Pd-catalyzed amination in the synthesis of cyclen-based macrotricycles

Article abstract of DOI:10.1016/j.tetlet.2011.11.024

Three approaches to three types of cyclen-based macrotricycles have been elaborated starting from trans-bis(3-bromobenzyl)cyclen. The macrotricycles were synthesized via Pd-catalyzed amination. The first approach employed consecutive macrocyclization and

Full text of DOI:10.1016/j.tetlet.2011.11.024

Tetrahedron Letters 53 (2012) 210–213
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed amination in the synthesis of cyclen-based macrotricycles
Sergei M. Kobelev a, Alexei D. Averin a,b, Alexei K. Buryak b, Franck Denat c, Roger Guilard c,
,
⇑
Irina P. Beletskaya a,b,
⇑
a Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119991, Russia
b A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, 31 Leninskii Prosp., Moscow 119991, Russia
c Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB), UMR CNRS 5260, 9 Av. Alain Savary, Dijon 21078, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Three approaches to three types of cyclen-based macrotricycles have been elaborated starting from trans-
bis(3-bromobenzyl)cyclen. The macrotricycles were synthesized via Pd-catalyzed amination. The first
approach employed consecutive macrocyclization and benzylation steps giving a cage-like tricycle. In
the second, cyclen amino groups were Boc-protected prior to formation of the second and the third rings.
In the third method, macrotricycles were synthesized according to a one-step procedure using diaza-
crown ethers.
Received 6 September 2011
Revised 18 October 2011
Accepted 4 November 2011
Available online 10 November 2011
Keywords:
Macrocycles
Ó 2011 Elsevier Ltd. All rights reserved.
Polyamines
Amination
Homogeneous catalysis
Diazacrown ethers
Macropolycyclic compounds attract interest from researchers
due to their suitability as frameworks for many receptor sites.1
Diazacrown ethers were the first to be employed in the construc-
tion of macrobicyclic and macrotricyclic compounds.2 The simplest
molecules comprise several isolated diazacrown ethers,3 and more
complex species possess cryptand-like structures. Polymacrocyclic
compounds may be of different geometry owing to various modes
of attaching several macrocycles. Spherical macrobicyclic cryptates
of the polyether series were introduced by Lehn,4 and cage-type
macrobicycles were thoroughly studied by Italian chemists.5 Also,
spherical and cylindrical macrotricycles were developed,6 with
the latter being arranged in a coplanar manner. Various methods
were developed for the introduction of arene moieties to the
framework of sophisticated macropolycyclic compounds which
serve as sensing units. In the majority of these compounds the
arene unit is linked to the nitrogen atoms of the macrocycle via
methylene goups,7 but in some compounds the arene moiety is at-
tached through a direct C(sp2)–N bond.8 The synthesis of chiral
macrobicycles, for example, those containing diazacrown and
binaphthol has been described.9 A number of macropolycycles de-
rived from cyclam and cyclen were reported,10 a mutual feature of
these compounds being the attachment of two tetraazamacrocy-
cles via xylyl linkers. Detailed information on various types of mac-
ropolycyclic ligands can be found in reviews.11
We were the first to employ Pd-catalyzed amination in the syn-
thesis of cryptand-like macrobicycles containing cyclen moieties;
macrotricyclic cyclodimers were formed in the majority of cases
as by-products.12 In this Letter, we describe approaches to three
structurally different types of macrotricycle each of which pos-
sesses a cyclen unit and which differs in the mode of attaching
oxadiamine linkers to the tetraazamacrocyclic backbone.
The first approach (Scheme 1) started from trans-bis(3-bromob-
enzyl)cyclen (2), which was synthesized via a previously described
two-step procedure from cyclen 1.12 On reacting 2 with trioxadi-
amine 3 under Pd-catalyzed amination conditions [Pd(dba)2/
BINAP, 8 mol %, tBuONa, 1,4-dioxane, c = 0.02 M], macrobicycle 4
was obtained in a 28% yield. Next, this compound was treated with
m-bromobenzyl bromide to give cyclen derivative 5. The yield in
this reaction was moderate due to substantial alkylation of the
alkylaryl amino groups in the bicycle, thus tri- and tetrabenzylated
products as well as isomeric dibenzyl derivatives competed with
the formation of the target compound 5.13 To suppress polybenzy-
lation it was necessary to use 1.7 equiv of bromobenzyl bromide.
