Facile synthesis of a selectively protected triazamacrocycle

Article abstract of DOI:10.1016/S0040-4039(02)01756-2

1,7-Diaminoheptane was selectively homologated with the novel reagent N-(2-nitrobenzenesulfonyl)aziridine. A series of reactions then followed to afford a selectively protected 14-membered triazamacrocyclic ring.

Full text of DOI:10.1016/S0040-4039(02)01756-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7569–7571
Facile synthesis of a selectively protected triazamacrocycle
Renato T. Skerlj,* Siqiao Nan, Yuanxi Zhou and Gary J. Bridger
AnorMED Inc., c200-20353 64th Ave, Langley, BC, Canada V2Y 1N5
Received 9 August 2002; revised 13 August 2002; accepted 22 August 2002
Abstract—1,7-Diaminoheptane was selectively homologated with the novel reagent N-(2-nitrobenzenesulfonyl)aziridine. A series
of reactions then followed to afford a selectively protected 14-membered triazamacrocyclic ring. © 2002 Elsevier Science Ltd. All
rights reserved.
Azamacrocycles and some of their N-substituted
derivatives are of synthetic interest due to their unique
binding properties with metal ions.1 The addition of
different pendant arms can enhance the selectivity of
the azamacrocycle for a metal cation, or inorganic
anion depending on the cavity size and on the nature of
the substituents. N-substituted azamacrocycles have
found biomedical applications in magnetic resonance
imaging1c and in radioimmunotherapy.1d In addition,
we have shown that substituted azamacrocycles are also
potent inhibitors of HIV-1 replication.2,3 However,
methods for the regioselective N-functionalization of
azamacrocycles are scarce.4 Herein, we report the syn-
thesis of a selectively protected 14-membered triaza-
macrocyclic ring 7, which allows for functionalization
at any of the three nitrogen atoms and is applicable to
the synthesis of larger or smaller sized azamacrocyclic
rings.
ondary amine to afford compound 3 in 67% yield,
which contains three different nitrogen-protecting
groups. Selective deprotection of the N-tert-butoxycar-
bamate protecting group was achieved by stirring a
solution of 3 in CH2Cl2 in the presence of TFA for 40
min at room temperature, thus liberating the primary
amine 4 in a yield of 85%. This material readily under-
went N-acylation with bromoacetyl bromide in the
presence of Na2CO3 in THF at −15°C affording the
amide 5 in 89% yield. Intramolecular N-alkylation was
accomplished by employing high dilution conditions
(0.006 M) in the presence of K2CO3 as base in CH3CN
at 60°C resulting in isolation of the macrocycle 6 in
90% yield.7 With this compound in hand functionaliza-
tion at any of the nitrogen atoms is possible. For
instance, selective deprotection of the 2-nitrobenzene-
sulfonyl group was achieved using standard conditions8
to afford 7 in 77% yield. N-Alkylation of the liberated
secondary amine followed by protecting group removal
afforded a biological target, which was evaluated for
antiviral activity.9 We have also shown7 in a related
example that the DEP protecting group can be selec-
tively removed in the presence of a 2-nitrobenzenesul-
fonyl group. The amide function of 7 also serves as a
protecting group and we have shown7 that reduction to
the corresponding amine in the presence of a 2-
nitrobenzenesulfonamide protecting group can be
achieved using BH3·THF. Thus, it is possible using the
combination of protecting groups illustrated (Scheme 1)
to selectively functionalize at any nitrogen atom of the
azamacrocyclic ring.
Treatment of 1,7-diaminoheptane 1 (5 equiv.) with 1.0
equiv. of N-(2-nitrobenzenesulfonyl)aziridine5 in THF
at room temperature resulted in a 12:1 ratio of the
desired mono-alkylated product 2 (59% yield) to the
corresponding bis-alkylated product (5% yield). To the
best of our knowledge this is the first example of chain
homologation of an amine by nucleophilic ring opening
of N-(2-nitrobenzenesulfonyl)aziridine. Chemoselective
carbamate formation at the primary amine was accom-
plished by the addition of N-tert-butoxycarbonyl anhy-
dride (1 equiv.) to a solution of 2 in THF at −78°C to
afford the corresponding carbamate in 63% yield after
purification by flash column chromatography. Treat-
ment of the resulting carbamate with diethylphosphoryl
chloride6 (DEPCl) resulted in protection of the sec-
In conclusion, we have developed a method for the
synthesis of selectively protected triazamacrocycles,
which allows for functionalization at any ring nitrogen
atom.
* Corresponding author. E-mail: rskerlj@anormed.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01756-2

