New synthesis of formylbenzoazacrown ethers

Article abstract of DOI:10.1007/s11178-005-0352-2

A new procedure has been developed for the synthesis of formyl-substituted benzoazacrown ethers via cyclization of halogen derivatives of aza podands by the action of sodium hydride.

Full text of DOI:10.1007/s11178-005-0352-2

Russian Journal of Organic Chemistry, Vol. 41, No. 9, 2005, pp. 1387–1391. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 9, 2005,
pp. 1415–1419.
Original Russian Text Copyright © 2005 by Dmitrieva, Tikhonova, Gromov.
Dedicated to Full Member of the Russian Academy of Sciences
N.S. Zefirov on His 70th Anniversary
New Synthesis of Formylbenzoazacrown Ethers
S. N. Dmitrieva, O. V. Tikhonova, and S. P. Gromov
Photochemistry Center, Russian Academy of Sciences, ul. Novatorov 7A, Moscow, 119421 Russia
e-mail: gromov@photonics.ru
Received June 8, 2005
Abstract—A new procedure has been developed for the synthesis of formyl-substituted benzoazacrown ethers
via cyclization of halogen derivatives of aza podands by the action of sodium hydride.
Crown compounds possess a unique ability to form
stable complexes with metal ions, organic cations, and
polar neutral molecules. Therefore, crown compounds
attract attention of researchers in many fields of chem-
istry [1–11]. Extensive search for new crown com-
pounds capable of effectively and selectively binding
various species in different media is now in progress.
From the viewpoint of using fragments of crown com-
pounds as components of light-sensitive ligands, of
specific interest are those derivatives in which a nitro-
gen atom is conjugated with a chromophore. Such
ligands can be used as a basis for building up optical
sensors for metal and ammonium ions, optical data
storage systems, photocontrolled molecular devices,
molecular machines for molecular electronics, carriers
of metal cations for photocontrolled transport through
membranes, etc. At present, derivatives of phenylaza-
crown ethers are used most widely for the above
purposes. A strong disadvantage of these compounds is
low complex formation constant with metal ions. In
this respect, benzo-fuzed azacrown ethers may be con-
siderably more advantageous.
ficulties in their synthesis by condensation of two
fragments and inaccessibility of podands necessary for
intramolecular cyclization [12]. We proposed a new
method for the synthesis of functionalized benzoaza-
crown ethers in which the nitrogen atom is conjugated
with the benzene ring via stepwise transformations
of readily accessible benzocrown ethers. The proposed
method seems to be a promising alternative to the
existing synthetic procedures [13].
Formyl-substituted derivatives of benzoazacrown
ethers are the most promising for the synthesis of light-
sensitive compounds (Scheme 1). We previously
showed [14, 15] that heating of formylbenzocrown
ethers Ia–Ic (which were prepared by known methods
[16, 17]) with an alcoholic solution of MeNH2 and
MeNH3+Cl– leads to formation of nitrogen-containing
podands IIa–IIc in 66–80% yield. The cyclization
of IIa–IIc to benzoazacrown ethers IIIa–IIIc was
effected via replacement of the terminal hydroxy group
in IIa–IIc by chlorine or iodine [18–20], i.e., readily
departing groups. As a result, we obtained up to 97%
of chloro and iodo derivatives IVa–IVc and Va–Vc.
Iodo derivatives Va–Vc were brought into cyclization
in the absence of a base and by the action of such weak
Until recently, the chemistry of 1-aza-2,3-benzo-
crown ethers has poorly been developed due to dif-
Scheme 1.
HO
Me
NH
O
Me
O
O
O
O
O
O
N
O
O
O
O
O
OCH
OCH
OCH
n
n
O
n
Ia–Ic
IIa–IIc
IIIa–IIIc
n = 0 (a), 1 (b), 2 (c).
1070-4280/05/4109-1387 © 2005 Pleiades Publishing, Inc.

DMITRIEVA et al.
