Diethoxyphosphoryl as a protecting-activating group in the synthesis of polyazacyclophanes

Article abstract of DOI:10.1002/(SICI)1522-2675(20000412)83:4<793::AID-HLCA793>3.0.CO;2-3

The fully diethoxyphosphoryl(Dep)-protected polyamines 1b-3b were prepared from the corresponding polyamines with 'diethyl phosphite' (= diethyl phosphonate) and CCl₄ in a solid base/organic liquid two-phase system in the presence of Bu₄NBr as phase-transfer catalyst. Subsequent phase-transfer-catalyzed alkylation of phosphoramidates 1b-3b with bis(chloromethyl)arenes 5-8 in the presence of Bu₄N(HSO₄) followed by deprotection gave good yields of polyazacyclophanes 9a-16a.

Full text of DOI:10.1002/(SICI)1522-2675(20000412)83:4<793::AID-HLCA793>3.0.CO;2-3

Helvetica Chimica Acta ± Vol. 83 (2000)
793
Diethoxyphosphoryl as a Protecting-Activating Group in the Synthesis
of Polyazacyclophanes
by Andrea Chellini and Roberto Pagliarin
Á
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, Via Venezian 21, I-20131
Milano
and Giovanni B. Giovenzana*
Á
Dipartimento di Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche, Universita degli Studi del
Piemonte Orientale ꢀA. Avogadroꢁ, Viale Ferrucci 33, I-28100, Novara
and Giovanni Palmisano* and Massimo Sisti
Â
Dipartimento di Scienze Chimiche Fisiche e Matematiche, Universita degli Studi dellꢁInsubria, Via Lucini 3,
I-22100 Como
The fully diethoxyphosphoryl(Dep)-protected polyamines 1b ± 3b were prepared from the corresponding
polyamines with ꢀdiethyl phosphiteꢁ (ˆdiethyl phosphonate) and CCl4 in a solid base/organic liquid two-phase
system in the presence of Bu4NBr as phase-transfer catalyst. Subsequent phase-transfer-catalyzed alkylation of
phosphoramidates 1b ± 3b with bis(chloromethyl)arenes 5 ± 8 in the presence of Bu4N(HSO4) followed by
deprotection gave good yields of polyazacyclophanes 9a ± 16a.
Introduction. ± Polyazacyclophanes represent one of the most useful macrocyclic
multidentate compounds for a variety of applications ranging from molecular
recognition (host molecules for inclusion of neutral organic molecules) to coordination
chemistry [1]. Furthermore, the reasons for the interest in polyazacyclophanes are
twofold: i) to modulate lipophilicity and to modify biodistribution of metal-complex-
based drugs, ii) to create molecules exhibiting new photophysical and photochemical
properties (i.e., the presence of a suitable chromophore is required in luminescent
lanthanide complexes) [2]. Many cyclization methods have been developed to
synthesize azamacrocycles under excellent control of the formed ring size, while
minimizing the extent of competing side reactions (i.e., linear oligomer formation and
reagent decomposition). The most efficient ring construction is based on the ring
closure involving the formation of two C N bonds by reaction of a,w-bis(electro-
philes) and the dianion formed from a suitably protected a,w-diamine (Richman-
Atkins procedure) [3][4]. p-Toluenesulfonamides have been used more frequently
than any other protective groups (PGs) for primary amines, because of the powerful
electron-withdrawing effect of the sulfonyl group, their ease of formation, and their
stability under a wide range of reaction conditions. Their removal is accomplished by
many different procedures, such as by refluxing in strong acids (H2SO4 or HBr), by
sodium naphthalenide, lithium aluminum hydride, or Red-Alꢂ, by dissolving-metal
methods, as well as by photochemical and electrochemical cleavage [5]. Recently, new
cleavage methods have been developed, which include the reagents SmI2 [6], Mg in

794
Helvetica Chimica Acta ± Vol. 83 (2000)
MeOH [7], Bu4NF [8], and Me3SiI [9]. Furthermore, many other PGs (e.g.,
nosylamides [9], 2,4-dinitrobenzenesulfonamides [10], naphthalene-2-sulfonamides
[11], tert-butylsulfonamides [12], trifluoroacetamides, carbamates) have already been
proposed for the protection of primary amines, keeping in view the sensitivity of the
molecule towards the acidic or basic conditions. All these PGs suffer from one or more
disadvantages, such as operationally difficult reaction conditions, long reaction times,
expensive precursors, low yields, or contamination of the final product with hardly
separable impurities.
In connection with our project designed to prepare new contrast agents with
enhanced relaxivity aimed at magnetic-resonance imaging (MRI), we synthesized a
series of azamacrocycles. Some of these have previously been prepared by the
Richman-Atkins method applied to the nosylamides [9] or tosylamides [1b][13]. While
good yields were reported, the reaction conditions were not favorable for an
application of the method to prepare other azacyclophanes embodying different
subunits. On this background, it appears that diethyl phosphoramidates of primary
amines would provide an interesting alternative to the arenesulfonamides in terms of
the planned alkylation-deprotection strategy for the synthesis of polyazacyclophanes. If
successful, advantages would arise from the easy removal of this PG.
