Syntheses of armed-macrocycles by reductive amination using NaBH(OAc) 3 under 1 MPa

Article abstract of DOI:10.1002/jhet.5570430123

Armed-monoaza-12-crown-4, monoaza-15-crown-5, diaza-12-crown-4, diaza-18-crown-6 ethers, and 1,4,7,10-tetraazacyclododecane having aromatic pendants were prepared by the reductive animation of the corresponding macrocycles with aromatic carboxyaldehydes i

Full text of DOI:10.1002/jhet.5570430123

Jan-Feb 2006
157
Syntheses of Armed-Macrocycles by Reductive Amination using
NaBH(OAc) under 1 MPa
3
Yoichi Habata*!, Futoshi Osaka, and Sachiko Yamada
Department of Chemistry, Faculty of Science, Toho University, Funabashi, Chiba 274-8510, Japan
!) Research Center for Materials with Integrated Properties, Toho University, Chiba 274-8510, Japan
* habata@chem.sci.toho-u.ac.jp
Received July 1, 2005
Armed-monoaza-12-crown-4, monoaza-15-crown-5, diaza-12-crown-4, diaza-18-crown-6 ethers, and
1,4,7,10-tetraazacyclododecane having aromatic pendants were prepared by the reductive amination of the cor-
responding macrocycles with aromatic carboxyaldehydes in the presence of NaBH(OAc) . Reductive amina-
3
tion under 1 MPa conditions provided significant shortening of the reaction time and yield enhancements.
J. Heterocyclic Chem., 43, 157 (2006).
The reductive amination using NaBH(OAc) as a reduc-
3
ing agent has been used to prepare many primary-, sec-
ondary- and tertiary-aliphatic, aromatic, and aliphatic-aro-
matic amines [1]. Recently, reductive amination was
applied to prepare armed-azacrown ethers having aromatic
pendants as additional binding sites, and those ligands
showed specific cation binding abilities toward several
metal ions [2]. We also have reported that 4-pyridylmethyl
armed-monoaza-15-crown-5 ether, which was prepared by
the reductive amination of monoaza-15-crown-5 with 4-
pyridinecarboxyaldehyde in the presence of NaBH(OAc) ,
3
formed a [3.3]paracyclophane-like silver complex [3]. In
order to further investigate effects of crown ring size, num-
ber of side-arms and structures of the side-arms of metal
complexes, we have prepared new armed-monoaza- and
diazacrown ethers, and cyclens having aromatic side arms.
When diazacrown ethers and 1,4,7,10-tetraazacyclodode-
cane were reacted with aromatic carbaldehydes in the pres-
ence of NaBH(OAc) in 1,2-dichloroethane, long reaction
3
times were required to finish the reaction. It is known that

158
Y. Habata, F. Osaka, and S. Yamada
Vol. 43
General Procedures for the Reaction of Monoazacrown Ethers
with Pyridinecarbaldehydes or 3,5-Difluorobenzene-
carblaldehyde.
the reductive amination using NH and H /Ni can be car-
ried out under high pressure [4]. This prompted us to carry
3
2
out the reductive amination using NaBH(OAc) under
3
After a mixture of monoazacrown ethers (10.0 mmol), aro-
high pressure conditions. Here, we report that the reduc-
tive amination under 1 MPa pressure is a useful procedure
to synthesize the armed-macrocycles (1-15).
matic aldehydes (15.1 mmol), NaBH(OAc) (20.2 mmol) in 1,2-
3
dichloroethane was stirred for 24 hours at rt under atmospheric
pressure or 1 MPa (Argon atmosphere), saturated aqueous
The experimental procedures are very simple and involve
NaHCO was added. The organic layer was separated, and the
3
stirring aromatic carbaldehydes, amines, and NaBH(OAc)
3
aqueous layer was extracted with chloroform (40 mL x 3). The
combined organic layer was washed with water, dried over
sodium sulfate, and concentrated. The residual yellow oil was
separated and purified by gel-permiation column chromatogra-
phy to give the following products.
in 1,2-dichloroethane at rt under 1 MPa (Argon atmos-
phere) as shown in Scheme 1. Reaction end times were
checked by TLC. Structures of new compounds were con-
1
firmed by H NMR, FABMS and elemental analyses.
