Formylation of deoxyvasicinone by alkylformates: Synthesis and reaction of α-hydroxymethylidenedeoxyvasicinone with isomeric aminophenols and aminobenzoic acids

Article abstract of DOI:10.1007/s10600-011-0005-3

A new method for formylation of deoxyvasicinone (DOV) was developed. Nucleophilic substitution of α-hydroxy- and -dimethylaminomethylidene-DOV by isomeric aminophenols and benzoic acids to give α-arylaminomethylidene- DOV was studied.

Full text of DOI:10.1007/s10600-011-0005-3

Chemistry of Natural Compounds, Vol. 47, No. 4, September, 2011 [Russian original No. 4, July-August, 2011]
FORMYLATION OF DEOXYVASICINONE BY ALKYLFORMATES:
SYNTHESIS AND REACTION OF ꢀ-HYDROXYMETHYLIDENEDE-
OXYVASICINONE WITH ISOMERIC AMINOPHENOLS
AND AMINOBENZOIC ACIDS
*
Zh. E. Turdibaev, B. Zh. Elmuradov, M. M. Khakimov,
and Kh. M. Shakhidoyatov
UDC 547.944/945+547.856
A new method for formylation of deoxyvasicinone (DOV) was developed. Nucleophilic substitution of
ꢀ-hydroxy- and -dimethylaminomethylidene-DOV by isomeric aminophenols and benzoic acids to give
ꢀ-arylaminomethylidene-DOV was studied.
Keywords: deoxyvasicinone, alkylformates, formylation, transamination, isomeric aminophenols and aminobenzoic acids.
We demonstrated earlier that Vilsmeier–Haack (DMF–POCl ) formylation of deoxyvasicinone (DOV, 1) gave,
3
depending on the work-up conditions, either ꢀ-hydroxymethylidene-DOV (2) or ꢀ-dimethylaminomethylidene-DOV (3) [1].
These compounds were isolated pure and their structures were convincingly proved [2]. However, 2 was to a certain extent
difficult to purify because of the presence of small quantities of other products.
Herein we present results from the development of an alternate synthetic method for 2 that includes the reaction of
DOV with ethyl- and n-propylformates in the presence of metallic sodium.
O
O
5
ꢂ
HCOOAlk/Na
4
N
N
ꢁ
7
N
ꢀ
N
1
OH
2
1
H
Alk = CH , n-C H
3 7
3
It was shown earlier that 2 reacts with aliphatic and aromatic amines to form ꢀ-aminomethylidene derivatives [3–6].
The hydroxyl of 2 undergoes nucleophilic substitution with o-, m-, and p-aminophenols (4a–c); o-, m-, and p-aminobenzoic
acids (4d–f); and 5-bromo-2-aminobenzoic acid (4g). The reaction of 2 with 4a–c was carried out by refluxing equimolar
amounts of the reagents in MeOH for 3 h. This produced the corresponding ꢀ-(o-, m-, and p-hydroxyphenylamino)methylidene-
DOV (5–7) in relatively high (77–80%) yields.
The reaction went more difficultly for the isomeric aminobenzoic acids. This produced the corresponding
ꢀ-(o-, m-, and p-hydroxycarbonylphenylamino) and (5ꢁ-bromo-2ꢁ-hydroxycarbonylphenylamino)methylidene-DOV (8–11).
