CH).
1
31P{ H} NMR (CD3OD): 81.0 s. MS, m/z (%): 339.3 (100, M + H+).
1,4,8,11-Tetraazacyclotetradecane-1,4-bis(methylphosphonic acid) (1,4-H4te2p). Th e Man n ich
reaction of protected cyclam 2a, paraform aldeh yde an d trieth yl ph osph ite was perform ed by
m odification of th e procedure reported by Sh erry et al.33 Com poun d 2a (4.28 g, 12.6 m m ol)
was dissolved in trieth yl ph osph ite (130 m l, large excess) an d paraform aldeh yde (total
2.28 g, 76 m m ol, 6 equivalen ts) was added in th ree portion s durin g th ree days. Th en , th e
suspen sion was stirred for an oth er 4–6 days at 40 °C. After coolin g, excess of paraform -
aldeh yde was filtered off an d volatiles were rem oved by rotary evaporation . Th e resultin g oil
was purified by colum n ch rom atograph y (eluen t C). Th e in term ediate 5 was obtain ed as a
1
viscous yellow oil (6.52 g, 81%). TLC (eluen t C, Draggen dorf detection ): RF 0.5. 31P{ H} NMR
(CDCl3): 27.1 s, 2 P (PO3Et2); 77.4 s, 1 P (P(S)Ph ). MS, m/z (%): 639.4 (100, M + H+); 661.4
(61, M + Na+); 677.4 (16, M + K+).
Th e reaction in term ediate 5 (6.52 g, 10.2 m m ol) was h ydrolyzed in refluxin g h ydroch loric
acid (6 M, 24 h ). Solven ts were evaporated on rotary evaporator. Excess HCl was rem oved by
co-distillation with water (3×). Th e resultin g product, 1,4-H4te2p, was purified on a stron g
acid cation exch an ge resin (Dowex 50, H+-form , elution with water followed by 5% aqueous
am m on ia). Th e fin al purification was m ade by ch rom atograph y on weak acid cation ex-
ch an ge resin (Am berlite CG50, H+-form , water elution ). Two com poun ds were obtain ed. In
th e very first fraction s, trisubstituted derivative H6te3p was eluted. It was followed by th e
target 1,4-H4te2p. Sim ple crystallization from water–aceton e m ixture afforded 1,4-H4te2p·
4H2O as a sm all wh ite n eedles (4.25 g; 91% for th e last step, 73% based on 2a); th e product
slowly loses water of h ydration on stan din g in air. TLC (eluen t D, Cu2+ detection ): RF 0.5;
m .p. 262 °C (dec.). For C12H30N4O6P2·4H2O (460.4) calculated: 31.31% C, 8.32% H, 12.17% N;
foun d: 31.48% C, 7.80% H, 12.05% N. 1H NMR (D2O, 90 °C): 1.95 p, 4 H, 3J(H-H) = 5.4
(CH2CH2CH2); 2.87 d, 4 H, 2J(P-H) = 12.4 (PCH2); 2.92 s, 4 H (NCH2CH2N); 3.11 t, 4 H,
3J(H-H) = 5.4 (CH2CH2CH2); 3.24 t,
4 4 H
H, 3J(H-H) = 5.4 (CH2CH2CH2); 3.28 s,
(NCH2CH2N). 13C NMR (D2O, 90 °C): 25.0 s, 2 C (CH2CH2CH2); 46.8 s, 2 C (NCH2); 51.5 s,
2 C (NCH2); 55.4 d, 2 C, 1J(P-C) = 158.3 (PCH2); 56.1 s, 2 C (NCH2); 61.3 s, 2 C (NCH2).
31P NMR (D2O, 90 °C): 16.6 t, 2J(P-H) = 12.6. MS, m/z (%): 389.2 (100, M + H+); 411.2 (88,
M + Na+); 427.2 (22, M + K+).
Th e by-product H6te3p was obtain ed as a viscous yellow oil, wh ich was crystallized from
aqueous 6 M HCl in a sm all yield as trih ydroch loride dih ydrate (0.20 g, 2.5% based on 2a).