The results are summarized in Table 1. When
monoaza-12-crown-4 and monoaza-15-crown-4 ethers
were used as the amine (entries 1-4 and 6-7), yields of
the corresponding armed-azacrown ethers were
increased about 1.1-1.9 times over those at atmospheric
conditions at the same reaction time. Reaction times
were reduced to half in the case of the reaction of
monoaza-15-crown-5 with 3,5- difluorobenzenecar-
baldehyde (entry 5). Preparation of double armed-diaza-
crown ethers required longer reaction times (72-144 h)
than those of the monoazacrown derivatives. In all cases
(entries 8-13), reaction times were shortened using the
higher pressure. Especially, yields of diaza-18-crown-6
derivatives having 4-pyridylmethyl and 3-pyridylmethyl
groups as side arms (entries 12 and 13) were signifi-
cantly increased by 3.3 and 3.9 times, respectively, than
under atmospheric conditions. When 1,4,7,10-tetraaza-
cyclododecane was used as an amine under 1 MPa pres-
sure conditions, reaction time was significantly short-
ened (72 h → 24 h) and yields increased about 1.2-1.4
times (entries 14 and 15). Yields of compounds 14 and
15 increased about 1.7 times, when the reaction times
were elongated for 72 h under 1 MPa.
N-(4-Pyridylmethyl)-1,4,7-trioxa-10-azacyclododecane (1).
Colorless crystals; mp 54.0-55.0 °C (recrystallized from
1
hexane); H nmr (deuteriochloroform): δ 8.53 (d, 2H, J = 5.9 Hz,
2H), 7.37 (d, J = 5.9 Hz, 2H), 3.80-3.69 (m, 10H), 3.67 (t, J = 5.0
Hz, 4H), 2.78 (t, J = 5.0 Hz, 4H); FABMS (NBA as a matrix):
+
266 ([M+1] , 100 %).
Anal. Calcd. for C
H N O : C, 63.14; H, 8.33; N, 10.52.
14 22 2 3
Found: C, 62.99; H, 8.46; N, 10.43.
N-(3-Pyridylmethyl)-1,4,7-trioxa-10-azacyclododecane (2).
1
Hygroscopic yellow oil; H nmr (deuteriochloroform): δ 8.58
(d, J = 1.8 Hz, 1H), 8.50 (dd, J = 4.9 and 1.8 Hz, 1H), 7.75 (d, J =
7.7 Hz, 1H), 7.22-7.28 (dd, J = 7.7 and 4.9 Hz, 1H), 3.74-3.61 (m,
14H), 2.74 (t, J = 4.8 Hz, 4H); FABMS (NBA as a matrix): 266
+
([M+1] , 100 %).
Anal. Calcd. for C
H N O +1/3H O: C, 61.74; H, 8.39; N,
14 22 2 3 2
10.29. Found: C, 61.57; H, 8.17; N, 10.03.
N-(3,5-Difluorobenzyl)-1,4,7-trioxa-10-azacyclododecane (3).
1
Yellow oil; H nmr (deuteriochloroform): δ 6.96 (dd, J = 8.5
and 2.4 Hz, 2H), 6.66 (triple triplet, J = 8.5 Hz, 2.4 Hz, 1H), 3.74-
3.68 (m, 8H), 3.65 (t, J = 4.8 Hz, 4H), 3.65 (s, 2H), 2.74 (t, J = 4.7
+
Hz, 4H); FABMS (NBA as a matrix): 300 ([M+1] , 100 %).
Anal. Calcd. for C
H NO F : C, 59.79; H, 7.02; N, 4.65.
15 21 3 2
Found: C, 59.52; H, 7.25; N, 4.68.
In addition, using the 1 MPa conditions also simplified
the workup procedure. The aromatic carbaldehydes in the
reaction mixtures completely disappeared as the reaction
finished, which facilitated the separation and purification
of the product.
