Synthesis of α-chloropyridine-containing oximes of 3β,5-dihydroxy-6-ketosteroids

Article abstract of DOI:10.1007/s10600-010-9732-0

New derivatives of steroidal 6-ketoximes containing α-chloropyridine neonicotinoid groups characteristic of bioactive compounds were synthesized by formation of oximes of cholestane and stigmastane 3β,5-dihydroxy-6- ketosteroids with O-(2-chloropyridin-5-ylmethyl)hydroxylamine in the presence of zinc or tin(IV) chloride.

Full text of DOI:10.1007/s10600-010-9732-0

Chemistry of Natural Compounds, Vol. 46, No. 5, 2010
SYNTHESIS OF ꢀ-CHLOROPYRIDINE-CONTAINING
OXIMES OF 3ꢁ,5-DIHYDROXY-6-KETOSTEROIDS
N. V. Kovganko,* S. N. Sokolov, Yu. G. Chernov,
Zh. N. Kashkan, and V. L. Survilo
UDC 547.92
New derivatives of steroidal 6-ketoximes containing ꢀ-chloropyridine neonicotinoid groups characteristic
of bioactive compounds were synthesized by formation of oximes of cholestane and stigmastane
3ꢁ,5-dihydroxy-6-ketosteroids with O-(2-chloropyridin-5-ylmethyl)hydroxylamine in the presence of zinc or
tin(IV) chloride.
Keywords: 3ꢁ,5-dihydroxy-6-ketosteroids, steroidal 6-ketoximes, O-(2-chloropyridin-5-ylmethyl)hydroxylamine,
synthesis.
Steroidal oximes represent a new class of biologically active compounds. It was found that several steroidal oximes
exhibit gestagenic [1], antiviral [2], and cytotoxic [3] activity. Aromatase inhibitors have also been found among them [4].
Certain steroidal oximes are natural compounds. Thus, several steroidal oximes were recently isolated from marine sponges
[2, 5].
One reason for our continuing interest in steroidal oximes is their great potential for biological activity. We have
previously synthesized [6–8] oximes of stigmastane 6-ketosteroids including (24R,6E)-24-ethylcholest-6-hydroximino-4-en-
3-one, which was isolated from Cinachyrella sponges. Herein we report the synthesis of O-substituted oximes of
3ꢁ,5-dihydroxy-6-ketosteroids containing an ꢀ-chloropyridine ring that is characteristic of neonicotinoid biologically active
compounds such as the natural analgesic epibatidine from the frog Epipedobates tricolor [9] or the widely employed insecticide
imidachloprid [10]. Therefore, we assumed that such chemical modification of 3ꢁ,5-dihydroxy-6-ketosteroids would increase
their insecticidal activity. We synthesized previously [11, 12] derivatives of these steroids containing ꢀ-chloropyridine rings
bonded to the 3-hydroxyl.
In order to prepare the target O-substituted 3ꢁ,5-dihydroxy-6-ketosteroid oximes, a synthetic method was required
for the previously unknown O-(2-chloropyridin-5-ylmethyl)hydroxylamine (3), which we synthesized through a series
of reactions including reaction of phthalic anhydride with hydroxylamine, subsequent alkylation of the resulting
N-hydroxyphthalimide by 2-chloro-5-chloromethylpyridine (1) to form the phthalimide (2), and hydrazinolysis of it to give
the target compound.
Our initial attempts to synthesize the corresponding O-substituted oxime via reaction of the 3ꢁ,5ꢀ-dihydroxy-6-
ketone (4) with the O-substituted hydroxylamine (3) in the presence of acid catalysts were unsuccessful. It was found that this
reaction did not occur in the presence of acetic acid. On the other hand, adding HCl to the reaction mixture produced three
compounds: secosteroid 5, 5-hydroxymethyl-2-chloropyridine (6), and the azomethine (7). These were isolated in yields of
70%, 63, and 25, respectively. The structures of the products were established using IR and NMR spectra. Furthermore, the
structure of 7 was also confirmed by convergent synthesis using the reaction of 6-chloronicotinic aldehyde with substituted
hydroxylamine 3.