However, the second macrocyclization step was successful and
was conducted using the same trioxadiamine 3 and catalyst, and
led to a 33% yield of the desired macrotricycle 6, in which two tri-
oxadiamine units are attached on opposite sides of the cyclen via
benzyl spacers, forming a spherical cryptand.
The alternative to this method of attaching the third macrocycle
is via preliminary protection of two secondary amino groups on the
dibenzyl cyclen 2 with Boc substituents (Scheme 2). The reaction
was run in CH2Cl2 using 2.5 equiv of Boc2O and gave the
⇑
Corresponding authors.
E-mail address: beletska@org.chem.msu.ru (I.P. Beletskaya).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.024

S. M. Kobelev et al. / Tetrahedron Letters 53 (2012) 210–213
211
Br
NH
N
N
N
N
N
N
NH
N
N
O
O
O
NH HN
Br
Br
2 equiv.
HN
NH2
H2N
HN
O
3
HN
O
HN
Br
NH HN
O
O
Pd(dba)2/BINAP
tBuONa, 1,4-dioxane
K2CO3
CH3CN
Br
NH
NH
1
Br
O
O
2
4, 28%
5, 33%
O
O
O
N
N
N
N
NH2
H2N
3
Pd(dba)2/BINAP
tBuONa, 1,4-dioxane
NH
HN
O
O
O
O
HN
NH
O
O
6, 33%
Scheme 1. Synthesis of macrotricycle 6.
Br
Boc
Boc
NH
N
N
N
N
N
N
N
N
N
N
Boc2O
O
O
O
HN
2.5 equiv.
Br
NH2
H2N
HN
Br
3
Br
Boc
Boc
CH2Cl2
K2CO3
CH3CN
Pd(dba)2/BINAP
tBuONa, 1,4-dioxane
O
Br
O
NH
Br
2
O
7, 98%
8, 33%
Boc
N
Boc
N
N
N
N
H2N
O
O
NH2
N
N
N
N
N
10
Boc
Boc
Pd(dba)2/BINAP
tBuONa, 1,4-dioxane
O
HN
O
Br
O
O
N
N
O
O
O
O
O
O
O
NH2
H2N
9, 58%
HN
Br
3
11, 24%
Pd(dba)2/BINAP
tBuONa, 1,4-dioxane
oligomers
Scheme 2. Synthesis of macrotricycle 11.
bis-protected cyclen derivative 7 in quantitative yield. This was
employed in the Pd-catalyzed amination reaction with trioxadi-
amine 3 to afford macrobicycle 8 which was isolated in a 33% yield
after column chromatography on silica gel. Compound 8 was re-
acted with 2 equiv of m-bromobenzyl bromide to give bis(bromob-
enzyl) derivative 9 in a 58% yield. The formation of this compound
was not quantitative due to easy quaternization of the tertiary
amino groups with the very reactive bromobenzyl bromide. In
the last step we carried out the reaction with a second molecule
of trioxadiamine 3, however, in this case the target macrotricycle
was not formed, and only the formation of cyclooligomers was ob-
served. Changing trioxadiamine 3 for dioxadiamine 10 with a
shorter chain resulted in a 24% yield of the macrotricyclic com-
pound 11. We assume that in this reaction the length of the dia-
mine is crucial for successful ring-closure of the third macrocycle.