N-(3-Pyridylmethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane
(4).
1
Hygroscopic yellow oil; H nmr (deuteriochloroform): δ 8.56
(d, J = 1.6 Hz, 1H), 8.50 (dd, J = 4.6 Hz, 1.6 Hz, 2H), 7.78 (d, J =
7.2 Hz, 1H), 7.26 (dd, J = 7.7 and 4.9 Hz, 1H), 3.77 (s, 2H), 3.68-
3.63 (m, 16H), 2.84 (t, J = 5.6 Hz, 4H); FABMS (NBA as a
In conclusion, we demonstrated that reductive amination
+
matrix): 311 ([M+1] , 100 %).
using NaBH(OAc) under 1 MPa provided significant
3
Anal. Calcd. for C
H N O +1/2H O: C, 60.17; H, 8.52; N,
16 26 2 4 2
reduction in the reaction time and yields of the addition
products were enhanced especially for reactions requiring
long reaction times.
8.77. Found: C, 60.02; H, 8.28; N, 8.74.
N-(3,5-Difluorobenzyl)-1,4,7,10-tetraoxa-13-azacyclopentade-
cane (5).
1
Yellow oil; H nmr (deuteriochloroform): δ 6.93 (d, J = 6.4 Hz,
EXPEERIMENTAL
2H), 6.66 (triple triplet, J = 9.0 Hz, 2.2 Hz, 1H), 3.69 (s, 2H),
3.70-3.64 (m, 16H), 2.81 (t, J = 5.9 Hz, 4H); FABMS (NBA as a
matrix): 346 ([M+1] , 100 %).
Anal. Calcd. for C
Found: C, 59.25; H, 7.48; N, 3.93.
1
13
H and C nmr spectra were recorded in deuteriochloroform
+
at 400 and 100 MHz, respectively. 1,4,7-Trioxa-10-azacyclodo-
decane, 1,4,7,10-tetraoxa-13-azacyclopentadecane, 1,4,7,10,13-
pentaoxa-16- azacyclooctadecane, 1,7-dioxa-4,10- diazacyclodo-
decane, 1,4,10,13-tetraoxa-7,16- diazacyclooctadecane, 1,4,7,10-
tetraazadodecane were used as purchased.
H NO F : C, 59.12; H, 7.30; N, 4.06.
17 25 4 2
N-(4-Pyridylmethyl)-1,4,7,10,13-pentaoxa-16-azacyclooctade-
cane (6).

Jan-Feb 2006
Syntheses of Armed-Macrocycles by Reductive Amination
159

160
Y. Habata, F. Osaka, and S. Yamada
Vol. 43
1
(deuteriochloroform): δ 7.48-7.11 (m, 10H), 3.74-3.47 (m, 12H),
Hygroscopic yellow oil; H nmr (deuteriochloroform): δ 8.51
(d, J = 5.7 Hz, 2H), 7.32 (d, J = 5.7 Hz, 2H), 3.74-3.62 (m, 18H),
3.63 (t, J = 5.9 Hz, 4H), 2.81 (t, J = 5.9 Hz, 4H); FABMS (NBA
+
2.79 (s, 8H); FABMS (NBA as a matrix): 355 ([M+1] , 100 %).
Anal. Calcd. for C
H N O : C, 74.54; H, 8.53; N, 7.90.
22 30 2 2
+
Found: C, 74.40; H, 8.77; N, 7.95.
as a matrix): 354 ([M+1] , 100 %).
Anal. Calcd. for C
7.90. Found: C, 59.79; H, 8.40; N, 7.75.
H N O +1/2H O: C, 59.48; H, 8.53; N,
18 30 2 5 2
N,N'-Bis(4-pyridylmethyl)-1,4,10,13-tetraoxa-7,16-diazacy-
clododecane (12).
N-(3-Pyridylmethyl)-1,4,7,10,13-pentaoxa-16-azacyclooctade-
cane (7).