If o-aminobenzoic acid was used as the nucleophilic reagent, the yield of 8 was 89%. In the other instances it did not exceed
38–65%. The difficulty in carrying out the reaction was probably related to the decreased nucleophilicity of the amine due to
the influence of the electron-accepting carboxylic group:
O
O
R
2
R
1
R
2
5
ꢂ
R
4
1
N
R
3
R
4
N
CH OH, tꢂ
3
ꢁ
2'
6'
4'
+
H N
2
R
3
7
N
N
ꢀ
1
X
N
R
4
H
H
H
2, 3
4à - g
5 - 11
2: X = OH
3: X = N(CH )
3 2
4a, 5: R = OH, R = R = R = H; 4b, 6: R = OH, R = R = R = H; 4c, 7: R = OH, R = R = R = H; 4d, 8: R = COOH, R = R = R = H
1
2
3
4
2
1
3
4
3
1
2
4
1
2
3
4
4e, 9: R = COOH, R = R = R = H; 4f, 10: R = COOH, R = R = R = H; 4g, 11: R = COOH, R = R = H, R = Br
2
1
3
4
3
1
2
4
1
2
3
4
S. Yu. Yunusov Institute of the Chemistry of Plant Substances,Academy of Sciences, Republic of Uzbekistan, Tashkent,
e-mail: burkhon@rambler.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2011, pp. 532–535.
Original article submitted January 20, 2011.
©
600
0009-3130/11/4704-0600 2011 Springer Science+Business Media, Inc.

We developed another method for preparing 5–11, i.e., transamination of ꢀ-dimethylaminomethylidene-DOV (3)
with the isomeric aminophenols (4a–c) and aminobenzoic acids (4d–g). The substitution reaction went slower and required
longer heating (5 h) if 3 was used rather than 2. The transamination products were formed in relatively low (34–40% for
aminophenols and 12–37% for aminobenzoic acids) yields. Thus, a new alternate method was developed for preparing
ꢀ-hydroxymethylidene-DOV (2).
The structures of the synthesized compounds were proved by spectral methods.
–1
Stretching vibrations ꢃ for 5–7 appeared in the IR spectrum at 3136–3342 cm ; ꢃ of carboxylic group (8–11),
OH
OH
at 3292-3593; ꢃ
, at 3088–3256; ꢃ
, at 1621–1666; ꢃ
(carboxyl) (8–11), at 1686–1715; ꢃ
, at 1547–1577; and
N–H
C=O
C=O
C=N
ꢃ
, at 1466–1480.
C–N
A study of mass spectra of the synthesized compounds suggested the following fragmentation pattern (using 6 as an
+
example, [M] = 305):
104
76
O
N
OH
288
184
NH
212
N
CH
197
144
6
The ꢄ-CH methylene protons of 5–7 appeared in the PMR spectrum at 4.09–4.11 ppm as 2H triplets with chemical
2
shifts (CS) of ꢅ-CH groups at 2.75–2.80 ppm (2H, triplet). Resonances of the hydroxyl protons of 5 and 6 were found at weak
2
field (10.97 and 10.89 ppm) as 1H singlets. Resonances of =CH–NH- protons had CS in the range 8.02–8.18 ppm as 1H
doublets with SSCC J = 14.0–14.2 Hz. Their CS differed slightly depending on the position of the hydroxyl. For example, if
the OH group was located in the ortho-position of the benzene ring (5), then its CS was 8.18 ppm; in the meta-position, 8.12;
and in the para-position, 8.02. Olefinic protons (CHNH) of 5–7 also appeared as 1H doublets in the range 7.77–8.02 ppm
(1H, d) with SSCC J = 14.0–14.2. The CS was located at relatively power (7.77 ppm) field for an o-OH group (5). This was
related to the electron-donating effect of the OH as compared with a =CH–NH- group. Moreover, resonances of the
corresponding protons in the aromatic part of the spectra could be observed in the range 6.44–7.85 ppm.
Resonances of olefinic protons (=CHNH) were shifted to weaker field (8.35 and 8.41 ppm) in spectra of 8–11 with an
electron-accepting substituent (COOH) or a substituent with a –I-inductive effect (Br) in the ortho-position of the benzene
ring (8 and 11) than in those of compounds with m- and p-isomeric aminobenzoic acids (8.13, 1H doublets). Furthermore, the
resonance of NH protons was observed only for 9 and 10 with SSCC 13.7–13.9 Hz also as 1H doublets. The ꢄ-methylene
protons of 8–11 were also found, like for 5–7, as 2H triplets but at relatively weaker (4.13–4.20 ppm) field than the ꢄ-CH
2
protons of 5–7 (4.09–4.11). Such a phenomenon was also observed for the ꢅ-CH groups of 8–11 (2.80–2.85 ppm, 2H,
2
triplet).
