Synthesis of mono protected 1,10-diaza-18-crown-6

Article abstract of DOI:10.1081/SCC-200031029

A synthetic procedure for the preparation of unsymmetrically protected 1,10-diaza-18-crown-6 has been elaborated. In contrast to previously published routes, no unprotected 1,10-diaza-18-crown-6 is needed as precursor and cheap bulk chemicals can be used.

Full text of DOI:10.1081/SCC-200031029

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Synthesis of Mono Protected
1,10‐Diaza‐18‐Crown‐6
Christian P. Mandl a & Burkhard König a
a Institut für Organische Chemie, Universität
Regensburg , D‐93040, Regensburg, Germany
Published online: 10 Jan 2011.
To cite this article: Christian P. Mandl & Burkhard König (2004) Synthesis of Mono
Protected 1,10‐Diaza‐18‐Crown‐6, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:19, 3573-3578,
DOI: 10.1081/SCC-200031029
To link to this article: http://dx.doi.org/10.1081/SCC-200031029
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 19, pp. 3573–3578, 2004
Synthesis of Mono Protected
1,10-Diaza-18-Crown-6
*
¨
Christian P. Mandl and Burkhard Konig
¨
Institut fu¨r Organische Chemie, Universitat Regensburg,
D-93040 Regensburg, Germany
ABSTRACT
A synthetic procedure for the preparation of unsymmetrically protected
1,10-diaza-18-crown-6 has been elaborated. In contrast to previously
published routes, no unprotected 1,10-diaza-18-crown-6 is needed as
precursor and cheap bulk chemicals can be used.
Key Words: Azacrown ether; Macrocycle; Cyclization.
Crown ethers are widely used for recognition of alkali and ammonium
cations. In contrast to regular crown ethers, aza crowns have the advantage
of simplified functionalization due to their nucleophilic nitrogen atoms.
*
¨ ¨
¨
Correspondence: Burkhard Konig, Institut fur Organische Chemie, Universitat
Regensburg, D-93040 Regensburg, Germany; E-mail: burkhard.koenig@chemie.uni-
regensburg.de.
3573
DOI: 10.1081/SCC-200031029
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

¨
Mandl and Konig
3574
Therefore, they have been used to generate ion channels,[1] lariat ethers,[2,3]
fluorescence responsive sensors,[4] and cryptands.[5]
Diaza crown ethers offer even more possibilities to generate new crown-
derived structures. Applicability is admittedly restricted by the similar reactiv-
ity of the crown nitrogens. Thus, fewer asymmetric, monosubstituted diaza
crown ethers have been synthesized due to the imminent loss of reaction
yield by the inevitable creation of the doubly substituted crown ether as
well. Hall et al. have reported two ways to generate mono-boc-protected
diaza crown ethers. Treatment of 1,10-diaza-18-crown-6 with 1 equivalent
of Boc-anhydride generates the mono-boc derivative in 44% yield.[6] The
other published route[7] starts off with the two-fold substituted 1,7-diaza-18-
crown-6 followed by selective removal of one of the two Boc-groups by treat-
ment with TFA and precipitation of the product. Although both routes are
reliable, they still require a diaza-crown precursor that is not always com-
mercially available or rather expensive as for 1,10-diaza-18-crown-6. As we
needed protected diaza crown ethers, we investigated for a way to synthesize
asymmetrically substituted diaza crown ethers by using cheaper bulk chemi-
cals. We report herein the synthesis of mono-boc-protected 1,10-diaza-18-
crown-6 in four steps, which is capable of generating the desired product at
reasonable costs.
Diethanolamine 1 was converted into N-Boc-diethanolamine 2 by follow-
ing a reported procedure.[8] Protected 2 was then substituted twice with
1,10-dichloro ethyl ether 3 in a phase transfer reaction using nBu4NHSO4 as
a phase transfer catalyst. The yield of 4 was 59%, whereas an attempted reac-
tion with N-Cbz-diethanolamine under the same conditions was not successful
at all. This is probably due to the lower stability against nucleophiles of a
Cbz group compared to a Boc group. The crown ether precursor 4 was then
cyclized with benzylamine to give the Bn- and Boc-protected diaza crown
ether 5 with a 29% yield. Other amines can be used instead of benzylamine
as long as they do not have functionalities that are vulnerable to nucleophilic
attack. Deprotection of the benzyl group is easily performed with a 88% yield
with dihydrogen and Pd/C as catalyst to form the mono-Boc-protected diaza
crown ether 6.
In summary, a way has been elaborated which gives unsymmetrically pro-
tected 1,10-diaza-18-crown-6 without the use of the unprotected crown ether
but with cheap bulk chemicals.
EXPERIMENTAL
General. IR spectra: Bio-Rad FTS 3000 FT-IR. 1H- and 13C-NMR
spectra: Bruker AC 250 or Bruker Avance 300; at 300 K; TMS as the internal

Mono Protected 1,10-Diaza-18-Crown-6
3575
Scheme 1. Synthesis of mono-Boc-protected diaza crown ether 6.
standard; s ¼ singlet, bs ¼ broad singlet, m ¼ multiplet; the multiplicity of
the 13C signals was determined using the DEPT technique and is quoted as
(þ) for CH3 or CH, (2) for CH2 and (Cquat) for quaternary carbons. Eleme-
ntal analysis was carried out by the microanalytical laboratory, University
of Regensburg. Commercially available reagents were used as received.