The third approach to macrotricycles based on cyclen is much
simpler than the two described above. The reaction of trans-
bis(3-bromobenzyl)cyclen (2) with 1 equiv of diaza-15-crown-5

212
S. M. Kobelev et al. / Tetrahedron Letters 53 (2012) 210–213
2. Martynov, A. G.; Gorbunova, Y. G. Inorg. Chim. Acta 2007, 360, 122–130.
3. Murillo, O.; Watanabe, S.; Nakano, A.; Gokel, G. W. J. Am. Chem. Soc. 1995, 117,
7665–7679.
4. Dietrich, B.; Lehn, J.-M.; Sauvage, J.-P.; Blanzat, J. Tetrahedron 1973, 29, 1629–
1645.
5. (a) Bencini, A.; Bianchi, A.; Bazzicalupi, C.; Ciampolini, M.; Dapporto, P.; Fusi, V.;
Micheloni, M.; Nardi, N.; Paoli, P.; Valtancoli, B. J. Chem. Soc., Perkin Trans. 2
1993, 715–720; (b) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Fusi, V.; Paoletti, P.;
Valtancoli, B. J. Chem. Soc., Perkin Trans. 2 1994, 815–820; (c) Bazzicalupi, C.;
Bencini, A.; Bianchi, A.; Fusi, V.; Mazzanti, L.; Paoletti, P.; Valtancoli, B.; Golub,
G.; Cohen, H.; Meyerstein, D. J. Chem. Soc., Dalton Trans. 1995, 2377–2384; (d)
Bencini, A.; Fusi, V.; Giorgi, C.; Micheloni, M.; Nardi, N.; Valtancoli, B. J. Chem.
Soc., Perkin Trans. 2 1996, 2297–2302; (e) Dapporto, P.; Formica, M.; Fusi, V.;
Giorgi, L.; Micheloni, M.; Pontellini, R.; Paoli, P.; Rossi, P. Eur. J. Inorg. Chem.
2001, 1763–1774.
N
NH
N
HN
n
O
N
O
n
N
HN
NH
O
N
NH
N
O
O
O
n = 1: 12, 10%
n = 2: 13, 30%
HN
Br
n = 1, 2
+
Pd(dba)2/DavePhos
tBuONa, 1,4-dioxane
O
Br
6. (a) Krakowiak, K. E.; Bradshaw, J. S.; Kou, X.; Dalley, N. K. J. Heterocycl. Chem.
1995, 32, 931–935; (b) Lachkar, M.; Guilard, R.; Atmani, A.; De Cian, A.; Fischer,
J.; Weiss, R. Inorg. Chem. 1998, 37, 1575–1584; (c) Krakowiak, K. E. J. Incl. Phen.
Mol. Recogn. 1997, 29, 283–288.
7. (a) Chae, M. K.; Lee, J. I.; Kim, N.-K.; Jeong, K.-S. Tetrahedron Lett. 2007, 48,
6624–6627; (b) Fages, F.; Desvergne, J.-P.; Bouas-Laurent, H.; Marsau, P.; Lehn,
J.-M.; Kotzyba-Hibert, F.; Albrecht-Gary, A.-M.; Al-Joubbeh, M. J. Am. Chem. Soc.
1989, 111, 8672–8680.
8. (a) He, H.; Mortellaro, M. A.; Leiner, M. J. P.; Fraatz, R. J.; Tusa, J. K. J. Am. Chem.
Soc. 2003, 125, 1468–1469; (b) Gouloumis, A.; Lawson, R. C.; Vazquez, P.;
Echegoyen, L.; Torres, T. Tetrahedron 2002, 58, 961–966.
9. Lehn, J.-M.; Simon, J.; Moradpour, A. Helv. Chim. Acta 1978, 61, 2407–2418.
10. (a) Brandes, S.; Denat, F.; Lacour, S.; Rabiet, F.; Barbette, F.; Pullumbi, P.;
Guilard, R. Eur. J. Org. Chem. 1998, 2349–2360; (b) Develay, S.; Tripier, R.;
Chuburu, F.; Le Baccon, M.; Handel, H. Eur. J. Org. Chem. 2003, 3047–3050.