Results. ± The required fully diethoxyphosphoryl(Dep)-protected polyamines 1b ±
3b were efficiently prepared by reacting the corresponding polyamines 1a ± 3a with
diethyl phosphite (ˆdiethyl phosphonate)/CCl4 in a solid base/organic liquid two-
phase system (mixture of solid K2CO3 and NaHCO3/CH2Cl2) in the presence of
Bu4NBr as phase-transfer catalyst at room temperature (Scheme). This procedure
(Atherton-Openshaw-Todd reaction [14]) was found to be far superior to the use of
diethyl phosphorochloridate (EtO)2POCl in pyridine as phosphorylating agent.
Although phosphoramidates have been alkylated in a number of cases [15], a single
report deals with the use of this PG during the synthesis of multidentate macrocyclic
compounds [16]. These successful syntheses by Mertes and co-workers [16] have
relied on the use of NaH in DMSO as base; however, in our cases, we were unable to
force the reaction to completion under the reported conditions and variations thereof;
messy reactions were uniformly observed. Thus, alternative conditions for macro-
cyclization involving phosphoramidates under phase-transfer conditions had to be
found.
In principle, the success of the alkylation of 1b ± 3b mainly depends on the efficient
generation of anions and their presence in the organic phase to undergo the subsequent
reaction with the bis(chloromethyl) derivatives 5 ± 8. Thus, we investigated the effect of
different phase-transfer catalysts, bases, and phase systems on the reaction. Tetrabu-
tylphosphonium bromide (Bu4PBr) and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-
1) did not catalyze the reaction at all, while tetrabutylammonium hydrogen sulfate
(Bu4N(HSO4)) was superior to triethyl(benzyl)ammonium chloride and Aliquatꢀ-336.
For example, in the liquid-liquid two-phase system, aqueous NaOH solution/toluene,
2b reacted with 7 under reflux for 4 h in the presence of Bu4N(HSO4) (10 mol-%),
providing the Dep-protected cyclophane 16b in modest to excellent isolated yield.
Variations in the concentration of NaOH significantly affected the yield of the
procedure. The reaction proceeded most satisfactorily (80%) with a 50% aqueous

Helvetica Chimica Acta ± Vol. 83 (2000)
795
Scheme
Dep ˆ (EtO)2P(O)
i) (EtO)2P(O)H, CCl4, NaHCO3, Bu4NBr, r.t. ii) 50% NaOH/PhMe, Bu4N(HSO4). iii) HCl(g) in dioxane, r.t.,
then NaOH.
solution (see Table 1), whereas the yields fell to only 25% when a 30% aqueous
solution was employed. Different phase systems (e.g., liquid/liquid or solid/liquid) and
different bases did not much influence the results. When the same reaction was
Table 1. Yields of the Macrocyclization of 1b ± 3b with 5 ± 8 in the Two-Phase System 50% Aqueous NaOH
Solution/Toluene in the Presence of Bu4N(HSO4)
(Dep)m‡1-Polyamine
m, n
a,w-Dihalide
(Dep)m‡1-Cyclophane
Yield [%]a)
3b
2b
2b
3b
1b
1b
3b
2b
2, 2
3, 1
3, 1
2, 2
2, 1
2, 1
2, 2
3, 1
5
5
6
6
7
8
7
7
9
78 (
73 (
52 (77) [1b]
56 (74) [1b]
82 (70) [19]
79 (85) [19]
)
)
10b
11b
12b
13b
14b
15b
16b
68 (
80 (63) [19]
)
a) In parentheses, reported yields for cyclizations employing PGs other than Dep.

796
Helvetica Chimica Acta ± Vol. 83 (2000)
conducted in the absence of a phase-transfer catalyst, the starting reagents were
recovered unconverted.
We have explored the scope of this phase-transfer-catalyzed reaction and
established that for the fully Dep-protected amines 1b ± 3b and bis(chloromethyl)
derivatives 5 ± 8 the alkylation proceeded uneventfully, yielding 9b ± 16b (see Table 1).
The failure to obtain the corresponding cyclophane with 4 illustrates the practical limit
of chemical stability that can be accommodated in this reaction. Moreover, the

Helvetica Chimica Acta ± Vol. 83 (2000)
797
efficiency of the phase-transfer catalyst allowed the use of a solvent (toluene) of lower
polarity than DMSO, which simplified the workup procedure substantially.
Finally, removal of the Dep groups could be easily accomplished by stirring the
crude protected macrocycles 9b ± 16b in 1,4-dioxane saturated with gaseous HCl [17] at
room temperature for 12 ± 24 h. The corresponding hydrochlorides of 9a ± 16a
precipitated from the reaction mixtures and were recovered by filtration. Neutraliza-
tion, basification, and extraction with CH2Cl2 gave the expected free bases 9a ± 16a in
excellent yields (Table 2).