¨
Mandl and Konig
3576
Thin-layer chromatography (TLC) was performed on alumina sheets (Merck
KgaA, 20 ꢀ 20 cm, Silica gel 60 F254).
Bis-f2-[2-(2-chloro-ethoxy)-ethoxy]-ethylg-carbamic acid tert-butyl
ester (4). Bis-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (2, 2.1 g,
10.2 mmol) was dissolved in 18 mL of 1,10-dichlorodiethyl ether (3, 22 g,
154 mmol). The mixture was cooled to 08C and 3.4 g (10 mmol) of
nBu4NHSO4 and 18 mL of 50% NaOH aq. solution was added. After stirring
for 2 d at room temperature, the mixture was diluted with 100 mL of H2O
and extracted with diethyl ether (100 mL). The aqueous phase was extracted
twice with diethyl ether (50 mL). The combined organic phases were washed
with H2O (50 mL), dried over MgSO4, and the solvent was evaporated in
vacuum. The remaining 1,10-dichlorodiethyl ether was distilled off prior to
column chromatography on silica gel with PE/EE 70/30 ! 60/40 (Rf (60/
40) ¼ 0.46). Compound 4 (2.54 g, 59%) was obtained as a colorless liquid.
1H NMR (300 MHz, CDCl3): d ¼ 1.45 (s, 9 H), 3.43–3.45 (m, 4 H),
3.57–3.67 (m, 16 H), 3.73–3.77 (m, 4 H).
13C NMR (75 MHz, CDCl3): d ¼ 28.5 (þ), 42.7 (2), 47.6 (2), 47.8 (2),
69.7 (2), 69.9 (2), 70.3 (2), 70.4 (2), 70.7 (2), 71.4 (2), 79.6 (Cquart), 155.5
(Cquart).
IR (NaCl): n (cm21) ¼ 2968 (m), 2869 (m), 1692 (s), 1463 (m), 1410 (m),
¯
1366 (m), 1294 (m), 1244 (m), 1146 (s), 1121 (s), 1064 (m), 972 (w), 920 (w),
865 (w), 747 (w), 667 (w).
MS (CI-MS, NH3): e/z (%) ¼ 418 (64, MHþ), 379 (58, M þ NH4þ
–
C4H8), 362 (83, MHþ – C4H8), 318 (100, MHþ – C4H8 – CO2), 180 (31).
C17H33Cl2NO6: calcd.: C, 48.81; H, 7.95; N, 3.35; Cl, 16.95; found: C,
48.59; H, 7.53; N, 3.20; Cl, 16.76.
16-Benzyl-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane-7-carboxylic
acid tert-butyl ester (5). Bis-f2-[2-(2-chloro-ethoxy)-ethoxy]-ethylg-carbamic
acid tert-butyl ester (4, 160 mg, 0.38 mmol) was dissolved in 5 mL of
acetonitrile with 50 mL of H2O. Benzylamine (44 mL, 43 mg, 0.4 mmol),
KI (133 mg, 0.8 mmol), and K2CO3 (552 mg, 4 mmol) were added and the
suspension was refluxed for 2 d. After cooling to room temperature,
the mixture was filtered over Celite and the remaining solids were
washed with CHCl3. Evaporation of the combined organic phases gave
an oil that was purified by column chromatography (silica, EE/EtOH 20/
1 ! 10/1, Rf(10/1) ¼ 0.23). Compound 5 (50 mg, 29%) was obtained
as a colorless oil.
1H NMR (300 MHz, CDCl3): d ¼ 1.45 (s, 9 H), 2.84 (bs, 4 H), 3.49–3.53
(m, 4 H), 3.51–3.62 (m, 16 H), 3.71 (bs, 2 H), 7.23–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d ¼ 28.5 (þ), 48.0 (2), 48.1 (2), 53.6 (2),
59.9 (2), 70.0 (2), 70.5 (2), 70.7 (2), 70.8 (2), 79.5 (Cquart), 127.1 (þ), 128.3 (þ),
129.0 (þ), 136.3 (Cquart), 155.5 (Cquart).

Mono Protected 1,10-Diaza-18-Crown-6
3577
IR (NaCl): n (cm21) ¼ 3482 (bw), 2926 (m), 2868 (m), 1693 (s), 1456
¯
(m), 1409 (m), 1364 (m), 1289 (m), 1246 (m), 1152 (s), 1122 (s), 927 (w),
736 (w), 698 (w). MS (ESI-MS, CH2Cl2/MeOH þ 10 mmol/l NH4OAc):
e/z (%) ¼ 475 (25, M þ Naþ), 453 (100, MHþ).
1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-7-carboxylic acid tert-
butyl ester (6). 16-Benzyl-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane-7-
carboxylic acid tert-butyl ester (5, 50 mg, 0.11 mmol) was dissolved in
20 mL of MeOH and 10% Pd/C were added. The mixture was pressurized
with 10 bar H2 over 2 d at 508C. The solvent was evaporated after removal
of the catalyst by filtration through Celite. Compound 6 (35 mg, 88%) was
obtained as a colorless oil.
1H NMR (300 MHz, CDCl3): d ¼ 1.43 (s, 9 H), 2.84–2.87 (m, 4 H),
3.48–3.51 (m, 4 H), 3.59–3.65 (m, 16 H).
13C NMR (75 MHz, CDCl3): d ¼ 28.5 (þ), 47.5 (2), 48.0 (2), 49.1 (2),
69.6 (2), 69.9 (2), 70.2 (2), 70.7 (2), 79.5 (Cquart), 155.5 (Cquart).
IR (NaCl): n (cm21) ¼ 3491 (bw), 2976 (m), 2871 (m), 1692 (s), 1460
¯
(m), 1411 (m), 1364 (m), 1289 (m), 1246 (m), 1150 (s), 1120 (s), 773 (w).
MS (ESI-MS, CH2Cl2/MeOH þ 10 mmol/l NH4OAc): e/z (%) ¼ 363
(100, MHþ).
ACKNOWLEDGMENT
We thank the Fonds der Chemischen Industrie for support of this work.
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Received in Poland May 25, 2004