11. (a) Ingham, A.; Rodopoulos, M.; Coulter, K.; Rodopoulos, T.; Subramanian, S.;
McAuley, A. Coord. Chem. Rev. 2002, 233–234, 255–271; (b) Hubin, T. J. Coord.
Chem. Rev. 2003, 241, 27–46.
2
N
O
N
NH
N
O
HN
NMe2
Cy2P
HN
n
DavePhos =
N
O
n
O
HN
n = 1: 14, 22%
n = 2: 15, 29%
O
Scheme 3. Synthesis of cylindrical cryptands 12, 13 and trimacrocycles 14 and 15.
12. Averin, A. D.; Shukhaev, A. V.; Buryak, A. K.; Denat, F.; Guilard, R.; Beletskaya, I.
P. Tetrahedron Lett. 2008, 49, 3950–3954.
13. All reactions were run under dry argon using MeCN distilled over CaH2 and 1,4-
dioxane distilled over Na. After completion of the reactions (1H NMR) the
mixture was evaporated in vacuo and chromatographed on silica gel using a
sequence of eluents: CH2Cl2, CH2Cl2–MeOH 50:1–3:1, CH2Cl2/MeOH/NH3(aq)
100:20:1–10:4:1. For the synthesis of macrobicycle 4 see Ref. 12.
32,37-Bis(3-bromobenzyl)-12,15,18-trioxa-1,8,22,29,32,37-hexaazatetracyclo
[27.5.5.13,7.123,27]hentetraconta-3(41),4,6,23(40),24,26-hexaene
(5)
was
6
11
12, 13
14, 15
synthesized from macrobicycle 4 (130 mg, 0.23 mmol) and 3-bromobenzyl
bromide (115 mg, 0.46 mmol) in MeCN (5 mL) in the presence of K2CO3 (95 mg,
0.69 mmol) at room temperature (reaction time 48 h). Eluent CH2Cl2–MeOH–
NH3(aq) 100:20:1. Yield 69 mg (33%). 1H NMR (400 MHz, CDCl3): d 1.85 (quin,
J = 6.1 Hz, 4H), 2.64–2.74 (m, 16H), 3.19 (q, J = 5.8 Hz, 4H), 3.38 (s, 4H), 3.41 (s,
4H), 3.57 (t, J = 6.0 Hz, 4H), 3.59–3.62 (m, 4H), 3.65–3.70 (m, 4H), 3.96 (t,
J = 5.4 Hz, 2H), 6.48 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 7.3 Hz, 2H), 6.74 (s, 2H), 7.06
(t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 7.7 Hz, 2H), 7.36 (d,
J = 8.3 Hz, 2H), 7.52 (s, 2H); 13C NMR (100.6 MHz, CDCl3): d 29.1 (2C), 41.6 (2C),
52.5 (4C), 53.0 (4C), 59.2 (2C), 60.5 (2C), 69.6 (2C), 70.2 (2C), 70.6 (2C), 110.8
(2C), 113.2 (2C), 117.6 (2C), 122.1 (2C), 127.5 (2C), 128.7 (2C), 129.7 (4C), 131.7
(2C), 141.0 (2C), 142.6 (2C), 148.6 (2C); MALDI-TOF m/z 905.3271 [M+H]+;
calcd for C46H63Br2N6O3: 905.3328.
Figure 1. Structural types of macrotricycles 6 and 11–13 and trimacrocycles 14 and
15.
or diaza-18-crown-6 led directly to the corresponding cylindrical
cryptands 12 and 13 (Scheme 3). These reactions were catalyzed
with Pd(dba)2/DavePhos catalyst because BINAP was found to be
much less active in the arylation of secondary amino groups in aza-
crown ethers. The target compounds were obtained in 10% and 30%
yields, respectively. Such pronounced differences in the yields can
be explained by the different distances between the two reacting
nitrogen atoms of the diazacrown ethers. In both reactions
bis(diazacrown) derivatives 14 and 15 were isolated in comparable
yields (22% and 29%); these molecules are also of interest as they
contain isolated macrocycles with different binding properties.