Table 2. Yields of the Deprotection of the Dep-Cyclophanes
(Dep)m‡1-Cyclophane 9b
10b
10a
11b
11a
12b
12a
13b
13a
14b
14a
15b
15a
16b
16a
Cyclophane
Yield [%]a)
9a
92 ( ) 90 ( ) 87 (53) [1b] 78 (43 [1b] 75 (67) [19] 95 (80) [20] 90 ( ) 86 (78) [19]
a) In parentheses, reported yields for procedures employing PGs other than Dep.
Conclusion. ± Phase-transfer-catalyzed alkylation of phosphoramidates 1b ± 3b and
subsequent deprotection give good yields of polyazacyclophanes 9a ± 16a that are
comparable to or slightly higher than those obtained in the alkylation of sulfonamides.
Furthermore, the solubility of the Dep-protected polyamines 1b ± 3b in a wide range of
solvents, excellent product recovery, as well as the easy deprotection after the
alkylation step extend their potential synthetic usefulness as valuable intermediates in
the synthesis of polyazacyclophanes.
Experimental Part
1. General. All amines and phase-transfer catalysts, ꢀdiethyl phosphiteꢁ (ˆdiethyl phosphonate), CCl4
(Caution!; when working with CCl4, the use of standard safety precautions is strongly recommended [18])
were purchased from Aldrich and used without purification. Anal. TLC: silica gel 60F254 (Macherey-
Nagel); detection by spraying with alkaline KMnO4 soln., followed by heating to 1208. M.p.: uncorrected;
Büchi-510 apparatus. IR Spectra: Perkin-Elmer-1420 spectrophotometer; film, unless stated otherwise; in
cm 1. 1H- and 13C-NMR Spectra: at 200 and 50.3 MHz, resp.; Bruker-AC200 spectrometer; CDCl3 soln., unless
stated otherwise, chemical shifts d in ppm downfield from internal SiMe4 (ˆ0.00 ppm; J in Hz). Mass spectra: Cl
mode (isobutane); VG7070EQ spectrometer. Elemental analyses were carried out on a Perkin Elmer 240
instrument.
2. Dep-Polyamines: General Procedure. To a soln. of polyamine 1a ± 3a (20 mmol) and CCl4 (200 mmol;
Caution!) in CH2Cl2 (50 ml), anh. K2CO3 (100 mmol for 1a and 3a; 120 mmol for 2a), NaHCO3 (100 mmol for
1a and 3a; 120 mmol for 2a) and Bu4NBr (2 mmol) are sequentially added. ꢀDiethyl phosphiteꢁ (ˆdiethyl
phosphonate; 65 mmol for 1a and 3a; 85 mmol for 2a) is slowly added to the vigorously stirred suspension. The
temp. of the mixture (exothermic reaction) is kept at 0 ± 58 by ice-bath cooling. After the addition, the mixture is
allowed to reach r.t. and stirred overnight. H2O (100 ml) is added to the suspension and the mixture stirred until
the inorg. salts are completely dissolved. The aq. phase is extracted with CH2Cl2 (2 Â 10 ml) and the combined
org. phase washed with 1m HCl (2 Â 20 ml), 10% K2CO3 (20 ml), and H2O (20 ml), dried (Na2SO4), and
evaporated. Compound 2b solidifies quickly and is crystallized from diisopropyl ether; pure 1b and 3b are
obtained as colorless oils after prolonged standing under vacuum to eliminate residual traces of diethyl
phosphite.
3. Cyclization: General Procedure. Dep-Polyamine 1b ± 3b (3 mmol), bis(chloromethyl)arene 5 ± 8
(3 mmol) and Bu4N(HSO4) (0.3 mmol) are dissolved in toluene (10 ml). Aq. 50% NaOH soln. (10 ml) is
added, and the vigorously stirred soln. is refluxed for 2 ± 8 h, until TLC (CH2Cl2/MeOH 9 :1) shows complete
disappearance of the starting materials. The two-phase system is then cooled, diluted with H2O (50 ml) and
thoroughly extracted with CH2Cl2 (4 Â 15 ml). The collected org. extracts are dried (Na2SO4), filtered, and

798
Helvetica Chimica Acta ± Vol. 83 (2000)
evaporated. The semisolid residue is crystallized from iPr2O/hexane or submitted to flash chromatography
(CH2Cl2/MeOH 95 :5): pure 9b ± 16b.
4. Dep Deprotection: General Procedure. Dep-polyazacyclophane 9b ± 16b (1 mmol) is dissolved in dioxane
saturated with gaseous HCl (10 ml), the resulting soln. is stirred overnight at r.t. Polyazacyclophane
hydrochlorides precipitate, either spontaneously or after addition of Et2O, and are isolated by filtration and
washed with Et2O. The free polyazacyclophanes are obtained by partitioning the hydrochlorides between 6m
NaOH and CH2Cl2. The org. extracts are dried (Na2SO4/K2CO3) and evaporated: pure 9a ± 16a.