The structures of the products led directly to the conclusion that required oxime 8a was in fact formed under these
conditions. However, it underwent further Beckmann rearrangement to form first the 3ꢁ-hydroxy-5-keto-6-carbonitrile that
then was dehydrated into enone 5 because the conditions were too harsh. 5-Hydroxymethyl-2-chloropyridine (6) was a
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Laboratory of Ecdysteroid Chemistry,
220141, Minsk, Belarus, e-mail: kovganko@iboch.bas-net.by. Translated from Khimiya Prirodnykh Soedinenii, No. 5,
pp. 632–636, September–October, 2010. Original article submitted October 7, 2009.
©
750
0009-3130/10/4605-0750 2010 Springer Science+Business Media, Inc.

second product of Beckmann rearrangement of the intermediate oxime 8a. Azomethine 7 was most probably formed by
conversion of 3 under the reaction conditions into 6-chloronicotinic aldehyde and its further condensation with another molecule
of 3.
O
H N
2
Cl
O
N
O
Cl
N
N
Cl
N
Cl
O
2
1
3
R
R
3
ZnCl (SnCl
2
)
4
HO
HO
HO
N
HO
O
O
4a,b
8a, b
N
Cl
HCl
3
4a: R = H; 4b: R = Et
8a:R = H; 8b: R = Et
OH
N
O
+
+
Cl
N
N
Cl
Cl
N
O
N
7
5
6
3
7
+
ZnCl (SnCl
)
4
2
HO
HO
HO
N
HO
O
O
N
Cl
9
10
Next, we used Lewis acids to catalyze the reaction of the 3ꢁ,5-dihydroxy-6-ketosteroids with 3 in order to synthesize
the steroidal O-substituted 6-ketoximes. Reaction of 4a and 3 with heating in toluene in the presence of anhydrous ZnCl
2
catalyst formed the required oxime 8a, which was isolated from the reaction mixture in about 70% yield. The structure of 8a
was elucidated unambiguously using spectral data. In particular, the IR spectrum of 8a lacked a band for stretching vibrations
–1
of the 6-ketone and contained bands at 1618 and 1621 cm that were characteristic of the C=N bond in an O-substituted
13
oxime. PMR and C NMR spectra of 8a showed resonances for the H and C atoms of the steroidal part and resonances
13
corresponding to the chloropyridine ring. Furthermore, resonances in the C NMR spectrum of 8a for C atoms of the
steroidal ring had chemical shifts similar to those in spectra of steroidal 6-ketoximes [13]. This determined rather convincingly
the site of attachment of the oxime.
Oxime 8b was synthesized by reacting stigmastane derivative 4b with 3 in pyridine in the presence of tin(IV) chloride
catalyst. The target compound 8b was obtained in >70% yield.
The effectiveness of the two aforementioned methods for forming the oxime was compared using 3 and a 3ꢁ,5ꢁ-
dihydroxy-6-ketosteroid (9) as an example. It was found that using ZnCl in toluene and SnCl in pyridine as catalysts
2
4
produced target oxime 10 in >90% yield based on starting steroid 9. A side product that was isolated in low yield in both
reactions was azomethine 7. This indicated that both methods were approximately equally effective.
Thus, we developed synthetic methods for new oxime derivatives of the 6-ketone in steroidal 3ꢁ,5-dihydroxy-6-
ketones that contain an additional ꢀ-chloropyridine moiety. Results from studies of the biological activity of the products will
be reported separately.
751

EXPERIMENTAL
–1
IR spectra were recorded on a Bomem-Michelson 100 FTIR spectrometer in the range 700–3600 cm ; UV spectra,
13
in EtOH on a Specord M400 spectrophotometer. PMR and C NMR spectra were taken on a Bruker Avance 500 NMR
1
13
spectrometer (operating frequency 500.13 MHz for H and 125.75 MHz for C). Chemical shifts are given vs. TMS as an
internal standard. The course of reactions and purity of products were monitored using Kieselgel 60F
Melting points were determined on a Kofler block.
plates (Merck).