Thus, the appearance of two 2H triplets for the ꢅ- and ꢄ-methylene groups in the aliphatic part of the spectrum and the
CS of the NH-groups as 1H doublets with SSCC 13.7–14.2 Hz (relative to olefinic protons =CHNH) confirmed the structures
of the nucleophilic substitution products 5–11.
EXPERIMENTAL
Mass spectra were recorded on an MS-30 (Kratos) instrument; IR spectra, in KBr pellets on a System 2000
IR-Fourier spectrometer; PMR spectra, in CD COOD (9) and TFA + CD COOD (5–8, 10, 11) on a Unity 400+ instrument
3
3
(operating frequency 400 MHz, HMDS internal standard, ꢆ scale). The purity of products and course of reactions were
monitored by TLC on Silufol UV-254 plates using CHCl :MeOH (5:1, system A; 10:1, system B).
3
Deoxyvasicinone (1) was prepared by the literature method [1].
ꢀ-Hydroxymethylidenedeoxyvasicinone (2) (from ethylformate). A mixture of 1 (1.0 g, 5 mmol) in ethylformate
(5 mL) was cooled to 0°C, stirred, and treated in portions with metallic sodium (0.23 g, 10 mmol) over 30 min. A thick dark-
yellow mass formed. The mixture was left at room temperature overnight, decomposed using ground ice, and extracted with
601

CHCl (2 ꢇ 30 mL). The extract was dried over anhydrous Na SO . The solvent was distilled off. The solid was recrystallized
3
2
4
from acetone to afford 2 (0.8 g, 70%), mp 206–208°C, in agreement with the literature (206–208°C [7]), R 0.48 (system B).
f
From n-propylformate: In analogy with the method given above, 1 (1 g, 5 mmol), n-propylformate (5 mL), and
metallic sodium (0.23 g, 10 mmol) afforded 2 (0.86 g, 75%), mp 206–208°C, R 0.48 (system B).
f
A mixed melting point sample of 2 obtained using ethyl- and n-propylformates did not show depression.
ꢀ-Dimethylaminomethylidenedeoxyvasicinone (3) was prepared by the literature method [1].
ꢀ-(o-Hydroxyphenylamino)methylidenedeoxyvasicinone (5). Method A (from 2): Starting 2 (0.21 g, 1 mmol) in
MeOH (50 mL) was treated with o-aminophenol (0.11 g, 1 mmol), refluxed for 3 h, and cooled when the reaction was finished.
The resulting precipitate was filtered off, washed with MeOH, and dried. Recrystallization from aqueous DMF afforded 5
(0.25 g, 80%), C H N O , mp 279–281°C, R 0.73 (system B).
18 15
3
2
f
Method B (from 3): ꢀ-Dimethylaminomethylidenedeoxyvasicinone (3) (0.12 g, 0.5 mmol) was dissolved in MeOH
(10 mL), treated with o-aminophenol (0.05 g, 0.5 mmol), refluxed for 5 h, and cooled. The resulting precipitate was filtered
off, washed with MeOH, and dried. The product was recrystallized from aqueous DMF to afford 5 (0.06 g, 40%).
–1
IR spectrum (ꢃ, cm ): 3136 (OH), 3092 (NH), 1666 (C=O), 1577 (C=N), 1466 (C–N).
PMR spectrum (ꢆ, ppm, J/Hz): 10.97 (1H, s, OH), 8.18 (1H, d, J = 14.2, NH), 7.85 (1H, d, J = 7.8, H-5), 7.77 (1H, d,
J = 14.2, CHNH), 7.47 (1H, t, J = 8.1, H-7), 7.16 (1H, t, J = 7.8, H-4ꢁ), 7.08 (1H, d, J = 8.1, H-8), 6.80 (1H, d, J = 7.8, H-3ꢁ),
6.71 (1H, t, J = 7.8, H-6), 6.60 (1H, t, J = 7.8, H-5ꢁ), 6.58 (1H, d, J = 7.8, H-6ꢁ), 4.11 (2H, t, J = 7.8, ꢄ-CH ), 2.80 (2H, t, J = 7.8,
2
ꢅ-CH ).