1388
Scheme 2.
I
Me
NH
O
Me
O
O
O
O
N
NH
O
M2CO3, MeCN
O
+
O
O
O
O
OCH
OCH
OCH
n
n
O
n
Va–Vc
IIIa–IIIc (53–67%)
VIa–VIc (11–18%)
M = Li, Na, K, Rb, Cs; n = 0 (a), 1 (b), 2 (c).
bases as alkali metal carbonates [18–20]. In the pres-
ence of weak bases, mixtures of benzoazacrown ethers
IIIa–IIIc and VIa–VIc were formed, N-methyl deriva-
tives IIIa–IIIc prevailing (Scheme 2). When the reac-
tion was carried out in the absence of a base, com-
pounds VIa–VIc were obtained as the major or only
product [20].
such strong bases as alkali metal hydroxides and
sodium hydride (Scheme 3).
By reactions of compounds IVa–IVc and Va–Vc
with alkali metal hydroxides in dioxane we obtained
aldehydes IIIa–IIIc in a considerably shorter time than
in reactions with metal carbonates, but the yields of the
target products were poor. The reaction was accom-
panied by elimination of hydrogen halide HX (X =
Cl, I) from the initial halogen derivative to produce
an appreciable amount of the corresponding vinyl ether
VIIa–VIIc. The maximal yield (33%) was obtained
in the synthesis of benzoazacrown ether IIIb from
chloride IVb.
We succeeded in effecting cyclization of com-
pounds IVa–IVc and Va–Vc and selectively obtaining
N-methylbenzoazacrown ethers IIIa–IIIc in high
yields and in short time by carrying out the reaction
with sodium hydride in tetrahydrofuran (Scheme 3, see
table). In this case, the reaction was also accompanied
by formation of vinyl ethers VIIa–VIIc, but their
fraction was much smaller than with the use of alkali
metal hydroxides.
Despite fairly high yields of target products IIIa–
IIIc in the cyclization of iodides Va–Vc in the pres-
ence of alkali metal carbonates, a considerable disad-
vantage of this procedure is very long reaction time.
Even after 150 h, the reaction was not complete.
Further increase of the reaction time leads to appreci-
able loss in the yield of IIIa–IIIc (especially of 18-
membered compound IIIc) because of strong tarring.
Moreover, it is difficult to separate N-methyl deriva-
tives IIIa–IIIc from their NH analogs VIa–VIc by
chromatography.
On the other hand, we showed that N-methylbenzo-
azacrown ethers IIIa–IIIc are clearly superior to
widely used N-phenylazacrown ethers with the same
size of the macroring [20, 21] in the complexing ability
toward Ca2+ ions. Benzoazacrown ethers IIIa–IIIc
may be promising from the viewpoint of synthesis of
light-sensitive compounds on their basis. Therefore,
we tried to find alternative synthetic routes to formyl
derivatives of N-methylbenzoazacrown ethers. For this
purpose, we examined the reactivity of chloro and iodo
aza podands IVa–IVc and Va–Vc in the presence of
The cyclization of chloro derivatives IVb and IVc
by the action of sodium hydride in anhydrous tetra-
hydrofuran on heating afforded N-methylbenzoaza-
crown ethers IIIb and IIIc in 59 and 27% yield (5.5
and 17 h, respectively). Compound IVa almost failed
to react under analogous conditions: even after pro-
longed heating (100 h), the yield of IIIa was as low as
Scheme 3.
X
Me
NH
Me
O
O
Me
O
O
NH
N
O
NaH, THF
O
+
O
O
O
O
OCH
OCH
OCH
n
O
O
n
n
IVa–IVc, Va–Vc
IIIa–IIIc
VIIa–VIIc
IV, X = Cl; V, X = I; n = 0 (a), 1 (b), 2 (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 9 2005

NEW SYNTHESIS OF FORMYLBENZOAZACROWN ETHERS
1389
Scheme 4.