Th e crystallization was in duced by son ication . TLC (eluen t D, Cu2+ detection ): RF = 0.2. For
C
13H33N4O9P3·3HCl·2H2O (627.8) calculated: 24.87% C, 6.42% H, 16.94% Cl, 8.92% N;
foun d: 25.05% C, 6.64% H, 15.29% Cl, 9.02% N. 1H NMR (D2O, 80 °C): 2.57–2.59 m , 4 H
(CH2CH2CH2); 3.46 d, 2 H, 2J(P-H) = 11.6 (PCH2); 3.05 t, 2 H, 3J(H-H) = 6.0 (NCH2); 3.54 d,
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
361
2 H, 2J(P-H) = 11.6 (PCH2); 3.56 t, 2 H, 3J(H-H) = 6.8 (NCH2); 3.62–3.76 m , 6 H, (NCH2);
3.79 d, 2 H, 2J(H-H) = 12.4 (PCH2); 3.83 t, 2 H, 3J(H-H) = 5.8 (NCH2); 3.90 t, 2 H, 3J(H-H) =
8.0 (NCH2); 4.05 t, 2 H, 3J(H-H) = 6.0 (NCH2). 13C NMR (D2O, 80 °C): 24.8 s, 1 C
(CH2CH2CH2); 25.1 s, 1 C (CH2CH2CH2); 45.5 + 47.3 + 52.9 + 53.9 4 × s, 4 × 1 C
(NCH2CH2CH2N); 53.2 d, 1 C, 1J(C-P) = 150.5 (PCH2); 53.6 d, 1 C, 1J(C-P) = 143.0 (PCH2);
54.1 d, 1 C, 1J(C-P) = 149.7 (PCH2); 55.2 + 55.6 + 56.2 + 56.9 4 × s, 4 × 1 C (NCH2CH2N).
1
31P{ H} NMR (D2O, 80 °C): 13.4 s, 1 P; 20.8 s, 1 P; 21.7 s, 1 P. MS, m/z (%): 483.2 (100, M +
H+); 521.2 (35, M + K+); 505.2 (19, M + Na+).
If ester 5 (prepared from 2.0 g (5.91 m m ol) of 2a) was n ot purified by ch rom atograph y
after rem oval of paraform aldeh yde an d volatiles, th e h ydrolysis of th e ester groups in
refluxin g 6 M aqueous HCl took th ree days. Th e reaction m ixture was processed as above.
Crude ligan ds H6te3p an d 1,4-H4te2p were eluted from Dowex 50 with diluted am m on ia so-
lution wh ile H2te1p was retain ed on Dowex 50 after elution with am m on ia solution an d it
was obtain ed by elution with 6 M aqueous HCl an d evaporation of th e eluate. Th e fin al puri-
fication on Am berlite CG50 as above gave first H6te3p·3HCl·2H2O (0.45 g, 12% yield based
on 2a) an d later 1,4-H4te2p·4H2O (1.14 g, 42% yield based on 2a). Th e crude H2te1p was re-
tain ed on th e sorben t an d was obtain ed27 after elution with 10% aqueous AcOH, evapora-
tion an d crystallization from con cen trated aqueous HBr as tetrah ydrobrom ide dih ydrate
(0.19 g, 5% yield based on 2a).
1,4-Dibenzyl-1,4,8,11-tetraazacyclotetradecane. Com poun d 2a (1.02 g, 3.0 m m ol) was dis-
solved in dry aceton itrile (30 m l) an d dry solid K2CO3 (4.00 g, 28.9 m m ol) was added. Ben -
zyl brom ide (1.23 g, 7.2 m m ol, 2.4 equivalen ts) was added an d th e suspen sion was stirred at
room tem perature for six days (TLC m on itorin g, eluen t A, Draggen dorf detection ). In soluble
salts were filtered off an d excess ben zyl brom ide was con verted to ben zylam in e by addition
of sm all am oun t of aqueous am m on ia (10%). Th e solution was evaporated on rotary evapo-
rator. Th e protected in term ediate was directly h ydrolyzed by refluxin g in aqueous 6 M HCl
(80 m l) for 12 h . Volatiles were rem oved on rotary evaporator an d excess HCl was rem oved
by co-distillation with water (3×). Th e resultin g oil was extracted in to ch loroform from
aqueous K2CO3 solution (pH 12). Th e organ ic ph ase was separated, dried (an h ydrous Na2SO4)
an d evaporated to obtain a brown viscous oil. Th e crude product was purified by colum n
ch rom atograph y on silica gel (eluen t E) givin g 1,4-diben zylcyclam m on oh ydrate (0.78 g,
65%) as a yellow oil an d 1,4,8-triben zylcyclam (trace am oun t) as an oran ge-brown oil.
