Investigations in 2,3′-biquinoline series 24. Synthesis of 3-hetarylquinolines and their 1,4-dihydro derivatives under conditions of the Vilsmeier reaction

Article abstract of DOI:10.1007/s10593-008-0138-x

Methods have been developed for the synthesis of 2,3′-biquinolines, their 1′,4′-dihydro derivatives, 3-pyrid-2-ylquinolines, and 3-pyrazin-2-ylquinoline based on the interaction of hetarylethylenes and vinyl butyl ether with imidoyl chlorides and Vilsmeie

Full text of DOI:10.1007/s10593-008-0138-x

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
INVESTIGATIONS IN 2,3'-BIQUINOLINE SERIES
24*. SYNTHESIS OF 3-HETARYLQUINOLINES
AND THEIR 1,4-DIHYDRO DERIVATIVES
UNDER CONDITIONS OF THE VILSMEIER
REACTION
1
2
1
T. P. Glushenko , V. I. Goncharov , and A. V. Aksenov
Methods have been developed for the synthesis of 2,3'-biquinolines, their 1',4'-dihydro derivatives,
-pyrid-2-ylquinolines, and 3-pyrazin-2-ylquinoline based on the interaction of hetarylethylenes and
vinyl butyl ether with imidoyl chlorides and Vilsmeier complexes. Using the example of the synthesis of
-hetarylquinolines and their dihydro derivatives the synthetic possibilities of the Vilsmeier method
3
3
were shown for creating various bonds in different quinoline nuclei of the bisheterocyclic system.
Keywords: acid amides, 2,3'-biquinolines, 1',4'-dihydro-2,3'-biquinolines, 3-pyrid-2-ylquinolines,
3
-pyrazin-2-ylquinoline, Vilsmeier reaction, cyclization.
A series of methods was developed previously for the synthesis of 2,3'-biquinolines 6 based on the
coupling of quinolines by the action of various catalysts, for example [2-5], with the closing of bonds N(1')–
C(2') and C(3')–C(4') [6-8], N(1)–C(2) and C(3)–C(4) [9, 10]. There are no methods comprising formation of the
C(4')–C(4'a) and C(4)–C(4a) bonds. In the present work we report a series of such methods developed by us
based on formylation and acylation of substituted ethylenes by compounds related to the Vilsmeier reagent.
We have shown that 2,3'-biquinolines 6a-f may be obtained by the interaction of acid amides with
compounds 3b in the presence of POCl . Yields were 27-61%.
3
Replacement of the dimethylamino group in compound 3b by hydrogen, alkyl, or aryl enabled the
2
reaction to be stopped at the stage of forming the dihydro derivatives 7a-e, the yield of which was 56-76%* .
The reaction probably includes the formation of salt 2 at the first stage, which adding at the double bond
of compounds 3 form cations 4. Their subsequent cyclization leads to compound 5, which by losing HCl, is
converted into the dihydro derivative 7 or, by losing HCl and dimethylamine, forms biquinolines 6.
The method may also be used for the synthesis of other 3-hetarylquinolines.
_
*
*
______
For Communication 23 see [1].
2
For a preliminary report see [11].
_
_________________________________________________________________________________________
1
2
Stavropol State University, Stavropol 355009, Russia; e-mail: biochem-org@stavsu.ru. Stavropol State
Medical Academy, Stavropol 355017, Russia; e-mail: sgma@statel.stravropol.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 8, pp. 1209-1215, August, 2008. Original article submitted October 4,
2
007.
0
009-3122/08/4408-0973©2008 Springer Science+Business Media, Inc.
973