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R. T. Skerlj et al. / Tetrahedron Letters 43 (2002) 7569–7571
10
Scheme 1.
Acknowledgements
diluted with ethyl acetate (1000 mL) and the organic
phase washed with 1N aqueous NaOH (300 mL), satu-
rated aqueous NaHCO3 (300 mL), brine (300 mL) and
dried over Na2SO4. The organic layer was concentrated
to afford crude N-(2-hydroxyethyl)-2-nitrobenzenesulfon-
amide (72 g, 90%) which was carried on to the next step.
1H NMR (300 MHz, CD3OD) l 3.16 (t, J=5.9 Hz, 2H),
3.60 (t, J=5.9 Hz, 2H), 7.79–7.88 (m, 3H), 8.09–8.12 (m,
1H); 13C (75 MHz, CD3OD) l 46.97, 62.10, 126.44,
130.84, 132.82, 135.11, 135.43, 150.00. To a solution of
crude N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide (20
g, 81.22 mmol) and triethylamine (14.2 mL, 97.46 mmol)
in anhydrous CH2Cl2 (200 mL) at 0°C was added
methanesulfonyl chloride (6.27 mL, 81.00 mmol) in anhy-
drous CH2Cl2 (20 mL). The reaction mixture was stirred
at room temperature for 18 h, concentrated, diluted with
ethyl acetate (1000 mL) and the organic phase was
washed with saturated aqueous NaHCO3 (200 mL), brine
(200 mL) and dried over Na2SO4. Concentration followed
by purification of the crude material by flash chromato-
graphy on silica gel using ethyl acetate/hexanes (40:60) as
eluant gave the mesylate (15.8 g, 60%) as a white solid.
1H NMR (300 MHz, CDCl3) l 3.03 (s, 3H), 3.51 (t,
J=4.5 Hz, 2H), 4.31 (t, J=4.5 Hz, 2H), 5.83, (s, 1H),
7.76–7.78 (m, 2H), 7.90–7.91 (m, 1H), 8.14–8.16 (m, 1H);
13C (75 MHz, CD3OD) l 37.95, 43.26, 68.15, 126.11,
131.22, 133.51, 133.95, 134.41, 150.20. To a solution of
methanesulfonic acid 2-(2-nitrobenzenesulfonylamino)
ethyl ester (16.10 g, 49.3 mmol) in anhydrous benzene
(350 mL) at room temperature was added KOH (16.3 g,
28.5 mmol) in H2O (88 mL). The reaction mixture was
stirred at room temperature for 1 h, concentrated, diluted
with ethyl acetate (1000 mL) and the organic phase was
washed with water (250 mL), brine (300 mL) and dried
over Na2SO4. The organic layer was concentrated and the
crude material was isolated as a white solid (11.7 g, 90%).
1H NMR (300 MHz, CDCl3) l 2.54 (s, 4H), 7.74–7.80
(m, 3H), 8.22–8.24 (m, 1H); 13C (75 MHz, CDCl3) l
29.80, 124.77, 128.74, 131.44, 132.73, 135.32, 148.86.
We thank the Analytical group at AnorMED for
support.
References
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Chem. Soc. Rev. 1990, 19, 271.
2. For a review on azamacrocycles as anti-HIV agents see:
Advances in Antiviral Drug Design; Bridger, G. J.; Skerlj,
R. T.; DeClercq, E., Ed; Jai Press: Connecticut, 1999;
Vol. 3, p. 161.
3. (a) Bridger, G. J.; Skerlj, R. T.; Padmanabhan, S.;
Martellucci, S. A.; Henson, G. W.; Struyf, S.; Witvrouw,
M.; Schols, D.; De Clercq, E. J. Med. Chem. 1999, 42,
3971; (b) Bridger, G. J.; Skerlj, R. T.; Padmanabhan, S.;
Martelluci, S. A.; Henson, G. W.; Abrams, M. J.; Joao,
H. C.; Witvtouw, M.; De Vreese, K.; Pauwels, R.; De
Clercq, E. J. Med. Chem. 1996, 39, 109; (c) Bridger, G. J.;
Skerlj, R. T.; Thornton, D.; Padmanabhan, S.; Martel-
luci, S. A.; Henson, G. W.; Abrams, M. J.; Yamamoto,
N.; De Vreese, K.; Pauwels, R.; De Clercq, E. J. Med.
Chem. 1995, 38, 366.
4. For a recent review on regioselective functionalization of
tetraazacycloalkanes see: Denat, F.; Brandes, S.; Guilard,
R. Synlett 1999, 5, 561.
5. Experimental procedure for the synthesis of N-(2-
nitrobenzenesulfonyl)aziridine: To
a
solution of
ethanolamine (20 g, 327 mmol) and triethylamine (15 mL,
103 mmol) in anhydrous CH2Cl2 (280 mL) at 0°C was
added 2-nitrobenzenesulfonylchloride (73 g, 327 mmol) in
anhydrous CH2Cl2 (30 mL). The reaction mixture was
stirred at room temperature for 18 h, concentrated,