In conclusion, we have elaborated approaches to three struc-
tural types of macrotricycles organized around the cyclen moiety.
The shapes of the synthesized macropolycycles 6 and 11–15 can
be outlined schematically as shown in Figure 1. Further work on
the synthesis of macrotricycles of these types bearing isomeric aro-
matic spacers and various oxadiamine linkers, which will alter the
sizes of certain cavities, is underway.
12,15,18,43,46,49-Hexaoxa-1,8,22,29,32,39,53,60-octaazaheptacyclo[30.30.
2.229,60.13,7.123,27.134,38.154,58]heptaconta-3(70),4,6,23(69),24,26,34(68),35,37,
54(67),55,57-dodecaene (6) was synthesized from compound
5 (130 mg,
0.14 mmol) and trioxadiamine (31 mg, 0.14 mmol), in the presence of
3
Pd(dba)2 (6.5 mg), BINAP (8 mg), tBuONa (40 mg, 0.42 mmol), in boiling
absolute 1,4-dioxane (6 mL, reflux time 24 h). Eluent CH2Cl2–MeOH 3:1.
Yield 45 mg (33%). 1H NMR (400 MHz, DMSO-d6): d 1.73 (quin, J = 6.2 Hz, 8H),
2.72–2.87 (m, 16H), 3.07 (t, J = 6.8 Hz, 8H), 3.38–3.48 (m, 16H), 3.50–3.55 (m,
16H), 5.27 (br s, 4H), 6.39 (d, J = 7.7 Hz, 4H), 6.51 (s, 4H), 6.53 (d, J = 8.3 Hz, 4H),
7.01 (t, J = 7.5 Hz, 4H); 13C NMR (100.6 MHz, DMSO-d6): d 28.8 (4C), 40.1 (4C),
50.0 (br s, 8C), 58.9 (4C), 68.1 (4C), 69.2 (4C), 69.5 (4C), 112.0 (4C), 113.0 (4C),
117.2 (4C), 128.3 (4C), 135.7 (4C), 148.8 (4C); MALDI-TOF m/z 965.84 [M+H]+;
calcd for C56H85N8O6: 965.66.
Di-tert-butyl 4,10-bis(3-bromobenzyl)-1,4,7,10-tetraazacyclo-dodecane-1,7-
dicarboxylate (7) was synthesized from compound 2 (510 mg, 1 mmol) and
Boc2O (545 mg, 2.5 mmol), in CH2Cl2 (1.5 mL), at room temperature. The
reaction was complete in 24 h. Yield 694 mg (98%). 1H NMR (400 MHz, CDCl3):
d 1.27 (s, 18H), 2.61 (br s, 8H), 3.29 (br s, 4H), 3.40 (br s, 4H), 3.52 (s, 4H), 7.12
(br t, Jobs = 6.3 Hz, 2H), 7.17 (br s, 2H), 7.31 (br d, Jobs = 6.5 Hz, 2H), 7.44 (br s,
2H); 13C NMR (100.6 MHz, CDCl3): d 28.2 (6C), 45.9 (4C), 54.7 (4C), 59.1 (2C),
79.5 (2C), 122.2 (2C), 127.7 (2C), 129.6 (2C), 130.0 (2C), 132.2 (2C), 141.5 (2C),
155.6 (2C); MALDI-TOF m/z 709.1920 [M+H]+; calcd for C32H47Br2N4O4:
709.1964.
Acknowledgments
This work was supported by RFBR Grant 09-03-00735 and by
the Russian Academy of Sciences program P-8 ‘Development of
methods for the synthesis of new chemicals and creation of new
materials’’.
