Synthesis of optically pure diaza-12-crown-4 with a pendant group

Article abstract of DOI:10.1081/SCC-120004151

The optically pure diaza-12-crown-4 that has a 2-hydroxymethyl sidearm is synthesized in fully protected form, starting from (R)-1-O-benzylglycerol.

Full text of DOI:10.1081/SCC-120004151

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
SYNTHESIS OF OPTICALLY PURE DIAZA-12-
CROWN-4 WITH A PENDANT GROUP
Chi-Wan Lee
To cite this article: Chi-Wan Lee (2002) SYNTHESIS OF OPTICALLY PURE DIAZA-12-
CROWN-4 WITH A PENDANT GROUP, Synthetic Communications, 32:10, 1595-1600, DOI:
10.1081/SCC-120004151
To link to this article: http://dx.doi.org/10.1081/SCC-120004151
Published online: 12 Dec 2006.
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SYNTHETIC COMMUNICATIONS, 32(10), 1595–1600 (2002)
SYNTHESIS OF OPTICALLY
PURE DIAZA-12-CROWN-4 WITH
A PENDANT GROUP
Chi-Wan Lee1
Department of Chemistry, Center for Superfunctional
Materials, Pohang University of Science and
Technology, San 31, Hyoja-dong, Namgu,
Pohang 790-784, Korea
Fax: 215-349-5035;
E-mail: cwlee@sunmac.spect.upenn.edu
ABSTRACT
The optically pure diaza-12-crown-4 that has a 2-hydroxy-
methyl sidearm is synthesized in fully protected form, starting
from (R)-1-O-benzylglycerol.
Crown ethers bearing pendant groups are important intermediates for
their immobilization on polymers2–5 and transformation into more complex
lariat crown ethers6–9 such as ionizable crown ethers,10–13 bis-crown
ethers14–16 and chromogenic crown ethers.17,18 Although racemates of func-
tionalized diaza-crown compounds are known,19–22 only a few reports are
found in the literature for optically pure aza-crown compounds with a
pendant group.23–25 Here we describe the synthesis of fully protected
diaza-12-crown-4 that has a hydroxymethyl pendant group.
The synthesis was carried out using protected glycerol 1 as the starting
material.26 Initially, we studied the coupling between benzylamine and
1595
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Scheme 1.
dimesylate 5, which is prepared along with Scheme 1, an apparently more
direct approach to diaza-12-crown-4, but we could not obtain the desired
diaza-12-crown-4 product in any appreciable amount.
It was reasoned that the intramolecular cyclization at the sterically
more hindered mesylate site in dimesylate 5 was hampered. Therefore, we
modified the synthetic route as shown in Scheme 2 to avoid this problem.
Protection of the hydroxyl group in 1 as acetate, and deprotection of the
benzyl group and subsequent tosylation, gave tosylate 7b in overall 78%
yield. Coupling of this tosylate 7b with tosylamide 327 produced chain
extended acetate 8 in 65% yield. Hydrolysis of the acetate with K2CO3 in
methanol followed by mesylation gave dimesylate 9 in overall 82% yield.
Scheme 2.