R. T. Skerlj et al. / Tetrahedron Letters 43 (2002) 7569–7571
7571
6. Qian, L.; Sun, Z.; Mertes, M. P.; Mertes, K. B. J. Org.
Chem. 1991, 56, 4904.
7. Skerlj, R. T.; Zhou, Y.; Wilson, T.; Bridger, G. J. J. Org.
Chem. 2002, 67, 1407.
8. Fukuyama, T.; Chueng, M.; Jow, C.-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831.
4.59 (br s, 1H), 6.22 (br s, 1H), 7.68–7.74 (m, 2H),
7.77–7.82 (m, 1H), 8.05–8.11 (m, 1H); 13C NMR (75
MHz, CDCl3) l 16.48 (2C, 3JPC=7.5 Hz), 26.97, 28.80
(3C), 29.30, 29.47, 30.33, 40.87, 42.86 (2C), 45.83 (d,
2JPC=5.2 Hz), 47.03 (d, 2JPC=3.6 Hz), 62.99 (2C, d,
2JPC=5.7 Hz), 79.37, 125.54, 131.15, 132.96, 133.91,
134.01, 148.48, 156.41, exact mass m/z calcd for
C24H43N4O9PS 594.2, found 595.3 [M+H]+; Compound 4:
1H NMR (300 MHz, CDCl3) l 1.28–1.33 (m, 12H),
1.42–1.51 (m, 4H), 2.60–2.67 (m, 5H), 2.87–2.96 (m, 2H),
3.20–3.22 (m, 4H), 4.00–4.07 (m, 4H), 7.70–7.73 (m, 2H),
7.81–7.82 (m, 1H), 8.09–8.12 (m, 1H); exact mass m/z
calcd for C19H35N4O7SP 494.2, found 495.2 [M+H]+;
9. Skerlj, R. T.; Bridger, G. J., unpublished results.
10. Experimental procedure for the synthesis of compound 2
and characterization data for compounds 2–7: To a
stirred solution of 1,7-diaminoheptane (33.4 g, 256.30
mmol) in anhydrous THF (220 mL) at room temperature
was added dropwise N-(2-nitrobenzenesulfonyl)aziridine
(11.7 g, 51.30 mmol) in anhydrous THF (80 mL). After
the addition was complete the mixture was stirred for 20
min at room temperature and concentrated in vacuo to
afford crude product as a yellow oil. The oil was purified
by silica gel chromatography using MeOH/NH4OH/
CH2Cl2 (1:1:18) as eluant to give compound 2 (10.9 g,
59% yield based on the aziridine) as a yellow oil. The
bis-alkylated product (1.5 g, 5%) was also isolated as a
1
Compound 5: H NMR (300 MHz, CDCl3) l 1.25–1.56
(m, 16H), 2.90–2.98 (m, 2H), 3.21–3.31 (m, 6H), 3.88 (s,
2H), 3.95–4.09 (m, 4H), 6.12 (br s, 1H), 6.60 (br s, 1H),
7.71–7.76 (m, 2H), 7.82–7.86 (m, 1H), 8.10–8.13 (m, 1H);
81
36
exact mass m/z calcd for C21H BrN4O8PS 616.1, found
617.1 [M+H]+; Compound 6: 1H NMR (300 MHz,
CDCl3) l 1.25–1.70 (m, 16H), 2.90–2.99 (m, 2H), 3.19–
3.47 (m, 6H), 3.93–4.04 (m, 6H), 6.30 (t, J=6.0 Hz, 1H),
7.65–7.69 (m, 1H), 7.72–7.77 (m, 2H), 8.16–8.19 (m, 1H);
exact mass m/z calcd for C21H35N4O8PS 534.1, found
535.2 [M+H]+; Compound 7: 1H NMR (300 MHz,
CDCl3) l 1.32 (dt, J=7.2, 0.6 Hz, 6H), 1.39–1.60 (m,
11H), 2.70 (t, J=7.4 Hz, 2H), 2.93–3.01 (m, 2H), 3.18–
3.26 (m, 2H), 3.30 (s, 2H), 3.33–3.36 (m, 2H), 3.93–4.05
(m, 4H), 7.41 (br s, H), exact mass m/z calcd for
C15H32N3O4P 349.1, found 350.2 [M+H]+.
1
yellow oil. Compound 2: H NMR (300 MHz, CDCl3) l
1.27–1.42 (m, 10H), 2.09 (br s, 4H), 2.47 (t, J=7.1 Hz,
2H), 2.67 (t, J=6.9 Hz, 2H), 2.73–2.77 (m, 2H), 3.14 (t,
J=6.0 Hz, 2H), 7.71–7.77 (m, 2H), 7.84–7.89 (m, 1H),
8.12–8.16 (m, 1H); exact mass m/z calcd for
C15H26N4O4S 358.1, found 359.2 [M+H]+; Compound 3:
1H NMR (300 MHz, CDCl3) l 1.24–1.25 (m, 8H), 1.28
(t, J=7.2 Hz, 6H), 1.41 (br s, 11H), 2.85–2.93 (m, 2H),
3.03–3.09 (m, 2H), 3.18–3.21 (m, 4H), 3.91–4.08 (m, 4H),