Di-tert-butyl 12,15,18-trioxa-1,8,22,29,32,37-hexaazatetra-cyclo[27.5.5.13,7.1
23,27]hentetraconta-3(41),4,6,23(40),24,26-hexaene-32,37-dicarboxylate
(8)
was synthesized from compound 7 (734 mg, 1.03 mmol), trioxadiamine 3
(220 mg, 1 mmol), in the presence of Pd(dba)2 (92 mg), BINAP (112 mg),
tBuONa (290 mg, 3.02 mmol), in boiling absolute 1,4-dioxane (50 mL, reflux
time 24 h). Eluent CH2Cl2–MeOH 25:1. Yield 294 mg (33%). 1H NMR (400 MHz,
CDCl3, 328 K): d 1.35 (s, 18H), 1.84 (quin, J = 5.5 Hz, 4H), 2.78 (br s, 8H), 3.23 (t,
J = 6.0 Hz, 4H), 3.36 (br s, 8H), 3.54 (br s, 4H), 3.55–3.60 (m, 8H), 3.65–3.68 (m,
References and notes
1. (a) Lehn, J.-M. Pure Appl. Chem. 1980, 52, 2441–2459; (b) Quici, S.; Manfredi, A.;
Raimondi, L.; Sironi, A. J. Org. Chem. 1995, 60, 6379–6388.

S. M. Kobelev et al. / Tetrahedron Letters 53 (2012) 210–213
213
4H), 6.46 (br d, Jobs = 7.5 Hz, 2H), 6.56 (br d, Jobs = 6.6 Hz, 2 H), 6.65 (br s, 2H),
7.04 (br t, Jobs = 7.3 Hz, 2H) (NH protons were not assigned); 13C NMR
(100.6 MHz, CDCl3, 328 K): d 28.5 (6C), 29.6 (2C), 41.9 (2C), 47.4 (4C), 54.4
(4C), 60.6 (2C), 69.8 (2C), 70.4 (2C), 70.8 (2C), 79.5 (2C), 111.8 (2C), 113.6 (2C),
118.3 (2C), 128.9 (2C), 140.0 (2C), 148.9 (2C), 156.1 (2C);); ESI-TOF m/z
769.5212 [M+H]+; calcd for C42H69N6O7: 769.5228.
0.46 mmol), in boiling absolute 1,4-dioxane (8 mL, reflux time 24 h). Eluent
CH2Cl2–MeOH 3:1. Yield 9 mg (10%). 1H NMR (400 MHz, CDCl3): d 2.64–2.93
(m, 16H), 3.44–3.52 (m, 8H), 3.60 (br s, 8H), 3.62 (m, 4H), 3.88 (t, J = 5.3 Hz,
4H), 6.48 (br s, 4H), 7.06 (t, J = 8.0 Hz, 2H), 7.15 (s, 2H) (NH protons were not
assigned); 13C NMR (100.6 MHz, CDCl3): d 49.4 (4C), 52.0 (6C), 54.3 (2C), 63.0
(2C), 69.6 (2C), 70.2 (2C), 70.4 (2C), 110.4 (2C), 114.0 (2C), 117.8 (2C), 128.6
(2C), 139.9 (2C), 149.2 (2C); MALDI-TOF m/z 567.3959 [M+H]+; calcd for
Di-tert-butyl
8,22-bis(3-bromobenzyl)-12,15,18-trioxa-1,8,22,29,32,37-
hexaazatetracyclo[27.5.5.13,7.123,27]-hentetraconta-3(41),4,6,23(40),24,26-
hexaene-32,37-dicarboxylate (9) was synthesized from compound 8 (315 mg,
0.4 mmol), 3-bromobenzyl bromide (200 mg, 0.8 mmol), in MeCN (8 mL) in the
presence of K2CO3 (138 mg, 1 mmol) at room temperature (reaction time 48 h).