5. Data. 1,4,7-Tris(diethoxyphosphoryl)-1,4,7-triazaheptane (ˆ Diethyl Bis{2-[(diethoxyphosphoryl)ami-
no]ethyl}phosphoramidate; 1b). Colorless viscous oil. IR: 3435, 3246, 2981, 2936, 2907, 2874, 1641, 1445, 1234,
1
1029, 967, 798. H-NMR: 3.85 ± 4.06 (m, 12 H); 3.43 (m, 2 H); 2.98 (m, 8 H); 1.61 (t, J ˆ 6.6, 4 H); 1.24 (t, J ˆ
7.04, 18 H). 13C-NMR: 62.2 (J(C,P) ˆ 5.6, C); 42.2 (CH2); 38.1 (CH2); 29.7 (CH2); 16.1 (J(C,P) ˆ 6.4, CH2). MS:
‡
512 (MH ). Anal. calc. for C16H40N3O9P3 (511.42): C 37.58, H 7.88, N 8.22; found: C 37.45, H 8.01, N 8.20.
1,4,7,10-Tetrakis(diethoxyphosphoryl)-1,4,7,10-tetraazadecane (ˆ Tetraethyl N,N'-Ethan-1,2-diylbis({2-[(di-
ethoxyphosphoryl)amino]ethyl}phosphoramidate); 2b): White solid. M.p. 778 (i-Pr2O). 1H-NMR: 3.91 ± 4.05
(m, 16 H); 3.30 (m, 2 H); 3.01 ± 3.12 (m, 12 H); 1.27 (t, 24 H). 13C-NMR: 62.5 (d, J(C,P) ˆ 5.3, Me); 62.2
‡
(d, CH2); 47.7 (CH2); 45.3 (CH2); 39.9 (CH2); 16.1 (d, J(C,P) ˆ 5.3, Me). MS: 691 (MH ). Anal. calc. for
C22H54N4O12P4 (690.58): C 38.26, H 7.88, N 8.11; found: C 38.07, H 8.01, N 8.09.
1,5,9-Tris(diethoxyphosphoryl)-1,5,9-triazanonane (ˆ Diethyl Bis{3-[(diethoxyphosphoryl)amino]propyl}-
phosphoramidate; 3b): Colorless viscous oil. IR: 3435, 3246, 2982, 2937, 2907, 2874, 1641, 1446, 1393, 1234, 1029,
967, 798. 1H-NMR: 3.96 (m, 12 H); 3.43 (m, 2 H); 2.98 (m, 8 H); 1.61 (t, 4 H, J ˆ 6.6); 1.24 (t, J ˆ 7.0, 18 H).
13C-NMR: 62.2 (J(C,P) ˆ 5.6, CH2); 62.0 (J(C,P) ˆ 5.2, CH2); 42.2 (CH2); 38.1 (CH2); 29.8 (CH2); 16.1
‡
(J(C,P) ˆ 6.4, CH2). MS: 540 (MH ). Anal. calc. for C18H44N3O9P3 (539.48): C 40.08, H 8.22, N 7.79; found:
C 39.99, H 8.37, N 7.82.
3,7,11-Tris(diethoxyphosphoryl)-3,7,11-triazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (9b): Colorless oil.
IR: 3468, 2981, 2932, 1636, 1446, 1392, 1367, 1240, 1029, 964, 801. 1H-NMR: 7.40 (s, 1 H); 7.26 (s, 3 H); 4.17
(d, J(C,P) ˆ 8.2, 4 H); 4.05 (m, 8 H); 3.83 (m, 4 H); 2.92 (dt, J ˆ 10.4, 7.1, 4 H); 2.69 (dt, J ˆ 10.4, 7.8, 4 H); 1.34
(quint., J ˆ 7.2, 4 H); 1.31 (t, J ˆ 7.1, 12 H); 1.17 (t, J ˆ 7.1, 6 H). 13C-NMR: 139.2 (J(C,P) ˆ 5.0, C); 129.2 (CH);
128.9 (CH); 127.9 (CH); 62.2 (d, J(C,P) ˆ 5.4, CH2); 61.7 (d, J(C,P) ˆ 5.4, CH2); 52.2 (CH2); 45.7 (CH2); 44.1
‡
(CH2); 27.9 (CH2); 16.1 (d, J(C,P) ˆ 6.7, Me); 15.9 (d, J(C,P) ˆ 6.7, Me). MS: 642 (MH ). Anal. calc. for
C26H50N3O9P3 (641.61): C 48.67, H 7.85, N 6.55; found: C 48.61, H 8.02, N 6.50.
3,6,9,12-Tetrakis(diethoxyphosphoryl)-3,6,9,12-tetraazabicyclo[12.3.1]octadeca-1(18),14,16-triene
(10b):
1
Thick colorless oil. IR: 3468, 2983, 2933, 2907, 1660, 1462, 1364, 1240, 1029, 962, 795. H-NMR: 7.38 (s, 3 H);
7.05 (s, 1 H); 4.20 (d, J ˆ 8.2, 4 H); 4.14 ± 3.82 (m, 16 H); 2.85 (m, 8 H); 2.65 (m, 4 H); 1.31 (t, 6 H); 1.22 (t, 6 H).