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OPTICALLY PURE DIAZA-12-CROWN-4
1597
Finally, coupling of dimesylate 9 with benzylamine with Na2CO3 in reflux-
ing acetonitrile afforded homochiral, fully protected diaza-12-crown-4 10
in 76% yield. In this case, the template effect of sodium cation presumably
accounts for the good coupling yield.
In summary, the presently described synthetic routes allow prepara-
tion of optically pure diaza-12-crown-4 with a pendant group. Moreover,
depending on the selective deprotection of three different protecting groups
of diaza-12-crown-4 10, this functionalized diaza crown compound can
serve as a versatile compound for further investigations on organic and
supramolecular chemistry.
EXPERIMENTAL
General Procedures
All reagents were commercial products and were used without
further purification. Flash column chromatography was performed on
230–400 mesh silica gel. Low and high resolution mass analyses were per-
formed by Taejon Analytical Laboratory of Korea Basic Science Institute.
1H NMR spectra were recorded on 300 MHz NMR spectrometer, and
chemical shifts d are in parts per million relative to TMS.
(S)-2-O-(2-Acetoxyethyl)-1-O-benzyl-3-O-(tert-butyldiphenylsilyl)glyce-
rol (6): To a pyridine (30 ml) solution of 1 (4.64 g, 10 mmol) at 0ꢀC was
added portionwise Ac2O (1.12 g, 11 mmol). After being stirred for 10 h at
room temperature, the reaction mixture was diluted with ether (50 ml), and
washed with brine. The ethereal layer was dried over MgSO4 and con-
centrated. The residue was purified by flash chromatography (9 : 1, hexanes–
23
ethyl acetate) to give 6 (4.6 g, 90%) as a colorless oil. ½aŠ À 7:92
D
1
(c 10.13 : CHCl3); H NMR (CDCl3) d 1.05 (s, 9H), 2.02 (s, 3H), 3.7–3.8
(m, 7H), 4.2 (m, 2H), 4.55 (s, 2H), 7.3–7.4 (m, 11H), 7.6–7.7 (m, 4H)
13C NMR (CDCl3) d 19.2, 20.9, 26.8, 63.5, 64.0, 68.4, 70.1, 73.4, 80.1,
127.5, 127.6, 128.3, 129.7, 133.3, 133.4, 135.6, 138.2, 171.1; FAB-MS m/z
507.1 ([M þ H]þ, calcd 507.2).
(S)-2-O-(2-Acetoxyethyl)-1-O-(tert-butyldiphenylsilyl)glycerol (7a): An
ethanol (40 ml) solution of 1-O-benzylglycerol 6 (4.6 g, 9 mmol) was
subjected to hydrogenolysis in the presence of 10% Pd/C (1 g) at room
temperature for 10 h under balloon-filled hydrogen atmosphere. Filtration
of the catalyst and evaporation of the solvent afforded 3.7 g (8.8 mmol) of
23
D
1
7a in 98% yield. ½aŠ À 17:15 (c 8.16 : CHCl3); H NMR (CDCl3) d 1.10
(s, 9H), 2.06 (s, 3H), 3.6–3.8 (m, 7H), 4.1–4.2 (m, 2H), 7.3–7.5 (m, 6H),
7.7 (m, 4H); 13C NMR (CDCl3) d 19.0, 20.8, 26.7, 62.5, 63.4, 63.7, 68.4, 81.1,

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1598
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127.7, 129.7, 133.0, 133.1, 135.5, 171.0; FAB-MS m/z 417.1 ([M þ H]þ,
calcd 417.2).
(R)-2-O-(2-Acetoxyethyl)-1-O-(tert-butyldiphenylsilyl)-3-O-( p-toluene-
sulfonyl)glycerol (7b): To pyridine (30 ml) solution of 7a (3.7 g, 8.8 mmol) at
0ꢀC was added portionwise p-toluenesulfonyl chloride (1.7 g, 8.8 mmol).
After being kept in a refrigerator for 16 h, the reaction mixture was diluted
with ether (50 ml), and washed with brine. The ethereal layer was dried over
MgSO4 and concentrated. Purification of the residue by flash chromato-
graphy (9 : 1, hexanes–ethyl acetate) gave 7b (4.2 g, 88%) as a colorless
23
D
1
oil. ½aŠ À 12:70 (c 9.00 : CHCl3); H NMR (CDCl3) d 1.01 (s, 9H), 2.01 (s,
3H), 2.42 (s, 3H), 3.6 (m, 5H), 4.0–4.1 (m, 3H), 4.2–4.3 (m, 1H), 7.3–7.4 (m,
8H), 7.6 (m, 4H), 7.8 (m, 2H); 13C NMR (CDCl3) d 19.1, 20.8, 21.6, 26.6,
62.2, 63.5, 68.5, 69.5, 78.3, 127.7, 127.9, 129.79, 129.82, 132.8, 132.9, 135.4,
135.5, 144.8, 170.9; FAB-MS m/z 571.2 ([M þ H]þ, calcd 571.2).
(S)-1-Acetoxy-4-[(tert-butyldiphenylsilyloxy)methyl]-6-N-( p-toluenesul-
fonyl)-6-aza-3,9-dioxa-11-undecanol (8): A mixture of sulfonamide 3 (1.9 g,
7.4 mmol), tosylate 7b (4.2 g, 7.4 mmol), and anhydrous K2CO3 (3 g,
22 mmol) in DMF (50 ml) was refluxed for 2 days with vigorous stirring.
The reaction mixture was cooled to room temperature, and the precipitate
was filtered and washed with CH2Cl2. The filtered solution was con-
centrated, and the residue was purified by column chromatography (4 : 1,
hexanes–ethyl acetate) to give 8 (2.8 g, 4.3 mmol, 65%) as a colorless oil.
23
1
½aŠ À 18:81 (c 2.1 : CHCl3); H NMR (CDCl3) d 1.05 (s, 9H), 2.02 (s, 3H),
D
2.40 (s, 3H), 3.1–3.2 (m, 1H), 3.5–3.7 (m, 14H), 4.1 (m, 2H), 7.2–7.7 (m,
14H); 13C NMR (CDCl3) d 19.2, 20.9, 21.5, 26.8, 49.1, 50.4, 61.6, 63.67,
63.71, 68.3, 69.3, 72.3, 80.4, 127.3, 127.7, 129.6, 129.8, 133.0, 133.1, 135.6,
136.5, 143.3, 171.0; FAB-MS m/z 658.3 ([M þ H]þ, calcd 658.3); HRMS
calcd 658.2870 for C34H48NO8SSi ([M þ H]þ), found 658.2896.
(S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-6-N-( p-toluenesulfonyl)-6-
aza-3,9-dioxa-1,11-bis(methanesulfonyloxy)undecane (9): A mixture of 8
(2.8 g, 4.3 mmol) and K2CO3 (690 mg, 5 mmol) in MeOH/H2O (10 ml, 1 : 1)
was stirred for 8 h at room temperature. The reaction mixture was extracted
with CH2Cl2. The organic layer was dried over MgSO4, concentrated, and the
residue was purified by flash chromatography (1 : 1, hexanes–ethyl acetate) to
give diol (2.2 g, 83%) as a colorless oil, which was subjected to the next step
without purification. To a pyridine (20 ml) solution of the diol (2.2 g,
3.6 mmol) at 0ꢀC was added methanesulfonyl chloride (0.84 g, 7.2 mmol),
and the resulting mixture was stirred overnight. The reaction mixture was
poured into a mixture of ice (50 g) and 2 N HCl (25 ml), and then extracted
with CH2Cl2 (3 ꢁ 40 ml). The organic layer was washed with brine, dried over
MgSO4, and concentrated. Purification of the residue by flash chromatogra-
23
D
phy (4 : 1, hexanes–ethyl acetate) gave 9 (2.7 g, 3.5 mmol, 99%). ½aŠ À 13:73