Eluent CH2Cl2–MeOH 25:1. Yield 255 mg (58%). 1H NMR (400 MHz, CDCl3): d
1.33 (s, 18H), 1.88 (quin, J = 6.1 Hz, 4H), 2.70 (br s, 8H), 3.31 (br s, 8H), 3.45–
3.59 (m, 16H), 3.65–3.69 (m, 4H), 4.48 (s, 4H), 6.50 (br d, Jobs = 6.2 Hz, 2H), 6.61
(d, J = 7.2 Hz, 2H), 6.73 (br s, 2H), 7.06 (t, J = 7.9 Hz, 2H), 7.11 (br s, 2H), 7.12 (t,
J = 7.6 Hz, 2H), 7.33 (br d, Jobs = 7.1 Hz, 2H), 7.34 (br s, 2H); 13C NMR
(100.6 MHz, CDCl3, 328 K): d 27.8 (2C), 28.5 (6C), 46.9 (4C), 48.2 (2C), 54.3
(2C), 54.5 (4C), 60.6 (2C), 68.8 (2C), 70.5 (2C), 70.9 (2C), 79.5 (2C), 111.9 (2C),
113.6 (2C), 118.3 (2C), 122.8 (2C), 125.4 (2C), 129.8 (2C), 129.9 (2C), 130.1 (4C),
139.9 (2C), 142.1 (2C), 148.7 (2C), 155.9 (2C); ESI-TOF m/z 1105.4373 [M+H]+;
calcd for C56H79N6O7: 1105.4377.
C32H51N6O3: 567.4023.
7,70-[1,4,7,10-Tetraazacyclododecane-1,7-diylbis(methylene-3,1-phenylene)]
bis-1,4,10-trioxa-7,13-diazacyclopentadecane (14) was obtained as the main
product in the synthesis of compound 12. Eluent CH2Cl2–MeOH–NH3(aq)
100:20:3. Yield 13 mg (22%). 1H NMR (400 MHz, CDCl3): d 2.65 (br s, 16H), 2.77
(t, J = 5.9 Hz, 4H), 2.78 (t, J = 5.2 Hz, 4H), 3.52–3.67 (m, 32H), 3.74 (t, J = 6.8 Hz,
4H), 6.52 (s, 2H), 6.56 (d, J = 7.6 Hz, 2H), 6.71 (d, J = 7.5 Hz, 2H), 7.18 (t,
J = 7.7 Hz, 2H) (NH protons were not assigned); 13C NMR (100.6 MHz, CDCl3): d
45.8 (4C), 48.5 (2C), 48.7 (2C), 51.6 (4C), 52.5 (2C), 52.9 (2C), 60.7 (2C), 68.9
(4C), 69.4 (2C), 70.0 (2C), 70.2 (2C), 71.0 (2C), 110.5 (2C), 112.7 (2C), 116.9 (2C),
129.3 (2C), 139.6 (2C), 147.9 (2C); MALDI-TOF m/z 785.58 [M+H]+; calcd for
C
42H73N8O6: 785.57.
24,27,32,35-Tetraoxa-1,8,11,14,21,41-hexaazapentacyclo-[19.8.8.58,14.12,6
116,20]tetratetraconta-2(44),3,5,16(38),17,19-hexaene (13) was synthesized
from compound (77 mg, 0.15 mmol), diaza-18-crown-6 (39 mg,
.
Di-tert-butyl
ptacyclo-[27.19.13.536,42.13,7.123,27.130,34.144,48]heptaconta-3(70),4,6,23(69),24,
26,30(68),31,33,44(62),45,47-dodecaene-39,65-dicarboxylate (11) was
synthesized from compound (126 mg, 0.114 mmol), dioxadiamine 10
12,15,18,52,55,58-hexaoxa-1,8,22,29,36,39,42,65-octaazahe-
2
0.15 mmol), in the presence of Pd(dba)2 (14 mg), DavePhos (11 mg), tBuONa
(44 mg, 0.46 mmol), in boiling absolute 1,4-dioxane (8 mL, reflux time 24 h).