254
2-(2ꢂ-Chloropyridin-5ꢂ-ylmethyloxy)isoindol-1,3-dione (2). A suspension of N-hydroxyphthalimide (17.94 g,
0.11 mol) and anhydrous NaOAc (10.09 g, 0.123 mol) in DMF (100 mL) was stirred, heated to 70°C, treated over 1.5 h with
a solution of 2-chloro-5-chloromethylpyridine (1, 20.0 g, 0.123 mol) (prepared by the literature method [14]) in DMF
(25 mL), stirred at 70°C for 1 h 45 min, treated in one portion with anhydrous NaOAc (1.0 g, 0.0123 mol) and a solution of 1
(2.0 g, 0.0123 mol) in DMF (10 mL) over 15 min, treated after 1 h 35 min with another portion of anhydrous NaOAc (1 g,
0.0123 mol) and a solution of 1 (2 g, 0.0123 mol) in DMF (10 mL) over 15 min, stirred at 70°C for 1.5 h, cooled to room
temperature, and poured in several portions with stirring into aqueous NaHCO (1000 mL, 1.5%). The resulting precipitate
3
was filtered off, washed with water (3 ꢃ 200 mL), and dried in air with gentle heating to afford 2 (26.67 g, 0.092 mol,
–1
84%), mp 150–155°C (EtOH). IR spectrum (KBr, ꢄ, cm ): 1725, 1780 (C=O). UV spectrum (ꢅ , nm, ꢆ): 221 (48,000), 265
max
(4,800), 296 (2,400).
PMR spectrum [(CD ) SO, , ppm, J/Hz]: 5.24 (2H, s, CH ), 7.59 (1H, d, J = 8, H-3ꢂ), 7.86 (4H, br.s, H-Ar), 8.05
3 2
2
(1H, dd, J = 8, J = 2, H-4ꢂ), 8.55 (1H, d, J = 2, H-6ꢂ).
1
2
O-(2-Chloropyridin-5-ylmethyl)hydroxylamine (3). A solution of 2 (26.56 g, 0.092 mol) in CH Cl (170 mL) and
2
2
MeOH (5 mL) was treated in one portion with a solution of hydrazine hydrate (4.48 mL, 0.092 mol) in MeOH (10 mL), stirred
for 3.5 h at room temperature, treated with aqueous ammonia (100 mL, 10%), and stirred for 5–10 min until the precipitate
dissolved completely. The organic phase was separated. The aqueous phase was extracted with CH Cl (3 ꢃ 50 mL), adding
2
2
additional water (150 mL). The combined organic extracts were dried over K CO . The desiccant was filtered off and washed
2
3
with CH Cl (100 mL). The CH Cl was evaporated at reduced pressure. The residue was vacuum distilled (1 mm Hg).
2
2
2
2
–1
Fractions with bp 90–99°C were collected to obtain 3 (12.21 g, 0.077 mol, 84%), mp 47–60°C. IR spectrum (KBr, ꢄ, cm ):
3320 (NH). UV spectrum (ꢅ , nm, ꢆ): 215 (10,000), 267 (3,600).
max
PMR spectrum (CDCl , , ppm, J/Hz): 4.59 (2H, s, CH ), 6.17 (1H, br.s, NH), 7.51 (1H, d, J = 8.5, H-3), 7.81 (1H, dd,
3
2
J = 8.5, J = 2.5, H-4), 8.37 (1H, d, J = 2.5, H-6).