Colorless crystals; mp 63.0-64.0 °C (recrystallized from hep-
tane) (lit.,[6] 60-61 °C, recrystallized from ether); H nmr (deu-
1
1
teriochloroform): δ 8.52 (d, J = 5.9 Hz, 4H), 7.33 (d, J = 5.9 Hz,
Hygroscopic yellow oil; H nmr (deuteriochloroform): δ 8.54
4H), 3.70 (s, 4H), 3.63 (t, J = 5.6 Hz, 8H), 3.60 (s, 8H), 2.84 (t, J
(d, J = 1.8 Hz, 1H), 8.48 (dd, J = 4.8 and 1.8 Hz, 1H), 7.72 (d, J =
7.7, 1H), 7.24 (dd, J = 7.7 and 4.8 Hz, 1H), 3.73-3.65 (m, 18H),
3.63 (t, J = 5.5 Hz, 4H), 2.80 (t, J = 5.5 Hz, 4H); FABMS (NBA
+
= 5.6 Hz, 8H); FABMS (NBA as a matrix): 445 ([M+1] , 100 %).
Anal. Calcd. for C
H N O : C, 64.84; H, 8.16; N, 12.60.
24 36 4 4
+
Found: C, 64.54; H, 8.38; N, 12.44.
as a matrix): 354 ([M+1] , 100 %).
Anal. Calcd. for C
7.73. Found: C, 60.10; H, 8.47; N, 7.91.
H N O +1/2H O: C, 60.13; H, 8.63; N,
18 30 2 5 2
N,N'-Bis(3-pyridylmethyl)-1,4,10,13-tetraoxa-7,16-diazacy-
clododecane (13).
General Procedures for the Reaction of Diazacrown Ethers with
Pyridinecarbaldehydes or 3,5-Difluorobenzenecarbaldehyde.
Colorless crystals; mp 69.5-70.0 °C (recrystallized from hep-
tane); H nmr (deuteriochloroform): δ 8.58 (s, 2H), 8.52 (d, J =
4.0 Hz, 2H), 7.85 (s, 2H), 7.27 (s, 2H), 3.86 (s, 4H), 3.69 (t, J =
1
After a mixture of diazacrown ethers (0.6 mmol), aromatic
5.1 Hz, 8H), 3.60 (s, 8H), 2.92 (s, 8H); FABMS (NBA as a
aldehydes (2.3 mmol), and NaBH(OAc) (2.3 mmol) in 1,2-
3
+
matrix): 445 ([M+1] , 100 %).
dichloroethane was stirred for 48-144 hours at rt under atmos-
pheric pressure or 1 MPa (Argon atmosphere), saturated aqueous
Anal. Calcd. for C
H N O : C, 64.84; H, 8.16; N, 12.60.
24 36 4 4
Found: C, 64.62; H, 8.25; N, 12.48.
NaHCO was added. The organic layer was separated, and the
3
aqueous layer was extracted with chloroform (20 mL x 3). The
combined organic layer was washed with water, dried over
sodium sulfate, and concentrated. The residual yellow oil was
separated and purified by gel-permiation column chromatogra-
phy to give the following products.
General Procedures for the Reaction of 1,4,7,10-
Tetraazacyclododecane with Pyridinecarbaldehydes.
After a mixture of 1,4,7,10-tetraazacyclododecane (1.9 mmol),
aromatic aldehydes (2.3 mmol), and NaBH(OAc) (2.3 mmol) in
3
1,2-dichloroethane was stirred for 48-144 hours at rt under
atmospheric pressure or 1 MPa (Argon atmosphere), saturated
N,N'-Bis(4-pyridylmethyl)-1,7-dioxa-4,10-diazacyclododecane
(8).
aqueous NaHCO was added. The organic layer was separated,
3
and the aqueous layer was extracted with chloroform (20 mL x
3). The combined organic layer was washed with water, dried
over sodium sulfate, and concentrated. The residual yellow oil
was separated and purified by gel-permeation column chro-
matography to give the following products.
Colorless crystals; mp 108.5-109.5 °C (recrystallized from ace-
1
tonitrile); H nmr (deuteriochloroform): δ 8.60 (d, J = 5.3 Hz, 4H),
7.45 (d, J = 5.3 Hz, 4H), 3.78 (s, 4H), 3.65 (t, J = 4.6 Hz, 8H), 2.85
+
(s, 8H); FABMS (NBA as a matrix): 357 ([M+1] , 100 %).