Eluent CH2Cl2-MeOH 3:1. Yield 27 mg (30%). 1H NMR (400 MHz, CDCl3): d
2.77–2.81 (m, 8H), 2.83–2.85 (m, 8H), 3.54–3.61 (m, 24H), 3.65 (s, 4H), 6.52 (d,
J = 7.3 Hz, 2H), 6.57 (dd, J = 8.3 Hz, J = 1.5 Hz, 2H), 6.77 (br s, 2H), 7.07 (t,
J = 7.7 Hz, 2H) (NH protons were not assigned); 13C NMR (100.6 MHz, CDCl3): d
48.1 (4C), 51.0 (4C), 51.6 (4C), 62.3 (2C), 68.8 (4C), 70.8 (4C), 112.1 (2C), 113.5
(2C), 117.7 (2C), 129.1 (2C), 139.6 (2C), 148.3 (2C); MALDI-TOF m/z 611.4261
[M+H]+; calcd for C34H55N6O4: 611.4285.
9
(17 mg, 0.115 mmol) in the presence of Pd(dba)2 (10.5 mg), BINAP (13 mg),
tBuONa (33 mg, 0.34 mmol), in boiling absolute 1,4-dioxane (6 mL, reflux time
24 h). Eluent CH2Cl2–MeOH 10:1. Yield 30 mg (24%). 1H NMR (400 MHz,
CDCl3): d 1.32 (s, 18H), 1.86 (br s, 4H), 2.60–2.95 (m, 8H), 3.17 (br s, 4H), 3.30–
3.70 (m, 40H), 4.41 (s, 2H), 4.43 (s, 2H), 6.44 (br s, 4H), 6.50–6.61 (m, 6H), 6.72
(br s, 2H), 7.05 (br s, 4H) (NH protons were not assigned); 13C NMR (100.6 MHz,
CDCl3, 328 K): d 27.9 (2C), 28.5 (6C), 43.8 (2C), 47.0 (4C), 48.0 (2C), 54.5 (4C),
54.7 (2C), 60.9 (2C), 68.9 (2C), 69.9 (2C), 70.5 (4C), 70.9 (2C), 110.8 (2C), 112.2
(4C), 113.7 (2C), 116.1 (2C), 117.8 (2C), 128.9 (2C), 129.4 (2C), 139.0 (2C), 140.5
(2C), 148.8 (2C), 149.3 (2C), 156.1 (2C) (two quaternary carbon atoms of Boc
groups were not assigned); MALDI-TOF m/z 1093.7032 [M+H]+; calcd for
7,70-[1,4,7,10-Tetraazacyclododecane-1,7-diylbis(methylene-3,1-phenylene)]
bis-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (15) was obtained as the
second product in the synthesis of compound 13. Eluent CH2Cl2–MeOH–
NH3(aq) 100:20:3. Yield 19 mg (29%). 1H NMR (400 MHz, CDCl3): d 2.64 (br s,
16H), 2.78 (t, J = 4.4 Hz, 8H), 3.55–3.63 (m, 36H), 3.65 (t, J = 4.9 Hz, 8H), 6.51 (s,
2H), 6.55 (d, J = 8.1 Hz, 2H), 6.69 (d, J = 7.5 Hz, 2H), 7.18 (t, J = 7.8 Hz, 2H) (NH
protons were not assigned); 13C NMR (100.6 MHz, CDCl3): d 45.8 (4C), 49.2
(4C), 50.5 (4C), 51.6 (4C), 60.6 (2C), 68.7 (4C), 70.4 (8C), 70.5 (4C), 110.2 (2C),
112.5 (2C), 116.6 (2C), 129.3 (2C), 139.7 (2C), 147.9 (2C); MALDI-TOF m/z
873.6090 [M+H]+; calcd for C46H81N8O8: 873.6177.
C
62H93N8O9: 1093.7066.
24,27,32-Trioxa-1,8,11,14,21,38-hexaazapentacyclo-[19.8.5.58,14.12,6.116,20
]
hentetraconta-2(41),3,5,16(35),17,19-hexaene (12) was synthesized from
compound 2 (77 mg, 0.15 mmol), diaza-15-crown-5 (33 mg, 0.15 mmol), in
the presence of Pd(dba)2 (14 mg), DavePhos (11 mg), tBuONa (44 mg,