1
2
Oximation of 3ꢁ,5-Dihydroxy-5ꢀ-cholestan-6-one (4a). A. A solution of 4a (0.42 g, 1 mmol) (prepared by the
literature method [15]) and 3 (0.17 g, 1.1 mmol) in EtOH (20 mL) was refluxed for 2 h, treated with acetic acid (1 mL), and
refluxed for another 2 h. The reaction mixture was treated after 18 h with HCl (1 mL, 36%), refluxed for another 9.5 h, and
evaporated to half the volume. The solution was poured into saturated NaHCO solution (30 mL). The resulting mixture was
3
extracted with CH Cl (3 ꢃ 30 mL). The extracts were washed with water (2 ꢃ 30 mL) and dried over K CO . The desiccant
2
2
2
3
was removed. The solvent was evaporated in vacuo. The residue was evaporated together with benzene (2 ꢃ 20 mL) and
chromatographed over a column of silica gel with elution by mixtures of petroleum ether (70–90°C) and EtOAc with increasing
polarity (20:1 to 2:1) to afford the following three fractions.
Fraction 1: amorphous 5,6-secocholest-3-en-5-on-6-carbonitrile (5, 0.28 g, 0.704 mmol, 70%). IR spectrum (film, ꢄ,
cm ): 1674, 1678 (C=O), 2243 (CꢇN).
–1
PMR spectrum (CDCl , , ppm, J/Hz): 0.69 (3H, s, 18-Me), 0.86 (3H, d, J = 6.5, 26-Me), 0.87 (3H, d, J = 6.5, 27-Me),
3
0.90 (3H, d, J = 6.5, 21-Me), 1.06 (3H, s, 19-Me), 2.11 (1H, dd, J = 17.5, J = 3.5, CH –CN), 2.22 (1H, br.d, J = 20, H-2ꢀ),
1
2
2
2.43 (1H, m, W/2 = 39, H-2ꢁ), 2.75 (1H, dd, J = 17.5, J = 3.5, CH CN), 6.06 (1H, dd, J = 10, J = 2, H-4), 6.84 (1H, m,
1
2
2
1
2
W/2 = 20, H-3).
13
C NMR spectrum (CDCl , , ppm): 11.82 (C-18), 17.27 (C-19), 18.51 (C-21), 19.47 (C-11), 22.56 (C-26), 22.80
3
(C-27), 23.28 (CH), 23.69 (C-23), 24.48 (C-15), 24.60 (CH ), 27.69 (C-16), 28.00 (C-25), 35.15 (C-20), 35.67 (CH), 35.67
2
(CH ), 35.90 (C-22), 39.35 (C-12), 39.45 (C-24), 41.31 (C-9), 42.23 (C-13), 47.49 (C-10), 53.40 (C-14), 56.07 (C-17), 118.30
2
(C-6), 128.76 (C-4), 147.48 (C-3), 208.86 (C-5).
Fraction 2: 1,4-di-(2-chloropyridin-5-ylmethyl)-2-aza-3-oxabut-1-ene (7, 0.04 g, 0.14 mmol, 25% calculated for
starting 3), mp 133–134°C (petroleum ether 70–90°C). The PMR spectrum of the isolated compound agreed with that of 7
obtained by convergent synthesis.
752

Fraction 3: 5-hydroxymethyl-2-chloropyridine (6, 0.1 g, 0.697 mmol, 63% calculated for starting 3), mp 47–49°C
(petroleum ether:EtOAc) (lit. [16] mp 39–40°C).
PMR spectrum [(CD ) SO, , ppm, J/Hz)]: 4.53 (2H, d, J = 6, CH ), 5.42 (1H, t, J = 6, OH), 7.48 (1H, d, J = 8, H-3),
3 2
2
7.79 (1H, dd, J = 8, J = 2, H-4), 8.35 (1H, d, J = 2, H-6).