X
Me
O
N
B
IIIa–IIIc
–BH+
–X–
O
O
OCH
O
n
IVa–IVc, Va–Vc
VIII
B
VIIa–VIIc
–HX
n = 0–2; X = Cl, I.
5%. Iodides Va–Vc were thus converted into IIIa–IIIc
in a much shorter time (0.5 h on heating), and the
yields were fairly good (57–68%), regardless of the
macroring size. Iodides Va–Vc underwent cyclization
even at room temperature, but in this case the reaction
time was longer, and the yields were lower (51–61%).
reference. The chemical shifts were measured with
an accuracy of ±0.01 ppm, and coupling constants,
with an accuracy of ±0.1Hz. The IR spectra were
obtained on a Bruker IFS-113V spectrophotometer.
The mass spectra were run on a Varian MAT-311A
instrument, and the high-resolution mass spectra were
recorded on a Finnigan MAT-8430 spectrometer using
perfluorokerosene as reference (electron impact,
70 eV; direct sample admission into the ion source).
Kieselgel 60 silica gel (0.063–0.100 mm, Merck) and
Al2O3 (0.063–0.200 mm, neutral, type E, Merck) were
used for column chromatography. The progress of
reactions was monitored by TLC on DC-Alufolien
Kieselgel 60 F254 plates (Merck).
Our results suggest that the cyclization of halogen
derivatives IVa–IVc and Va–Vc by the action of so-
dium hydride involves formation of reactive arylamide
ion VIII (Scheme 4). This follows from the much
shorter reaction time, as compared to the reaction with
alkali metal carbonates in acetonitrile. As shown pre-
viously [20], in the latter case the cyclization occurs
via intramolecular N-alkylation with formation of
macrocyclic ammonium salt. The yields of vinyl ethers
VIIa–VIIc depend only slightly on the length of the
polyether chain, indicating intermolecular mechanism
of hydrogen halide elimination; i.e., compounds VIIa–
VIIc are formed directly from halides IVa–IVc and
Va–Vc rather than via intramolecular transformation
of anion VIII. The structure of the isolated compounds
was determined on the basis of their 1H NMR, IR, and
mass spectra (including high-resolution mass spectra).
Benzoazacrown ethers IIIa–IIIc and vinyl ethers
VIIa–VIIc (general procedure). a. A mixture of
Cyclization of halogen derivatives IVa–IVc and Va–Vc into
formylbenzoazacrown ethers IIIa–IIIc and vinyl ethers
VIIa–VIIc by the action of NaH in THF
Initial halide Reaction
Yield (%)
no.
time, a h
100
IIIa (5),c,d VIIa (11),c, d IVa (9)d
IIIb (59), VIIb (16)
IIIc (27), VIIc (9)
IVa
IVb
IVc
Va
Thus we have developed a new effective procedure
for the synthesis of formyl-substituted N-methylbenzo-
azacrown ethers from halogen derivatives of aza pod-
ands by the action of sodium hydride. The procedure is
advantageous due to good yields of the target products,
short reaction time, and the possibility for preparing
N-methylbenzoazacrown ether IIIb from chloro deriv-
ative IVb in a fewer number of steps.
005.5
017
000.5
072b
000.5
024b
000.5
019b
IIIa (68), VIIa (8)
IIIa (61), VIIa (19)
IIIb (63), VIIb (10)
IIIb (61), VIIb (13)
IIIc (57), VIIc (23)
IIIc (51), VIIc (20)
Vb
Vc
EXPERIMENTAL
a
b
c
Heating under reflux.
At room temperature.
Calculated from the H NMR spectrum of a mixture of IIIa,
VIIa, and IVa.
1
The H and 13C NMR spectra were recorded at
1
30°C on a Bruker DRX-500 spectrometer from solu-
tions in C6D6 or CDCl3 using the solvent as internal
d
Calculated on the reacted chloride IVa.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 9 2005

DMITRIEVA et al.