X
X
POCl3
1
+
N
R
NH
R
O
R
Cl
1
a–g
2a–g
Y
Y
+
Y
Het
R
+
X
Het
R
X
–
H
2
a–g
Het
N
R
N
R
Cl
Cl
3
a–h
1
1
4
5
–
HCl
–
–
Me NH Y = NMe
2
2
1
HCl
R = H
Y
N
Het
R
X
N
N
1
7
a–f
R
6a–j
1
1
1
, 2 a−e R = X = H, a R = H, b R = Me, c R = Pr, d R = Bu, e R = Ph, f R = R = H, X = Br,
1
g R = X = H, R = Me; 3 a−d Het = quinol-2-yl, а Y = H, b Y = NMe , c Y = Me, d Y = Ph,
2
e−h Y = NMe , e Het = pyrid-2-yl, f Het = 5-methylpyrid-2-yl, g Het = 5-bromopyrid-2-yl,
2
h Het = pyrazin-2-yl; 6 a−f Het = quinol-2-yl, a R = X = H, b R = Me, X = H, c R = Pr,
X = H, d R = Bu, X = H, e R = Ph, X = H, f R = H, X = Br, g−j R = X = H, g Het = pyrid-2-yl,
h Het = 5- methylpyrid-2-yl, i Het = 5- methylpyrid-2-yl, j Het = pyrazin-2-yl;
1
1
1
1
7
a R = Y = H, b R = H, Y = Me, c R = H, Y = Ph, d R = Me, Y = H,
1
1
e Y = R = Me, f R = Me, Y = Ph
In the following part of our work we carried out a variant of the Vilsmeier procedure for the synthesis of
3
-hetarylquinolines. We showed that 2,3'-biquinolines 6a,k,l may be obtained in 72-78% yield by the reaction of
salt 8a with chloroimminium salts in pyridine. 3-(2-Pyridyl)quinoline (6g) was obtained in 75% yield from salt
8
b.
Me
R
Me
Cl
+
N
Cl
HN
R
N
+
N
Py
N
Et
I
6
a,k,l
8
a
Me
Me
+
N
Cl
Cl
HN
N
+
N
Py
N
I
Me
8
b
6g
6
a R = H, k R = Me, l R = Ph
9
74

+
N
Me
Me
Me
Me
+
N
Cl
Py
N
N
8
b
Me
N
N
1
0
Me
9
Me
Me
N
+
N
+
N
N
–
Me NH
2
6
g
Me
Me
N
H
N
+
1
1
1
2
-
N
Me
This method, unlike the previous, enables 4-substituted 3-hetarylquinolines to be obtained.
The reaction probably proceeds through the following sequence of steps (synthesis of compound 6g as
example). In the first stage deprotonation of salt 8b occurs. The resulting enamine 9 is converted into salt 10,
which is cyclized with the formation of salt 11. Subsequently dimethylamine is lost forming salt 12,
demethylation of which with pyridine leads to compound 6g.
We then showed the use of the Vilsmeier reaction for building the 2-substituted quinoline fragment in
2
3
,3'-biquinolines. The problem is the creation of the C(2)–C(3) and C(4)–C(4') bonds. Anilides of quinoline-
-carboxylic acids 13a,b were taken as starting materials. We have shown that the sequential reaction of the
initial anilide with SOCl in chloroform, treatment of the reaction mixture with triethylamine, and then boiling
2
with butyl vinyl ether leads to biquinolines 6a,f in 58 and 52% yields respectively.
O
Cl
X
1
. SOCl2
X
N
N
H
2
. Et N
3
N
N
1
3a,b
Bu
+
O
OBu
N
OBu
X
N
X
N
N
–
BuOH
6
a,f
1
3 a X = H, b X = Br
The synthetic possibilities of the Vilsmeier procedure has therefore been shown for creating different
bonds in various quinolines in bisheterocyclic systems, using the example of the synthesis of 3-hetaryl-
quinolines and their dihydro derivatives.
9
75

EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker WP-200 (200 MHz) instrument, internal standard was
TMS. A check on the progress of reactions and the homogeneity of the synthesized compounds was carried out
on Silufol UV-254 plates, solvent system was ethyl acetate–petroleum ether, 1:1.
Synthesis of 3-Hetarylquinolines and 1',4'-Dihydro-2,3'-biquinolines by the Reaction of
Compounds 3a-h with Acid Anilides in the Presence of POCl (M1). (General Method). A mixture of
3
compound 3a-h (1 mmol), anilide (1.1 mmol), and POCl (2 mmol) in chloroform (5 ml) was boiled for 2.5 h,
3
poured into water (20 ml), neutralized with ammonia solution, and extracted with benzene (3×50 ml). The
obtained solution was evaporated and the residue chromatographed. Compounds 6a-j and 7a-f were obtained.
Synthesis of 3-Hetarylquinolines from Salts 8 (M2). (General Method). To the formylating
Vilsmeier mixture obtained by adding POCl (0.34 ml, 3.5 mmol) dropwise to the dimethylamide (4 mmol) in
3
pyridine (3 ml), was added a solution of salt 8 (2 mmol) in pyridine (2 ml) in small portions with vigorous
stirring. The obtained reaction mixture was boiled for 5 h, cooled, poured onto finely ground ice (30 g), and
washed with water. The mixture was extracted with benzene (3×50 ml). The obtained solution was evaporated
and the residue chromatographed. Compounds 6a,g,k,l were obtained.
Synthesis of 2,3'-Biquinolines from Anilides of Quinoline-3-carboxylic Acids (M3). (General
Method). A mixture of quinoline-3-carboxylic acid anilide (1 mmol), thionyl chloride (1.5 mmol) in chloroform
(
10 ml) was boiled for 10 min. A precipitate of chloroimminium salt formed. The reaction mixture was cooled
and triethylamine (2 ml) was carefully added. The mixture was heated to boiling and butyl vinyl ether (2 mmol)
in chloroform (3 ml) was added during 1 h. The mixture was boiled for 4 h, poured into water (20 ml), and
extracted with benzene (3×50 ml). The obtained solution was evaporated, and the residue chromatographed.
Compounds 6a,f were obtained.
2
,3'-Biquinoline (6a). Yield 27 (M1), 78 (M2), 58% (M3); mp 175-176°C (benzene). Lit. mp
o
1
1
75-176 C [2]. A mixing test with an authentic sample gave no depression of melting point. The H NMR
spectrum was identical to that given in [3].
'-Methyl-2,3'-biquinoline (6b). Yield 45%; mp 57-58°C (benzene with hexane). Lit. mp 57-58°C
2
1
[
12]. A mixing test with an authentic sample gave no depression of melting point. The H NMR spectrum was
identical to that given in [12].
'-Propyl-2,3'-biquinoline (6c). Yield 41%. White oil. H NMR spectrum (acetone-d ), δ, ppm (J, Hz):
1
2
6
0
.95 (3H, t, J = 7.2, 2'-CH CH CH ); 1.70 (2H, m, 2'-CH CH CH ); 3.20 (2H, t, J = 7.65, 2'-CH CH CH ); 7.60
2 2 3 2 2 3 2 2 3
(
1H, dd, J5',6' = 8.4, J6',7' = 7.0, H-6'); 7.67 (1H, dd, J = 8.05, J = 7.0, H-6); 7.79 (1H, dd, J = 7.0, J7',8 = 8.35,
5,6 6,7 6',7'
H-7'); 7.85 (1H, dd, J6,7 = 7.0, J7,8 = 8.3, H-7); 7.87 (1H, d, J3,4 = 8.5, H-3); 8.02 (1H, d, J5',6' = 8.4, H-5'); 8.07
(
(
1H, d, J8',7' = 8.35, H-8'); 8.06 (1H, d, J5,6 = 8.05, H-5); 8.12 (1H, d, J7,8 = 8.3, H-8); 8.43 (1H, s, H-4'); 8.52
1H, d, J3,4 = 8.5, H-4). Found, %: C 84.81; H 6.02; N 9.17. C H N . Calculated, %: C 84.52; H 6.08; N 9.39.
21
18
2
1
2
'-Butyl-2,3'-biquinoline (6d). Yield 38%. White oil. The H NMR spectrum was identical to that
given in [12].
'-Phenyl-2,3'-biquinoline (6e). Yield 61%; mp 76-77°C (benzene with hexane). Lit. mp 76-77°C [12].
A melting test with an authentic sample gave no depression of melting point. The H NMR spectrum was
identical to that given in [12].
2
1
6
'-Bromo-2,3'-biquinoline (6f). Yield 34 (M1), 52% (M3); mp 238-239°C (ethanol). Lit. mp
1
2
38-239°C [13]. A mixing test with an authentic sample gave no depression of melting point. The H NMR
spectrum was identical to that given in [13].
-Pyrid-2-ylquinoline (6g). Yield 22 (M1), 75% (M2); mp 99-101°C Lit. mp 99-100°C [14]. H NMR
spectrum (CDCl ), δ, ppm (J, Hz): 7.18 (1H, d, J = 7.7, H-3'); 7.31 (1H, dd, J = 7.5, J5',6' = 4.7, H-5'); 7.52
1
3
3
4',5'
(
2H, m, H-4',6); 7.71 (1H, dd, J6,7 = 7.0, J7,8 = 8.1, H-7); 7.89 (1H, d, J = 8.1, H-5); 8.14 (1H, d,
9
76