1
2
B. A solution of 4a (0.42 g, 1 mmol) and 3 (0.17 g, 1.1 mmol) in toluene (20 mL) was refluxed for 3 h, treated with
anhydrous ZnCl (0.15 g, 1.1 mmol), refluxed for another 14 h 45 min, treated with additional 3 (0.17 g, 1.1 mmol) and
2
MgSO (0.12 g, 1 mmol), and refluxed for another 20.5 h. The precipitate was filtered out of the hot reaction mixture and
4
washed twice with small portions of toluene with heating and then CH Cl . The filtrate was evaporated in vacuo. The solid
2
2
was dissolved in CH Cl (50 mL), washed successively with aqueous NaHCO (5%, 30 mL) and water (2 ꢃ 30 mL), and dried
2
2
3
over anhydrous MgSO . The desiccant was filtered and washed on the filter with CH Cl . The filtrate was evaporated in
4
2
2
vacuo. The resulting oil was chromatographed over a column of silica gel with elution by mixtures of CH Cl and MeOH of
2
2
increasing polarity (40:1 to 35:1) to afford amorphous 8a (0.39 g, 0.697 mmol, 70%). Recrystallization from EtOH (5 mL)
–1
afforded crystalline 8a (0.28 g, 50%), mp 93–96°C (EtOH). IR spectrum (KBr, ꢄ, cm ): 1621, 1618 (C=N–).
PMR spectrum (CDCl , , ppm, J/Hz): 0.64 (3H, s, 18-Me), 0.76 (3H, s, 19-Me), 0.86 (3H, d, J = 6.5, 26-Me), 0.86
3
(3H, d, J = 6.5, 27-Me), 0.90 (3H, d, J = 6.5, 21-Me), 4.04 (1H, m, W/2 = 25, H-3ꢀ), 5.01 (2H, s, =N–O–CH –), 7.28 (1H, d,
2
J = 8, H-3 ), 7.64 (1H, dd, J = 8, J = 2, H-4 ), 8.35 (1H, br.s, W/2 = 4.8, H-2 ).
Py
13
1
2
Py
Py
C NMR spectrum (CDCl , , ppm): 12.12 (C-18), 14.39 (C-19), 18.61 (C-21), 21.39 (C-11), 22.56 (C-26), 22.82
3
(C-27), 23.86 (C-23), 24.07 (C-15), 25.90 (C-7), 28.01 (C-25), 28.17 (C-16), 29.82 (C-1), 30.62 (C-2), 34.87 (C-8), 35.77
(C-20), 36.13 (C-22), 38.30 (C-4), 39.49 (C-24), 39.71 (C-12), 41.02 (C-10), 42.99 (C-13), 44.68 (C-9), 56.12 (C-17), 56.17
(C-14), 67.42 (C-3), 71.87 (CH O), 123.94 (C-3 ), 132.98 (C-5 ), 139.20 (C-4 ), 149.72 (C-6 ), 150.53 (C-2 ), 162.40
2
Py
Py
Py
Py
Py
(C-6).
Further elution afforded starting 4a (0.07 g, 0.167 mmol, 17%). The PMR spectrum of the sample isolated from the
reaction was identical to that of the authentic compound.
Oximation of (24R)-3ꢁ,5-Dihydroxy-5ꢀ-stigmastan-6-one (4b). A solution of 4b (0.45 g, 1 mmol) (prepared by
the literature method [17]) and 3 (0.48 g, 3 mmol) in Py (4 mL) was treated with SnCl (two drops) and refluxed for 23.5 h.
4
Additional 3 (0.16 g, 1 mmol) was added during the refluxing. The mixture was diluted with water (50 mL) and extracted
with CH Cl (50 mL, 30 mL). The organic extract was washed with HCl (2 N, 20 mL) and water (30 mL) and dried over
2
2
K CO . The desiccant was filtered off and washed with CH Cl (50 mL, 20 mL). The extract was evaporated in vacuo. The
2
3
2
2
resulting solid was treated with EtOAc (5 mL). The resulting precipitate was filtered off. The filtrate was evaporated in vacuo.
The solid was dissolved in dichloroethane and filtered through a layer of silica gel with elution first by dichloroethane and then
mixtures of dichloroethane and MeOH of increasing polarity (50:1 to 30:1) to afford 8b (0.6 g) that was recrystallized from
–1
EtOH to afford the final product (0.42 g, 0.72 mmol, 72%), mp 96–99°C (EtOH). IR spectrum (KBr, ꢄ, cm ): 1637, 1631
(C=N).