1,4-Bn 2cyclam . For C24H36N4·H2O (398.6) calculated: 72.32% C, 9.61% H, 14.06% N;
foun d: 71.80% C, 9.31% H, 13.85% N. TLC (eluen t E, Draggen dorf detection ): RF 0.5.
1H NMR (CDCl3): 1.81 m , 4 H (CH2CH2CH2); 2.37 t, 4 H, 3J(H-H) = 11.2 (CH2CH2CH2);
2.39 s,
4 H (NCH2CH2N); 2.79 t, 4 = 10.0 (CH2CH2CH2); 2.94 s, 4 H
H, 3J(H-H)
(NCH2CH2N); 3.45 s, 4 H, (CH2Ph ); 7.15–7.38 m , 10 H (aryl H). 13C NMR (CDCl3): 25.2 s,
2 C (CH2CH2CH2); 46.6 s, 2 C (NCH2); 46.7 s, 2 C (NCH2); 51.2 s, 2 C (NCH2); 51.6 s, 2 C
(NCH2); 57.8 s, 2 C (CH2Ph ); 127.0 s, 2 C (arom . C); 128.1 s, 4 C (arom . C); 129.5 s, 4 C
(arom . C); 138.3 s, 2 C (Cipso). MS, m/z (%): 381.4 (100, M + H+); 403.4 (2, M + Na+).
Th e m ore air stable form (1,4-Bn 2cyclam ·4HCl·2H2O) was obtain ed after crystallization
of th e free am in e from aqueous 6 M HCl. For C24H36N4·4HCl·2H2O (562.5) calculated:
51.25% C, 7.88% H, 25.21% Cl, 9.96% N; foun d: 51.63% C, 8.01% H, 24.52% Cl, 10.38% N.
M.p. 167–169 °C (dec.).
Th e iden tity of 1,4,8-triben zylcyclam was con firm ed by TLC com parison with auth en tic34
sam ple: RF 0.7 (eluen t E, Draggen dorf detection ).
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362
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
13-Phenyl-1,4,7,10-tetraaza-13λ5-phosphabicyclo[8.2.1]tridecane-13-thione (2′). Cyclen (1′;
2.50 g, 14.5 m m ol) was dissolved in dry ch loroform (250 m l). Dry trieth ylam in e (2.94 g,
29.0 m m ol) was added an d ph en ylph osph on oth ioic dich loride (3.06 g, 14.5 m m ol) was
slowly added to th e solution . Th e m ixture was stirred at room tem perature for 4 h . Part of
cyclen crystallized out in th e form of dih ydroch loride an d was recovered by filtration . Th e
filtrate was extracted with aqueous K2CO3 solution (pH 12). Th e organ ic ph ase was evapo-
rated on rotary evaporator to give a yellow sem isolid. Th e residue could n ot be com pletely
dissolved in com m on organ ic solven ts (eth an ol, aceton e, aceton itrile, toluen e, ch loroform ,
DMSO, DMF). Eth an ol (100 m l) was added, som e am oun t of a solid was filtered off an d th e
filtrate was left stan din g for 14 days. Th en , th e crystallin e product 6 was collected by filtra-
tion (0.79 g, 9%; th e crystal suitable for X-ray an alysis was isolated before filtration ). Two
oth er com poun ds were detected in th e filtrate by TLC (eluen t C, Dragen dorff detection ): th e
required product 2′ (RF 0.4) an d by-product 3′ (RF 0.9). Th e filtrate was con cen trated in vac-
uum an d purified by colum n ch rom atograph y on silica gel (gradien t of aqueous NH3–MeOH
from 1:6 to 1:3). Th e red-brown oily 2′ was obtain ed as a m ixture of isom ers an d (accordin g
to 31P NMR spectrum ) it was con tam in ated with a sm all am oun t of oth er in separable com -
poun ds in a yield of 0.90 g (~20%). Surprisin gly, a sm all am oun t of pure com poun d
2a′·0.5H2SO4·3H2O crystallized in NMR tube as wh ite crystals suitable for X-ray an alysis.
Th ese crystals were used for furth er ch aracterisation of com poun d 2a′.