1390
0.1 mmol of iodide Va–Vc, 7 ml of anhydrous THF,
and 40 mg (1 mmol) of 60% NaH (in paraffin) was
heated for 30 min under reflux with stirring. The mix-
ture was cooled, diluted with water, and extracted with
benzene. The extract was washed with water and
evaporated under reduced pressure, and the residue
was subjected to column chromatography on silica gel
[successive elution with benzene–EtOAc (1:1) and
EtOAc]. Benzoazacrown ethers IIIa–IIIc and vinyl
ethers VIIa–VIIc were isolated as light yellow oily
liquids; compounds IIIa and IIIb crystallized on
storage. The yields are given in table.
4-Methylamino-3-(2-{2-[2-(vinyloxy)ethoxy]-
ethoxy}ethoxy)benzaldehyde (VIIb). Yield 16% (c),
Rf 0.75 (AcOEt). Light yellow oily substance. IR spec-
trum (KBr), ν, cm–1: 3441, 3385 (NH); 1667 (C=O).
1H NMR spectrum (C6D6), δ, ppm: 2.25 d (3H, MeN,
J = 5.2 Hz), 3.34 m (8H, CH2O), 3.52 m (2H,
CH2CH2OAr), 3.64 m (2H, CH2OAr), 3.91 d.d (1H,
OCH=CH-cis, J = 6.8, 1.8 Hz), 4.12 d.d (1H,
OCH=CH-trans, J = 14.3, 1.8 Hz), 4.85 br.s (1H, NH),
6.21 d (1H, 5-H, J = 8.0 Hz), 6.37 d.d (1H, OCH=CH2,
J = 14.3, 6.8 Hz), 7.22 br.d (1H, 6-H, J = 8.0 Hz),
7.42 br.s (1H, 2-H), 9.83 s (1H, CHO). Mass spectrum,
m/z (Irel, %): 309 (24) [M]+, 283 (41), 162 (31), 150
(81), 149 (79), 88 (61), 73 (32), 71 (57), 58 (100), 57
(38). High-resolution mass spectrum, m/z: Found:
[M]+ 309.1589. C16H23NO5. Calculated: M 309.1576.
b. A mixture of 0.1 mmol of iodide Va–Vc, 7 ml of
anhydrous THF, and 40 mg (1 mmol) of 60% NaH (in
paraffin) was stirred for 3 days (Va), 24 h (Vb), or 19 h
(Vc) at room temperature. The mixture was then
treated as described above in a. The yields of products
IIIa–IIIc and VIIa–VIIc are given in table.
20-Methyl-6,7,9,10,12,13,15,16,19,20-decahydro-
18H-5,8,11,14,17-pentaoxa-20-azabenzocycloocta-
decene-3-carbaldehyde (IIIc). Yield 57% (a), Rf 0.15
c. A mixture of 0.1 mmol of chloride IVb or IVc,
7 ml of anhydrous THF, and 40 mg (1 mmol) of 60%
NaH (in paraffin) was heated under reflux with stirring
for 5.5 (IVb) or 17 h (IVc). The mixture was then
treated as described above in a. The yields of IIIb,
IIIc, VIIb, and VIIc are given in table.
1
(AcOEt). Light yellow oily substance. H NMR spec-
trum (CDCl3), δ, ppm: 3.02 s (3H, MeN), 3.59 t (2H,
CH2N, J = 6.0 Hz), 3.62–3.68 m (8H, CH2O), 3.71 m
(4H, CH2O), 3.83 t (2H, CH2CH2N, J = 6.0 Hz),
3.93 m (2H, CH2CH2OAr), 4.21 m (2H, CH2OAr),
6.85 d (1H, 1-H, J = 8.2 Hz), 7.32 d (1H, 4-H, J =
1.7 Hz), 7.37 d.d (1H, 2-H, J = 8.2, 1.7 Hz), 9.76 s
(1H, CHO) [20].