PMR spectrum (CDCl , , ppm, J/Hz): 0.64 (3H, s, 18-Me), 0.76 (3H, s, 19-Me), 0.81 (3H, d, J = 6.8, 26-Me), 0.83
3
(3H, d, J = 6.8, 27-Me), 0.84 (3H, t, J = 7.6, 29-Me), 0.90 (3H, d, J = 6.4, 21-Me), 4.05 (1H, m, W/2 = 25, H-3ꢀ), 4.99 (1H, d,
J
= 13, =N–O–CH ), 5.02 (1H, d, J = 13, =N–O–CH ), 7.27 (1H, d, J = 8, H-3ꢂ), 7.65 (1H, dd, J = 8, J = 2, H-4ꢂ), 8.33
AB
2 AB 2 1 2
(1H, d, J = 2, H-6ꢂ).
13
C NMR spectrum (CDCl , , ppm): 11.98 (C-18), 12.11 (C-29), 14.39 (C-19), 18.66 (C-21), 19.02 (C-26), 19.83
3
(C-27), 21.38 (C-11), 23.03 (C-28), 24.07 (C-15), 25.90 (C-7), 26.09 (C-23), 28.19 (C-16), 29.10 (C-25), 29.82 (C-1), 30.61
(C-2), 33.88 (C-22), 34.86 (C-8), 36.15 (C-20), 38.29 (C-4), 39.70 (C-12), 41.02 (C-10), 43.00 (C-13), 44.68 (C-9), 45.81
(C-24), 56.03 (C-17), 56.18 (C-14), 67.42 (C-3), 71.86 (CH O), 123.95 (C-3 ), 132.99 (C-5 ), 139.28 (C-4 ), 149.73
2
Py
Py
Py
(C-6 ), 150.52 (C-2 ), 162.40 (C-6).
Py
Py
Oximation of 3ꢁ,5-Dihydroxy-5ꢁ-cholestan-6-one (9). A. A solution of 9 (0.42 g, 1 mmol) (prepared by the
literature method [11]) and 3 (0.24 g, 1.5 mmol) in toluene (20 mL) was treated with anhydrous ZnCl (0.2 g, 1.5 mmol) and
2
refluxed for 67 h. Additional portions of 3 (0.24 g, 1.5 mmol; 0.16 g, 1 mmol) and anhydrous ZnCl (0.07 g, 0.5 mmol) were
2
added during the refluxing. The precipitate was filtered off and washed with toluene (30 mL) with heating. The toluene
filtrate was evaporated in vacuo. The solid was treated with CH Cl (30 mL) and water (20 mL). The organic layer was
2
2
separated. The aqueous layer was extracted with CH Cl (20 mL). The combined organic extracts were added to the solid
2
2
obtained after evaporation of the toluene, washed with water (2 ꢃ 20 mL), and dried over MgSO . The desiccant was filtered
4
off and washed with CH Cl . The filtrate was evaporated in vacuo. The solid was chromatographed over a column of silica
2
2
753

gel with elution first by dichloroethane and then by mixtures of dichloroethane and MeOH of increasing polarity (200:1 to
80:1) to afford two fractions.
Fraction 1: 1,4-di-(2-chloropyridin-5-ylmethyl)-2-aza-3-oxabut-1-ene (7, 0.05 g, 0.18 mmol).
Fraction 2: amorphous 6-(2ꢂ-chloropyridin-5ꢂ-ylmethyloximino)-5ꢁ-cholestan-3ꢁ,5-diol (10, 0.51 g, 0.91 mmol).
–1
IR spectrum (film, ꢄ, cm ): 1589, 1568 (C=N).
PMR spectrum (CDCl , , ppm, J/Hz): 0.64 (3H, s, 18-Me), 0.74 (3H, s, 19-Me), 0.86 (3H, d, J = 6.4, 26-Me), 0.87
3
(3H, d, J = 6.5, 27-Me), 0.90 (3H, d, J = 6.5, 21-Me), 4.01 (1H, br.s, W/2 = 13, H-3ꢀ), 4.26 (1H, s, 5ꢁ-OH), 4.49 (1H, br.d,
J = 8.5, 3ꢁ-OH), 5.09 (2H, s, =N–O–CH ), 7.33 (1H, d, J = 8, H-3ꢂ), 7.63 (1H, dd, J = 8, J = 2, H-4ꢂ), 8.37 (1H, d, J = 2,
2
1
2
H-6ꢂ).