13C-NMR: 137.8 (d, J(C,P) ˆ 4.7, C); 129.7 (CH); 129.2 (CH); 128.1 (CH); 62.5 (J(C,P) ˆ 5.7, CH2); 62.2
(J(C,P) ˆ 5.6, CH2); 50.6 (J(C,P) ˆ 4.4, CH2); 45.9 (CH2); 44.8 (CH2); 43.7 (CH2); 16.1 (J(C,P) ˆ 5.7, Me); 16.0
‡
(J(C,P) ˆ 5.6, Me). MS: 793 (MH ). Anal. calc. for C30H60N4O12P4 (792.72): C 45.45, H 7.63, N 7.07; found:
C 45.31, H 7.70, N 6.98.
3,6,9,12-Tetrakis(diethoxyphosphoryl)-3,6,9,12-tetraazabicyclo[12.2.2]octadeca-14,16,17-triene (11b): Color-
1
less wax. IR: 3468, 2982, 1664, 1450, 1362, 1244, 1028, 964, 800. H-NMR: 7.27 (s, 4 H); 4.09 (d, J ˆ 6.07, 4 H);
3.94 ± 4.08 (m, 8 H); 3.72 ± 3.94 (m, 8 H); 2.82 (m, 4 H); 2.52 (m, 4 H); 2.34 (m, 4 H); 1.25 (t, J ˆ 7.05, 12 H);
1.14 (t, J ˆ 6.07, 12 H). 13C-NMR: 137.5 (J(C,P) ˆ 6.8, C); 129.3 (CH); 62.5 (J(C,P) ˆ 5.5, CH2); 62.2 (J(C,P) ˆ
5.4, CH2); 52.3 (J(C,P) ˆ 4.4, CH2); 45.8 (CH2); 45.1 (CH2); 44.7 (J(C,P) ˆ 4.36, CH2); 16.1 (J(C,P) ˆ 7.1, Me);
‡
15.9 (J(C,P) ˆ 7.1, Me). MS: 793 (MH ). Anal. calc. for C30H60N4O12P4 (792.72): C 45.45, H 7.63, N 7.07; found:
C 45.24, H 7.72, N 6.95.
3,7,11-Tris(diethoxyphosphoryl)-3,7,11-triazabicyclo[11.2.2]heptadeca-13,15,16-triene (12b): Colorless wax.
IR: 3468, 2982, 2933, 2907, 1646, 1446, 1392, 1367, 1240, 1167, 1029, 965. 800. 1H-NMR: 7.36 (s, 4 H); 4.15 ± 3.73
(m, 6 H); 2.85 (m, 4 H); 2.39 (m, 6 H); 1.31 (t, J ˆ 7.0, 12 H); 1.18 (t, J ˆ 7.0, 6 H); 0.96 (m, 4 H). 13C-NMR:
139.3 (J(C,P) ˆ 5.5, C); 129.7 (CH); 62.3 (J(C,P) ˆ 5.2, CH2); 61.8 (J(C,P) ˆ 4.6, CH2); 53.4 (CH2); 46.2 (CH2);
‡
44.2 (CH2); 29.7 (CH2); 16.1 (J(C,P) ˆ 5.7, Me); 16.0 (J(C,P) ˆ 5.5, Me). MS: 642 (MH ). Anal. calc. for
C26H50N3O9P3 (641.61): C 48.67, H 7.85, N 6.55; found: C 48.51, H 8.00, N 6.46.
3,6,9-Tris(diethoxyphosphoryl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (13b): Colorless
oil. 1H-NMR: 7.62 (t, J ˆ 7.6, 1 H); 7.21 (d, J ˆ 7.6, 2 H); 4.23 (d, 4 H); 3.71 ± 3.97 (m, 12 H); 2.82 (m, 8 H); 1.14
(m, 12 H). 13C-NMR: 156.2 (d, J(C,P) ˆ 4.8); 138.3 (CH); 122.9 (CH); 62.1 (d, J(C,P) ˆ 4.7, CH2); 61.9
‡
(d, J(C,P) ˆ 5.3, CH2); 52.8 (CH2); 43.3 (CH2); 42.1 (CH2); 15.9 (d, J(C,P) ˆ 5.4, Me). MS: 615 (MH ). Anal.
calc. for C23H45N4O9P3 (614.55): C 44.95, H 7.38, N 9.12; found: C 44.95, H 7.50, N 9.09.