14-Methyl-6,7,9,10,13,14-hexahydro-12H-5,8,11-
trioxa-14-azabenzocyclododecene-3-carbaldehyde
(IIIa). Yield 68% (a), mp 71–72°C (from hexane)
[20], Rf 0.38 (C6H6–AcOEt, 1:1).
4-Methylamino-3-(3,6,9,12-tetraoxa-13-tetra-
decenyloxy)benzaldehyde (VIIc). Yield 23% (a),
Rf 0.54 (AcOEt). Light yellow oily substance. IR
spectrum (KBr), ν, cm–1: 3394 (NH), 1670 (C=O).
1H NMR spectrum (C6D6), δ, ppm: 2.27 d (3H, MeN,
J = 5.2 Hz), 3.34 m (4H, CH2O), 3.38 m (8H, CH2O),
3.53 m (2H, CH2CH2OAr), 3.65 m (2H, CH2OAr),
3.91 d.d (1H, OCH=CH-cis, J = 6.8, 1.9 Hz), 4.13 d.d
(1H, OCH=CH-trans, J = 14.3, 1.9 Hz), 4.91 br.s (1H,
NH), 6.22 d (1H, 5-H, J = 8.1 Hz), 6.38 d.d (1H,
OCH=CH2, J = 14.3, 6.8 Hz), 7.22 d.d (1H, 6-H, J =
8.1, 1.4 Hz), 7.42 d (1H, 2-H, J = 1.4 Hz), 9.83 s (1H,
CHO). Mass spectrum, m/z (Irel, %): 353 (34) [M]+,
178 (28), 162 (28), 151 (100), 150 (94), 149 (27), 122
(28), 94 (32), 89 (32), 73 (32). High-resolution mass
spectrum, m/z: Found: [M]+ 353.1830. C18H27NO6.
Calculated: M 353.1838.
4-Methylamino-3-{2-[2-(vinyloxy)ethoxy]-
ethoxy}benzaldehyde (VIIa). Yield 19% (b), Rf 0.73
(C6H6–AcOEt, 1:1). Light yellow oily substance. IR
spectrum (KBr), ν, cm–1: 3392 (NH), 1671 (C=O).
1H NMR spectrum (C6D6), δ, ppm: 2.22 d (3H, MeN,
J = 5.2 Hz), 3.28 m (4H, CH2O), 3.48 m (2H,
CH2CH2OAr), 3.60 m (2H, CH2OAr), 3.91 d.d (1H,
OCH=CH-cis, J = 6.8, 1.9 Hz), 4.12 d.d (1H,
OCH=CH-trans, J = 14.3, 1.9 Hz), 4.78 br.s (1H, NH),
6.21 d (1H, 5-H, J = 8.1 Hz), 6.35 d.d (1H, OCH=CH2,
J = 14.3, 6.8 Hz), 7.22 d.d (1H, 6-H, J = 8.1, 1.4 Hz),
7.40 d (1H, 2-H, J = 1.4 Hz), 9.83 s (1H, CHO). Mass
spectrum, m/z (Irel, %): 265 (63) [M]+, 151 (83), 150
(100), 122 (40), 94 (50), 78 (40), 77 (45), 73 (68), 71
(67), 65 (42). High-resolution mass spectrum, m/z:
Found: [M]+ 265.1307. C14H19NO4. Calculated:
M 265.1314.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 03-03-32177), by the Presidium of the Russian
Academy of Sciences, by the Moscow Government,
and by the INTAS Foundation (grant no. 2001-0267).
17-Methyl-6,7,9,10,12,13,16,17-octahydro-15H-
5,8,11,14-tetraoxa-17-azabenzocyclopentadecene-3-
carbaldehyde (IIIb). Yield 59% (c), mp 50–51°C
(from hexane) [20], Rf 0.34 (AcOEt).
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NEW SYNTHESIS OF FORMYLBENZOAZACROWN ETHERS
1391
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