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OPTICALLY PURE DIAZA-12-CROWN-4
(c 2.54 : CHCl3); 1H NMR (CDCl3)
1599
d
1.04 (s, 9H), 2.42 (s, 3H),
2.99 (s, 3H), 3.1–3.7 (m, 13H), 4.2–4.3 (m, 4H), 7.2–7.3 (m, 2H), 7.4 (m,
6H), 7.6–7.7 (m, 6H); 13C NMR (CDCl3) d 19.2, 21.5, 26.8, 37.5, 37.6, 49.3,
50.9, 63.7, 68.1, 68.6, 68.8, 69.0, 69.7, 80.3, 127.3, 127.8, 129.7, 129.9, 133.1,
135.6, 136.2, 143.5; FAB-MS m/z 772.2 ([M þ H]þ, calcd 772.2).
(S)-2-[(tert-Butyldiphenylsilyloxy)methyl]-4-( p-toluenesulfonyl)-10-
benzyl-4,10-diaza-1,7-dioxacyclododecane (10): A mixture of 9 (2.7 g,
3.5 mmol), benzylamine (375 mg, 3.5 mmol), and anhydrous Na2CO3 (1.1 g,
10.5 mmol) in MeCN (40 ml) was refluxed for 40 h with vigorous stirring.
The reaction mixture, cooled at room temperature, was filtered and
the filtered solution was concentrated. The residue was purified by flash
chromatography (1 : 1, hexanes–ethyl acetate) to give 10 (1.8 g, 76%).
23
D
1
½aŠ À 21:31 (c 1.22 : CHCl3); H NMR (CDCl3) d 1.03 (s, 9H), 2.41 (s,
3H), 2.6–2.7 (m, 4H), 3.01 (m, 2H), 3.5–3.9 (m, 13H), 7.2–7.4 (m, 13H),
7.6–7.7 (m, 6H); 13C NMR (CDCl3) d 19.2, 21.5, 26.8, 29.7, 51.2, 52.7, 54.7,
55.0, 61.1, 64.0, 69.0, 69.2, 79.3, 126.9, 127.1, 127.5, 127.7, 128.2, 128.5,
128.9, 129.6, 129.7, 133.4, 135.6, 139.3, 143.1; FAB-MS m/z 687.3
([M þ H]þ, calcd 687.3); HRMS calcd 687.3288 for C39H51N2O5SSi
([M þ H]þ), found 687.3300.
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Received in the USA June 6, 2001