Helvetica Chimica Acta ± Vol. 83 (2000)
799
12-[(4-Bromobenzyl)oxy]-3,6,9-tris(diethoxyphosphoryl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-
1
triene (14b): Light yellow oil. H-NMR: 7.49 (d, J ˆ 8.4, 2 H); 7.35 (d, J ˆ 8.4, 2 H); 7.30 (d, J ˆ 8.4, 1 H); 7.21
(d, J ˆ 8.4, 1 H); 5.07 (s, 2 H); 4.54 (d, J ˆ 5.6, 2 H); 4.29 (d, J ˆ 7.8, 2 H); 3.86 ± 4.05 (m, 12 H); 2.94 ± 3.15
(m, 8 H); 1.16 ± 1.33 (m, 12 H). 13C-NMR: 152.6 (C); 148.2 (d, J(C,P) ˆ 4.5, C); 145.0 (d, J(C,P) ˆ 7.7, C); 134.7
(C); 131.7 (CH); 128.7 (CH); 124.3 (CH); 122.0 (C); 120.3 (CH); 69.4 (CH2); 62.1 ± 62.3 (3 CH2); 52.6
(d, J(C,P) ˆ 4.6, CH2); 48.1 (d, J(C,P) ˆ 4.6, CH2); 43.9 (CH2); 42.8 (2s, CH2); 41.9 (CH2); 15.9 ± 16.1 (3s, Me).
‡
MS: 799, 801 (MH ). Anal. calc. for C30H50BrN4O10P3 (779.57): C 45.07, H 6.30, N 7.01; found: C 44.89, H 6.31,
N 6.95.
3,7,11-Tris(diethoxyphosphoryl)-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (15b): Color-
less viscous oil. IR: 3469, 2981, 2932, 1642, 1576, 1456, 1392, 1368, 1245, 1029, 964, 800. 1H-NMR: 7.60 (t, J ˆ 7.6,
1 H); 7.35 (d, J ˆ 7.6, 3 H); 4.24 (d, J ˆ 9.9, 4 H); 3.99 (m, 8 H); 3.80 (m, 4 H); 2.91 (m, 4 H); 2.73 (dt, J ˆ 10.2,
7.6, 4 H); 1.44 (quint., J ˆ 7.3, 2 H); 1.24 (t, J ˆ 7.1, 12 H); 1.14 (t, J ˆ 7.1, 6 H). 13C-NMR: 158.1 (C); 137.2 (CH);
122.4 (CH); 62.1 (d, J(C,P) ˆ 5.3, CH2); 61.7 (d, J(C,P) ˆ 5.3, CH2); 53.5 (d, J(C,P) ˆ 4.4, CH2); 45.7 (CH2); 45.3
‡
(CH2); 28.3 (CH2); 15.9 (d, J(C,P) ˆ 6.7, Me). MS: 643 (MH ). Anal. calc. for C25H49N4O9P3 (642.60): C 46.73,
H 7.69, N 8.72; found: C 46.55, H 7.89, N 8.62.
3,6,9,12-Tetrakis(diethoxyphosphoryl)-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene (16b):
Colorless crystals. M.p. 878 (i-Pr2O). 1H-NMR: 7.74 (t, J ˆ 7.7, 1 H); 7.47 (d, J ˆ 7.7, 2 H); 4.38 (d, J ˆ 10.4, 4 H);
4.04 (m, 16 H); 3.01 (m, 8 H); 2.85 (m, 4 H); 1.35 (m, 6 H); 1.29 (d, J ˆ 7.1, 6 H). 13C-NMR: 157.5 (C); 137.6
(CH); 122.3 (CH); 62.5 (d, J(C,P) ˆ 19.8, CH2); 62.3 (d, J(C,P) ˆ 19.4, CH2); 52.1 (CH2); 45.9 (CH2); 44.5
‡
(CH2); 43.7 (CH2); 16.1 ± 15.9 (2 Me). MS: 794 (MH ). Anal. calc. for C29H59N5O12P4 (793.70): C 43.88, H 7.49,
N 8.82; found: C 43.74, H 7.57, N 8.82.
3,7,11-Triazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (9a): Colorless wax. 1H-NMR: 7.71 (s, 1 H); 7.23
(t, J ˆ 7.0, 2 H); 7.05 (d, J ˆ 7.0, 1 H); 3.89 (s, 4 H); 2.78 (t, J ˆ 5.6, 4 H); 2.54 (t, J ˆ 5.9, 4 H); 1.71 (quint., J ˆ 5.7,
4 H); 1.60 (br. s, exch. with D2O, 3 H). 13C-NMR: 140.3 (C); 127.9 (CH); 126.8 (CH); 124.3 (CH); 52.7 (CH2);
‡
46.3 (CH2); 43.9 (CH2); 28.9 (CH2). MS: 234 (MH ). Anal. calc. for C14H23N3 (233.36): C 72.06, H 9.93, N 18.01;
found: C 71.93, H 10.15, N 18.00.
3,6,9,12-Tetraazabicyclo[12.3.1]octadeca-1(18),14,16-triene (10a): Colorless foam. 1H-NMR: 7.72 (s, 1 H);
7.40 ± 7.06 (m, 3 H); 3.82 (s, 4 H); 2.72 (m, 8 H); 2.68 (s, 4 H); 1.99 (br. s, exch. with D2O, 4 H). 13C-NMR: 141.4
‡
(C); 127.8 (CH); 126.8 (CH); 126.6 (CH); 52.8 (CH2); 49.1 (CH2); 48.8 (CH2); 48.2 (CH2). MS: 249 (MH ).