2
+
+
+
Mass spectrum (m/z, %): 305 (90) [M] , 288 (28) [M – OH] , 212 (7.6) [M – C H OH] , 197 (33)
6
4
+
[M – NH – C H OH] , 186 (100), 185 (98), 159 (8), 145 (3.5), 144 (10), 130 (7).
6
4
Mixed melting point samples of 5–7 prepared by methods A and B did not show depression.
ꢀ-(m-Hydroxyphenylamino)methylidenedeoxyvasicinone (6). In analogy with method A given above 2 (0.21 g,
1 mmol) and m-aminophenol (0.11 g, 1 mmol) afforded 6 (0.23 g, 77%), C H N O , mp 274–276°C (MeOH), R 0.64
18 15
3
2
f
(system B).
In analogy with method B, 3 (0.24 g, 1 mmol) and m-aminophenol (0.11 g, 1 mmol) afforded 6 (0.1 g, 34%).
–1
IR spectrum (ꢃ, cm ): 3342 (OH), 3100 (NH), 1656 (C=O), 1547 (C=N), 1470 (C–N).
PMR spectrum (ꢆ, ppm, J/Hz): 10.89 (1H, s, OH), 8.12 (1H, d, J = 14.0, NH), 8.00 (1H, d, J = 14.0, CHNH), 7.86 (1H,
d, J = 7.8, H-5), 7.49 (1H, t, J = 8.4, H-7), 7.18 (1H, t, J = 8.1, H-6), 7.08 (1H, d, J = 8.4, H-8), 6.90 (1H, d, J = 8.1, H-5ꢁ), 6.51
(1H, d, J = 2.0, H-2ꢁ), 6.44 (2H, d, J = 8.1, H-4ꢁ, 6ꢁ), 4.10 (2H, t, J = 8.1, ꢄ-CH ), 2.77 (2H, t, J = 8.1, ꢅ-CH ).
2
2
+
+
+
+
Mass spectrum (m/z, %): 305 (100) [M] , 304 (90) [M – 1] , 288 (1.5) [M – OH] , 212 (17) [M – C H OH] ,
197 (10) [M – NH – C H OH] , 186 (13), 184 (6), 171 (6.3), 144 (6), 130 (19).
6
4
+
6
4
ꢀ-(p-Hydroxyphenylamino)methylidenedeoxyvasicinone (7). According to method A as described above, 2
(0.21 g, 1 mmol) and p-aminophenol (0.11 g, 1 mmol) afforded 7 (0.24 g, 79%), C H N O , mp 290–292°C (MeOH),
18 15
3 2
R 0.53 (system B).
f
In analogy with method B, 3 (0.24 g, 1 mmol) and p-aminophenol (0.11 g, 1 mmol) afforded 7 (0.11 g, 35%).
–1
IR spectrum (ꢃ, cm ): 3333 (OH), 3256 (NH), 1650 (C=O), 1574 (C=N), 1466 (C–N).
PMR spectrum (ꢆ, ppm, J/Hz): 8.07 (1H, d, J = 14.1, NH), 8.02 (1H, d, J = 14.1, CHNH), 7.84 (1H, d, J = 7.7, H-5),
7.46 (1H, t, J = 8.4, H-7), 7.15 (1H, t, J = 7.7, H-6), 7.06 (1H, d, J = 8.4, H-8), 6.7 (2H, d, J = 9.0, H-2ꢁ, 6ꢁ), 6.61 (2H, d, J = 9.0,
H-3ꢁ, 5ꢁ), 4.09 (2H, t, J = 8.2, ꢄ-CH ), 2.75 (2H, t, J = 8.2, ꢅ-CH ).