13
C NMR spectrum (CDCl , , ppm): 12.04 (C-18), 16.82 (C-19), 18.62 (C-21), 21.45 (C-11), 22.56 (C-26), 22.81
3
(C-27), 23.81 (C-23), 24.13 (C-15), 24.69 (C-1), 27.16 (C-2), 27.84 (C-7), 28.02 (C-25), 28.09 (C-16), 34.91 (C-8), 35.70
(C-20), 36.12 (C-22), 38.87 (C-4), 39.49 (C-24), 39.63 (C-12), 42.31 (C-10), 42.59 (C-9), 44.97 (C-13), 56.09 (C-17), 56.74
(C-14), 66.45 (C-3), 72.57 (CH O), 77.63 (C-5), 124.08 (C-3 ), 132.07 (C-5 ), 138.61 (C-4 ), 149.38 (C-6 ), 151.06
2
Py
Py
Py
Py
(C-2 ), 161.75 (C-6).
Py
B. Asolution of 9 (0.42 g, 1 mmol) and 3 (0.48 g, 3 mmol) in Py (4 mL) was treated with SnCl (two drops), refluxed
4
for 5 h, diluted with water (50 mL), and etracted with CH Cl (70 mL, 30 mL). The organic extract was washed successively
2
2
with HCl (1 N, 2 ꢃ 20 mL) and water (30 mL) and dried over K CO . The desiccant was filtered off and washed with CH Cl
2
3
2
2
(50 mL, 20 mL). The filtrate was evaporated in vacuo. The resulting solid was chromatographed over a column of silica gel
with elution first by dichloroethane and then mixtures of dichloroethane and MeOH of increasing polarity (100:1 to 40:1) to
afford two fractions.
Fraction 1: 7 (0.03 g, 0.11 mmol).
Fraction 2: 10 (0.53 g, 95%).
1,4-Di-(2-chloropyridin-5-ylmethyl)-2-aza-3-oxabut-1-ene (7). 6-Chloronicotinic aldehyde (0.14 g, 1 mmol) [16]
and 3 (0.16 g, 1 mmol) were dissolved in EtOH (5 mL) and left for 20 h at 5°C. The resulting precipitate was filtered off to
afford 7 (0.14 g). The filtrate was evaporated. The solid was recrystallized from petroleum ether (70–100°C) to afford
additional 7 (0.06 g). Total yield 0.2 g (0.71 mmol, 71%), mp 134–136°C (EtOH), 133–134°C (petroleum ether 70–100°C).
–1
IR spectrum (KBr, ꢄ, cm ): 1585, 1568 (C=N).
PMR spectrum (CDCl , , ppm, J/Hz): 5.20 (2H, s, CH ), 7.34 (1H, d, J = 8, H-3 ), 7.35 (1H, d, J = 8.5, H-3 ), 7.70
3
2
Py
Pyꢂ
(1H, dd, J = 8, J = 2.5, H-4 ), 7.92 (1H, dd, J = 8.5, J = 2, H-4 ), 8.10 (1H, s, CH=N), 8.43 (1H, d, J = 2.5, H-6 ), 8.47
1
2
Py
1
2
Pyꢂ
Py
(1H, d, J = 2, H-6 ).
Pyꢂ
13
C NMR spectrum (CDCl , , ppm): 77.17 (C-4), 124.20 (C-3 ), 124.57 (C-3 ), 126.87 (C-5 ), 131.66
3
Py
Pyꢂ
Py
(C-5 ), 135.91 (C-1), 138.96 (C-4 ), 145.68 (C-4 ), 148.68 (C-6 ), 149.70 (C-6 ), 151.33 (C-2 ), 152.74 (C-2 ).
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