Anal. calc. for C14H24N4 (248.37): C 67.70, H 9.74, N 22.56; found: C 67.57, H 9.93, N 22.50.
1
3,6,9,12-Tetraazabicyclo[12.2.2]octadeca-14,16,17-triene (11a): Colorless wax. H-NMR: 7.29 (s, 4 H); 3.71
(s, 4 H); 2.76 (m, 4 H); 2.46 (m, 4 H); 2.12 (br. s, exch. with D2O, 3 H); 2.03 (s, 4 H). 13C-NMR: 141.0 (C); 129.7
‡
(CH); 53.6 (CH2); 49.1 (CH2); 48.9 (CH2); 46.2 (CH2). MS: 249 (MH ). Anal. calc. for C14H24N4 (248.37):
C 67.70, H 9.74, N 22.56; found: C 67.58, H 9.82, N 22.40.
3,7,11-Triazabicyclo[11.2.2]heptadeca-13,15,16-triene (12a): Colorless wax. 1H-NMR: 7.27 (s, 4 H); 3.68
(s, 4 H); 2.45 (m, 4 H); 2.31 (br. s, exch. with D2O, 3 H); 2.12 (m, 4 H); 1.33 (quint., J ˆ 7.1, 4 H). 13C-NMR:
‡
140.2 (C); 129.1 (CH); 53.0 (CH2); 43.3 (CH2); 41.7 (CH2); 29.7 (CH2). MS: 234 (MH ). Anal. calc. for
C14H23N3 (233.36): C 72.06, H 9.93, N 18.01; found: C 71.95, H 10.05, N 17.89.
3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (13a): White solid. M.p. 75 ± 788 (t-BuOMe).
1H-NMR: 7.49 (t, J ˆ 7.6, 1 H); 6.98 (d, J ˆ 7.6, 2 H); 3.94 (s, 4 H); 2.69 (m, 4 H); 2.33 (br. s, exch. with D2O,
3 H); 2.25 (m, 4 H). 13C-NMR: 159.5 (C); 136.2 (CH); 119.6 (CH); 53.7 (CH2); 49.1 (CH2); 48.9 (CH2). MS: 207
‡
(MH ). Anal. calc. for C11H18N4 (206.29): C 64.05, H 8.79, N 27.16; found: C 63.93, H 8.91, N 26.98.
12-[(4-Bromobenzyl)oxy]-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (14a): Light yellow
solid. M.p. 92 ± 958 (i-Pr2O-hexane). 1H-NMR: 7.54 (d, J ˆ 7.7, 2 H); 7.30 (d, J ˆ 7.7, 2 H); 7.08 (d, J ˆ 8.3, 1 H);
6.96 (d, J ˆ 8.3, 1 H); 5.04 (s, 2 H); 4.06 (s, 2 H); 3.95 (s, 2 H); 2.75 (m, 4 H); 2.41 (m, 4 H); 2.29 (br. s, exch. with
D2O, 3 H). 13C-NMR: 150.5 (C); 149.8 (C); 148.6 (C); 136.7 (C); 131.6 (CH); 128.8 (CH); 123.0 (CH); 121.9
(C); 120.0 (CH); 69.3 (CH2); 52.1 (CH2); 48.6 (CH2); 47.8 (CH2); 47.1 (CH2); 47.0 (CH2); 46.4 (CH2). MS: 391,
‡
393 (MH ). Anal. calc. for C18H23BrN4O (391.31): C 55.25, H 5.92, N 14.32; found: C 55.02, H 6.02, N 14.21.
3,7,11,17-Tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (15a): White solid. M.p. 83 ± 858 (t-BuOMe).
1H-NMR: 7.54 (t, J ˆ 7.5, 1 H); 7.01 (d, J ˆ 7.5, 2 H); 3.88 (s, 4 H); 2.76 (t, J ˆ 6.0, 4 H); 2.63 (t, J ˆ 6.0, 4 H); 2.36
(br. s, exch. with D2O, 3 H); 1.75 (quint., J ˆ 6.0, 4 H). 13C-NMR: 159.0 (C); 136.6 (CH); 120.7 (CH); 54.1
‡
(CH2); 47.6 (CH2); 46.4 (CH2); 28.8 (CH2). MS: 235 (MH ). Anal. calc. for C13H22N4 (234.24): C 66.63, H 9.46,
N 23.91; found: C 66.43, H 9.63, N 23.79.
1
3,6,9,12,18-Pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene (16a): White wax. H-NMR: 7.54 (t, J ˆ 7.5,
1 H); 7.04 (d, J ˆ 7.5, 2 H); 3.90 (s, 4 H); 2.84 (m, 4 H); 2.77 (m, 4 H); 2.75 (s, 4 H); 2.33 (br. s, exch. with D2O,

800
Helvetica Chimica Acta ± Vol. 83 (2000)
4 H). 13C-NMR: 156.1 (C); 136.6 (CH); 121.3 (CH); 53.9 (CH2); 48.6 (CH2); 47.8 (CH2); 47.1 (CH2). MS: 250
‡
(MH ). Anal. calc. for C13H23N5 (249.36): C 62.62, H 9.30, N 28.09; found: C 62.62, H 9.45, N 27.98.