2a′ TLC (eluen t C, Draggen dorf detection ): RF 0.4. 1H NMR (CD3OD): 2.78–2.93 m , 4 H
(NHCH2); 3.02–3.13 m , 2 H (PNCH2); 3.14–3.36 m , 6 H (NCH2); 3.36–3.48 m , 2 H (PNCH2);
3.77–3.90 m , 2 H (PNCH2); 7.37–7.47 m , 3 H (aryl H); 7.55–7.63 m , 2 H (aryl H). 13C NMR
(CD3OD): 45.2 d, 2 C, 2J(C-P) = 10.7 (PNCH2); 45.5 s, 2 C (NHCH2); 46.3 s, 2 C (NHCH2);
46.7 s, 2 C (PNCH2); 129.4 d, 2 C, 3J(C-P) = 14.2 (PCCHCH); 130.4 d, 2 C, 2J(C-P) = 11.5
(PCCH); 131.9 d, 1 C, 4J(C-P) = 3.0 (PCCHCHCH); 140.8 d, 1 C, 1J(C-P) = 133.5 (P-C).
1
31P{ H} NMR (CD3OD): 89.3 s. MS, m/z (%): 311.2 (100, M + H+).
By-product 3′ was foun d to be a m ixture of isom ers as it sh owed several peaks at ~80 ppm
(
31P NMR), but th e in ten sity ratio arom atic/aliph atic h ydrogen s in 1H NMR agrees well with
th e assum ption of 2:1 ph osph on oth ioate-m acrocycle adduct. MS, m/z (%): 449.5 (100, M +
H+). Yield 0.97 g (~15%).
Th e com poud 6 was h igh ly in soluble in all com m on solven ts; th erefore, attem pts at spec-
tral ch aracterization failed. M.p. 224–227 °C (dec.).
X-ray Diffraction Studies
Th e diffraction -quality sin gle crystals of com poun d 2a were grown from its oil overn igh t.
Th e sin gle crystals of com poun ds 2a·0.5H2SO4·1.375H2O, 3a an d 2a′·0.5H2SO4·3H2O were
grown from CDCl3 solution s used for NMR ch aracterization after stan din g for several days
or som e weeks. Th e diffraction -quality sin gle crystals of com poun d 2b·0.5H2SO4·3H2O were
grown from dich lorom eth an e by slow evaporation . Crystals of com poun d 4·H2O were ob-
tain ed from ch loroform by slow diffusion of h exan e vapour. Sin gle crystals of 6 were form ed
in eth an olic solution of th e reaction m ixture (see above). Colorless rods of 1,4-H4te2p·4H2O
were prepared by slow diffusion of aceton e vapour in to aqueous solution of th e ligan d.
Sin gle crystals of H8tetp·10H2O were obtain ed from HCl–H2O–D2O solution on stan din g of
an NMR sam ple after acid h ydrolysis of 5 for several weeks.
Th e diffraction data were collected at 150(2) K (Cryostream Cooler Oxford Cryosystem )
usin g a Non ius Kappa CCD diffractom eter an d Mo-Kα radiation (λ = 0.71073 Å). Th e data
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
363
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364
Vitha, Kotek, Rudovský, Kubíček, Císařová, Hermann, Lukeš:
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Selective Protection of 1,4,8,11-Tetraazacyclotetradecane
365
were an alyzed usin g th e HKL DENZO program package35. Th e structures were solved by pro-
gram SIR92 36, an d refin ed by program SHELXL97 37. All n on -h ydrogen atom s were refin ed
an isotropically; th e h ydrogen atom s were located in differen ce Fourier m ap an d were refin ed
isotropically. In th e structures of 4·H2O an d H8tetp·10H2O, h ydrogen atom s attach ed to car-
bon atom s were placed in th eoretical position s usin g th e ridin g m odel. Experim en tal data
are given in Table V.
CCDC 287912 (2a ), 287914 (2a ·0.5H2SO4·1.375H2O), 287911 (2b ·0.5H2SO4·3H2O),
287915 (3a ), 287917 (4·H2O), 287913 (2a ′·0.5H2SO4·3H2O), 287910 (6), 287909
(1,4-H4te2p·4H2O) an d 287916 (H8tetp·10H2O) con tain th e supplem en tary crystal-
lograph 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).
We thank Bracco SpA (Italy) for a kind gift of cyclen. Support of the Grant Agency of the Czech
Republic (No. 203/02/0493 and No. 203/06/0467) is acknowledged. The work was done in the frame
of COST D18 and EC-FP6 projects EMIL (LSHC-2004-503569) and DiMI (LSHB-2005-512146).
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