J =8.1, H-8); 8.68 (1H, d, J = 2.1, H-4); 8.81 (1H, dd, J5',6' = 4.7, H-6'); 9.56 (1H, d, J = 2.1, H-2). Found, %:
C 81.28; H 4.71; N 13.53. C H N . Calculated, %: C 81.53; H 4.89; N 13.58.
1
4
10
2
1
3
-(5-Bromopyrid-2-yl)quinoline (6h). Yield 36%; mp 148-149°C. Lit. mp 150°C [14]. H NMR
spectrum (CDCl ), δ, ppm (J, Hz): 7.46 (1H, dd, J6,7 = 7.0, J7,8 = 8.1, H-6); 7.75 (2H, m, H-5,7); 7.79 (2H, m,
3
H-4',8); 8.03 (1H, d, J = 8.3, H-3'); 8.58 (1H, d, J = 2.2, H-4); 8.68 (1H, d, J = 3.2, H-6'); 9.34 (1H, d, J = 2.2,
H-2). Found, %: C 58.83; H 3.16; N 9.54. C H BrN . Calculated, %: C 58.97; H 3.18; N 9.82.
1
4
9
2
1
3
-(5-Methylpyrid-2-yl)quinoline (6i). Yield 32%; mp 103-104°C. Lit. mp 105°C [15]. H NMR
spectrum (CDCl ), δ, ppm (J, Hz): 2.36 (3H, s, CH ); 7.55 (2H, m, H-6,3'); 7.72 (2H, m, H-7,4'); 7.87 (1H, d,
3
3
J = 8.1, H-5); 8.13 (1H, d, J = 8.1, H-8); 8.56 (1H, s, H-6'); 8.69 (1H, d, J = 2.1, H-4); 9.51 (1H, d, J = 2.1, H-2).
Found, %: C 81.93; H 5.38; N 12.96. C H N . Calculated, %: C 81.82; H 5.45; N 12.72.
1
5
12
2
o
1
3
-Pyrazin-2-ylquinoline (6j). Yield 56%; mp 145-146 C. Lit. mp 146°C [14]. H NMR spectrum
(
CDCl ), δ, ppm (J, Hz): 7.18 (1H, d, J = 7.7, H-3'); 7.31 (1H, dd, J = 7.5, J5',6' = 4.7, H-5'); 7.52 (2H, m,
3
4',5'
H-4',6); 7.71 (1H, dd, J6,7 = 7.0, J7,8 = 8.1, H-7); 7.89 (1H, d, J = 8.1, H-5); 8.14 (1H, d, J = 8.1, H-8); 8.68 (1H,
d, J = 2.1, H-4); 8.81 (1H, dd, J5',6' = 4.7, H-6'); 9.56 (1H, d, J = 2.1, H-2). Found, %: C 75.15; H 4.52; N 19.99.
C H N . Calculated, %: C 75.35; H 4.38; N 20.28.
1
3
9
3
4
'-Methyl-2,3'-biquinoline (6k). Yield 72%; mp 137-138°C (benzene with hexane). Lit. mp 137-138°C
1
[
16]. A mixing test with an authentic sample gave no depression of melting point. The H NMR spectrum was
identical to that given in [16].
'-Phenyl-2,3'-biquinoline (6l). Yield 76%; mp 133-134°C (benzene with hexane). Lit. mp 133-134°C
4
1
[
17]. A mixing test with an authentic sample gave no depression of melting point. The H NMR spectrum was
identical to that given in [17].
',4'-Dihydro-2,3'-biquinoline (7a). Yield 56%; mp 209-211 C (benzene). Lit. mp 209-211°C [4]. A
o
1
1
mixing test with an authentic sample gave no depression of melting point. The H NMR spectrum was identical
to that given in [4].
4
'-Methyl-1',4'-dihydro-2,3'-biquinoline (7b). Yield 59%; mp 148-149°C (benzene). Lit. mp
1
1
48-149°C [18]. A mixing test with an authentic sample gave no depression of melting point. The H NMR
spectrum was identical to that given in [18].
'-Phenyl-1',4'-dihydro-2,3'-biquinoline (7c). Yield 76%; mp 213-214°C (benzene). Lit. mp
4
o
1
2
13-214 C [17]. A mixing test with an authentic sample gave no depression of melting point. The H NMR
spectrum was identical to that given in [17].
'-Methyl-1',4'-dihydro-2,3'-biquinoline (7d). Yield 61%; mp 146-147°C (ethanol). Lit. mp 213-
1
o
1
2
14 C [19]. A mixing test with an authentic sample gave no depression of melting point. The H NMR spectrum
was identical to that given in [19].
',4'-Dimethyl-1',4'-dihydro-2,3'-biquinoline (7e). Yield 61%; mp 126-127°C (benzene with hexane).
1
1
Lit. mp 126-127°C [20]. A mixing test with an authentic sample gave no depression of melting point. The H
NMR spectrum was identical to that given in [20].
1
'-Methyl-4'-phenyl-1',4'-dihydro-2,3'-biquinoline (7f). Yield 76%; mp 173-174°C (ethanol). Lit. mp
1
1
73-174°C [17]. A mixing test with an authentic sample gave no depression of melting point. The H NMR
spectrum was identical to that given in [17].
REFERENCES
1
.
T. P. Glushchenko, V. I. Goncharov, and A. V. Aksenov, Khim. Geterotsikl. Soedin., 409 (2008).
Chem. Heterocycl. Comp., 44, 313 (2008)].
[
2
3
.
.
H. Weidel, Monatsh., 2, 491 (1881).
A. V. Aksenov, I. V. Magedov, and Yu. I. Smushkevich, J. Chem. Soc., Perkin Trans. 1, 759 (1992).
9
77