We wish to thank the CNR, Rome, through the CNR Target Project on ꢁBiotechnologyꢂ for financial support.
Prof. S. Aime is gratefully acknowledged for his interest and helpful discussions.
REFERENCES
[1] a) F. Diederich, ꢀCyclophanesꢁ, The Royal Society of Chemistry, London, 1991; b) A. Bencini, M. I.
Ä
Burguete, E. Garcìa-Espana, S. V. Luis, J. F. Miravet, C. Soriano, J. Org. Chem. 1993, 58, 4749 and refs. cit.
therein; c) ꢀThe Chemistry of Heterocyclic Compoundsꢁ, Eds. J. S. Bradshaw, K. E. Krakowiak, R. M. Izatt,
Wiley-Interscience, New York, 1993.
[2] M. Pietraszkiewicz, in ꢀComprehensive Supramolecular Chemistryꢁ (Luminescent Probes), Pergamon,
London, 1996, Vol. 10.
[3] J. E. Richman, T. J. Atkins, J. Am. Chem. Soc. 1974, 96, 2268; T. J. Atkins, J. E. Richman, W. F. Oettle, in
ꢀOrganic Synthesesꢁ, Wiley, New York, Coll. Vol. VI, p. 652; B. K. Vriesema, J. Buter, R. M. Kellogg, J. Org.
Chem. 1984, 49, 110; F. Chavez, A. D. Sherry, J. Org. Chem. 1989, 54, 2990.
[4] R. J. Jones, H. Rapoport, J. Org. Chem. 1990, 55, 1144; J. R. Henry, L. R. Marcin, M. C. McIntosh, P. M.
Scola, G. D. Harris, S. M. Weinreb, Tetrahedron Lett. 1989, 30, 5709.
[5] T. W. Green, P. G. M. Wuts, in ꢀProtective Groups in Organic Synthesisꢁ, Wiley, New York, 1991; P. J.
Kocienski, in ꢀProtecting Groupsꢁ, Thieme, Stuttgart, 1994.
[6] H. Knowles, A. F. Parsons, R. M. Peltifer, Synth. Lett. 1997, 271.
[7] B. Nyasse, L. Grehn, U. Ragnarsson, Chem. Commun. 1997, 1017.
[8] A. Yasuhara, T. Sakanoto, Tetrahedron Lett. 1998, 39, 595.
[9] G. Sabitha, B. V. S. Reddy, S. Abraham, J. S. Yadav, Tetrahedron Lett. 1999, 40, 1569.
[10] S. Kobayashi, G. Peng, T. Fukuyama, Tetrahedron Lett. 1999, 40, 1519.
[11] B. Nyasse, L. Grehn, H. L. S. Maia, L. S. Monteiro, U. Ragnarsson, J. Org. Chem. 1999, 64, 7135.
[12] P. Sun, S. M. Weinreb, M. Shang, J. Org. Chem. 1997, 62, 8604.
[13] J. A. E. Pratt, I. O. Sutherland, R. Newton, J. Chem. Soc., Perkin Trans. 1 1988, 13.
[14] F. R. Atherton, H. T. Openshaw, A. R. Todd, J. Chem. Soc. 1945, 660.
[15] A. Zwierzak, Synthesis 1984, 332; A. Zwierzak, K. Osowska-Pacewicka, Synthesis 1984, 223; A. Dumont, V.
Jacques, P. Qixiu, J. F. Desreux, Tetrahedron Lett. 1994, 35, 3707; G. J. Bridger, R. T. Skerlj, S.
Padmanabhan, S. A. Martellucci, G. W. Henson, S. Struyf, M. Witvrouw, D. Schols, E. DeClercq, J. Med.
Chem. 1999, 42, 3971.
[16] L. Qian, Z. Sun, M. P. Mertes, K. Bowman Mertes, J. Org. Chem. 1991, 56, 4904.
[17] A. Zwierzak, J. Piotrowicz-Brylikowska, Angew. Chem., Int. Ed. 1977, 16, 107.
[18] P. Patnaik, ꢀA Comprehensive Guide to the Hazardous Properties of Chemical Substancesꢁ, Van Nostrand
Reinhold, New York, 1992.
[19] H. Stetter, W. Frank, R. Mertens, Tetrahedron 1981, 37, 767; S. Aime, M. Botta, S. Geninatti Crich, G. B.
Giovenzana, G. Jommi, R. Pagliarin, M. Sisti, Inorg. Chem. 1997, 36, 2992.
[20] S. Aime, M. Botta, L. Frullano, S. Geninatti Crich, G. B. Giovenzana, R. Pagliarin, G. Palmisano, M. Sisti,
Chem.-Eur. J. 1999, 5, 1253.
Received December 29, 1999