2
2
ꢀ-(o-Hydroxycarbonylphenylamino)methylidenedeoxyvasicinone (8). The reaction was performed analogously
to method A using 2 (0.67 g, 3.1 mmol) and o-aminobenzoic acid (0.42 g, 3.1 mmol) to afford 8 (0.91 g, 89%), C H N O ,
19 15
3 3
mp 266°C (dec.) (aq. DMF), R 0.34 (system A).
f
In analogy with method B (from 3), 3 (0.12 g, 0.5 mmol) and o-aminobenzoic acid (0.07 g, 0.5 mmol) synthesized 8
(0.05 g, 27%).
–1
IR spectrum (ꢃ, cm ): 3467 (OH), 3137 (NH), 1697, 1621 (C=O), 1567 (C=N), 1478 (C–N).
PMR spectrum (ꢆ, ppm, J/Hz): 8.41 (1H, s, CHNH), 7.91 (2H, d, J = 8.2, H-5), 7.90 (1H, d, J = 8.5, H-3ꢁ), 7.54 (1H,
t, J = 8.5, H-4ꢁ), 7.36 (1H, t, J = 8.5, H-5ꢁ), 7.24 (1H, t, J = 8.2, H-7), 7.18 (1H, d, J = 8.5, H-6ꢁ), 7.09 (1H, d, J = 8.2, H-8), 6.94
(1H, t, J = 8.2, H-6), 4.2 (2H, t, J = 8.4, ꢄ-CH ), 2.85 (2H, t, J = 8.4, ꢅ-CH ).
2
2
+
+
+
Mass spectrum (m/z, %): 333 (65) [M] , 288 (100) [M – COOH] , 212 (14) [M – C H COOH] , 199 (44), 197 (15)
[M – NH – C H COOH] , 186 (68), 185 (50), 184 (32) [M – CH – NH – C H COOH] , 169 (29), 130 (25).
6
4
+
+
6
4
6 4
602

ꢀ-(m-Hydroxycarbonylphenylamino)methylidenedeoxyvasicinone (9). In analogy with method A as described
above, 2 (0.43 g, 2 mmol) and m-aminobenzoic acid (0.27 g, 2 mmol) afforded 9 (0.39 g, 64%), C H N O , mp 288°C (dec.)
19 15
3 3
(DMF), R 0.29 (system A).
f
In analogy with method B, 3 (0.12 g, 0.5 mmol) and m-aminobenzoic acid (0.07 g, 0.5 mmol) afforded 9 (0.06 g,
36%).
–1
IR spectrum (ꢃ, cm ): 3406 (ꢃ ), 3244 (ꢃ ), 1697, 1677 (ꢃ
), 1555 (ꢃ
), 1480 (ꢃ
).
C–N
OH
NH
C=O
C=N
PMR spectrum (ꢆ, ppm, J/Hz): 8.29 (1H, br.d, J = 13.9, NH), 8.13 (1H, br.d, J = 13.9, CHNH), 7.88 (1H, d, J = 8.0,
H-5), 7.62 (2H, br.d, J = 8.3, H-4ꢁ, 6ꢁ), 7.51 (1H, d, J = 8.0, H-7), 7.21 (1H, d, J = 8.0, H-2ꢁ), 7.17 (1H, t, J = 8.0, H-5ꢁ), 7.09
(2H, br.d, J = 8.0, H-6, 8), 4.13 (2H, t, J = 7.6, ꢄ-CH ), 2.80 (2H, t, J = 7.6, ꢅ-CH ).
2
2
+
+
+
Mass spectrum (m/z, %): 333 (100) [M] , 332 (49) [M – 1] , 288 (3.5) [M – COOH] , 286 (10.5), 212 (25)
[M – C H COOH] , 197 (8) [M – NH – C H COOH] , 186 (9), 185 (31), 184 (5) [M – CH – NH – C H COOH] , 172 (4.2),
+
+
+
6
4
6
4
6 4
158 (4), 146 (7), 130 (4).