Anal. Calcd. for C
H N O : C, 67.39; H, 7.92; N, 15.72.
20 28 4 2
Found: C, 67.30; H, 7.88; N, 15.73.
N,N',N'',N'''-Tetrakis(4-pyridylmethyl)-1,4,7,10-tetraazacyclodo-
decane (14).
N,N'-Bis(3-pyridylmethyl)-1,7-dioxa-4,10-diazacyclododecane
(9).
Orange crystals; mp 158.0-159.0 °C (recrystallized from ace-
1
tonitrile); H nmr (deuteriochloroform): δ 8.53 (d, J = 5.6 Hz,
Colorless crystals; mp 99.0-100.0 °C (recrystallized from ace-
8H), 7.30 (d, J = 5.6 Hz, 8H), 3.59 (s, 8H), 2.95 (s, 16H); FABMS
1
tonitrile); H nmr (deuteriochloroform): δ 8.60 (s, 2H), 8.52 (dd,
+
(NBA as a matrix): 537 ([M+1] , 100 %).
J = 4.7 and 1.6 Hz, 2H), 7.87 (d, J = 7.0 Hz, 2H), 7.29(dd, J = 7.7
and 4.7 Hz, 2H), 3.75 (s, 4H), 3.62 (t, J = 5.1 Hz, 8H), 2.81 (s,
Anal. Calcd. for C
H N : C, 71.61; H, 7.51; N, 20.88.
32 40 8
Found: C, 71.69; H, 7.59; N, 20.83.
+
8H); FABMS (NBA as a matrix): 357 ([M+1] , 100 %).
Anal. Calcd. for C
Found: C, 67.63; H, 8.10; N, 15.72.
H N O : C, 67.39; H, 7.92; N, 15.72.
20 28 4 2
N,N',N'',N'''-Tetrakis(3-pyridylmethyl)-1,4,7,10-tetraazacyclodo-
decane (15).
N,N'-Bis(3,5-difluorobenzyl)-1,7-dioxa-4,10-diazacyclodode-
cane (10).
Colorless crystals; mp 151.0-152.0 °C (recrystallized from
acetonitrile); H nmr (deuteriochloroform): δ 8.54 (d, J = 4.0 Hz,
4H), 8.47 (s, 4H), 7.68 (d, J = 7.6 Hz, 4H), 7.25 (dd, J = 7.7 and
1
Colorless crystals; mp 128.0-129.0 °C (recrystallized from
4.7 Hz, 4H), 3.58 (s, 8H), 2.93 (s, 16H); FABMS (NBA as a
1
acetonitrile); H nmr (deuteriochloroform): δ 7.02 (d, J = 7.6 Hz,
+
matrix): 537 ([M+1] , 100 %).
4H), 6.68 (t, J = 7.6 Hz, 2H), 3.69 (s, 4H), 3.62 (s, 8H), 2.78 (s,
Anal. Calcd. for C
H N : C, 71.61; H, 7.51; N, 20.88.
+
32 40 8
8H); FABMS (NBA as a matrix): 426 ([M+1] , 100 %).
Found: C, 71.87; H, 7.63; N, 20.82.
Anal. Calcd. for C
H N O F +1/4CH CN: C, 61.88; H,
22 26 2 2 4 3
6.17; N, 7.22. Found: C, 61.90; H, 6.37; N, 7.17.
Acknowledgement.
N,N'-Dibenzyl-1,7-dioxa-4,10-diazacyclododecane (11).
Colorless crystals; mp 88.5-89.5 °C (recrystallized from acetoni-
trile) (lit.,[5] 89-90 °C (recrystallized from n-hexane)); H nmr
This work was supported by Grant-in Aid for Scientific
Research (No. 16550129) from the Ministry of Education,
Culture, Sports, Science and Technology (Japan).
1

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Syntheses of Armed-Macrocycles by Reductive Amination
161
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