ꢀ-(p-Hydroxycarbonylphenylamino)methylidenedeoxyvasicinone (10). In analogy with method A, 2 (0.43 g,
2 mmol) and p-aminobenzoic acid (0.27 g, 2 mmol) afforded 10 (0.43 g, 65%), C H N O , mp 334–336°C (1,4-dioxane),
19 15
3 3
R 0.47 (system A).
f
In analogy with method B, 3 (0.12 g, 0.5 mmol) and p-aminobenzoic acid (0.07 g, 0.5 mmol) afforded 10 (0.06 g,
37%).
–1
IR spectrum (ꢃ, cm ): 3292 (ꢃ ), 3165 (ꢃ ), 1715, 1672 (ꢃ
), 1570 (ꢃ
), 1474 (ꢃ
).
C–N
OH
NH
C=O
C=N
PMR spectrum (ꢆ, ppm, J/Hz): 8.26 (1H, br.d, J = 13.7, NH), 8.13 (1H, br.d, J = 13.7, CHNH), 7.89 (1H, dd, J = 8.1,
1.1, H-5), 7.78 (2H, br.d, J = 8.7, H-3ꢁ, 5ꢁ), 7.52 (1H, t, J = 8.1, H-6), 7.22 (1H, dd, J = 8.1, 1.1, H-7), 7.15 (1H, d, J = 8.1,
H-8), 6.91 (2H, br.d, J = 8.7, H-2ꢁ, 6ꢁ), 4.14 (2H, t, J = 7.9, ꢄ-CH ), 2.81 (2H, t, J = 7.9, ꢅ-CH ).
2
2
+
+
+
+
Mass spectrum (m/z, %): 333 (100) [M] , 332 (49) [M – 1] , 288 (17) [M – COOH] , 212 (15) [M – C H COOH] ,
197 (12) [M – NH – C H COOH] , 185 (22.4), 184 (21) [M – CH – NH – C H COOH] , 169 (12.6), 144 (3), 131 (6.0).
6
4
+
+
6
4
6 4
ꢀ-(5ꢁ-Bromo-2ꢁ-hydroxycarbonylphenylamino)methylidenedeoxyvasicinone (11). In analogy with method A as
described above, 2 (0.43 g, 2 mmol) and 5-bromo-2-aminobenzoic acid (0.43 g, 2 mmol) afforded 11 (0.31 g, 38%),
C H N O Br, mp 320°C (dec.) (DMF), R 0.25 (system A).
19 14
3
3
f
Compound 3 (0.12 g, 0.5 mmol) and 5-bromo-2-aminobenzoic acid (0.11 g, 0.5 mmol) afforded 11 (0.025 g, 12%).
IR spectrum (ꢃ, cm ): 3593 (ꢃ ), 3088 (ꢃ ), 1686 (ꢃ
–1
), 1570 (ꢃ
), 1507 (ꢃ
).
OH
NH
C=O
C=N
C–N
PMR spectrum (ꢆ, ppm, J/Hz): 11.49 (1H, s, OH), 8.35 (1H, br.d, J = 13.6, CHNH), 7.97 (1H, d, J = 2.3, H-6ꢁ), 7.90
(1H, d, J = 7.8, H-5), 7.53 (1H, t, J = 7.8, H-6), 7.42 (1H, dd, J = 9.1, 2.3, H-4ꢁ), 7.23 (1H, t, J = 7.8, H-7), 7.18 (1H, d, J = 7.8,
H-8), 6.96 (1H, d, J = 9.1, H-3ꢁ), 4.17 (2H, t, J = 7.8, ꢄ-CH ), 2.80 (2H, t, J = 7.8, ꢅ-CH ).
2
2
+
+
Mass spectrum (m/z, %): 411/413 (50) [M] , 367/369 (52) [M – CO ] , 286 (21), 212 (17), 198 (20), 186 (75), 185
2
(100), 184 (37), 142 (13), 119 (15), 101 (17.5), 76 (36).
Mixed melting point samples of 8–11 prepared by methods A and B did not show depression.
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