4
.
A. V. Aksenov, A. Yu. Polykarpov, Yu. I. Smushkevich, and I. V. Magedov, J. Chem. Res. (S), 402
1994).
(
5
6
7
8
9
.
.
.
.
.
M. Ishikura, I. Oda, and M. Terashima, Heterocycles, 2375 (1985).
E. Carlier and A. Einhorn, Ber., 23, 2894 (1890).
W. Borsche and R. Manteuffel, Liebigs Ann. Chem., 526, 22 (1936).
W. H. Mills and H. G. Orgish, J. Chem. Soc., 81 (1928).
G. Koller and H. Ruppersberg, Monatsh., 58, 238 (1931).
1
1
0.
1.
F. Krőhnke, H. Dickhäuser, and I. Vogt, Liebigs Ann. Chem., 644, 93 (1961).
V. V. Trifonov, I. V. Aksenova, V. I. Goncharov, and A. V. Aksenov, Khim. Geterotsikl. Soedin., 1867
(
2005). [Chem. Heterocycl. Comp., 41, 1541 (2005)].
A. V. Aksenov, O. N. Nadein, I. V. Borovlev, and Yu. I. Smushkevich, Khim. Geterotsikl. Soedin., 350
1998). [Chem. Heterocycl. Comp., 34, 316 (1998)].
A. V. Aksenov and N. V. Demidova, Khim. Geterotsikl. Soedin., 1051 (2002). [Chem. Heterocycl.
Comp., 38, 913 (2002)].
1
1
2.
3.
(
1
1
1
4.
5.
6.
S. Dumouchel, F. Mongin, F. Trecourt, and G. Queguiner, Tetrahedron, 59, 8629 (2003).
J. Mathieu, P. Gros, and Y. Fort, Tetrahedron Lett., 41, 1879 (2001).
D. V. Moiseev and A. V. Aksenov, Khim. Geterotsikl. Soedin., 707 (2001). [Chem. Heterocycl. Comp.,
3
7, 654 (2001)].
A. V. Aksenov, I. V. Aksenova, I. V. Borovlev, and Yu. I. Smushkevich, Khim. Geterotsikl. Soedin.,
094 (1997). [Chem. Heterocycl. Comp., 33, 954 (1997)].
A. V. Aksenov, O. N. Nadein, I. V. Borovlev, and Yu. I. Smushkevich, Khim. Geterotsikl. Soedin., 232
1998). [Chem. Heterocycl. Comp., 34, 207 (1998)].
A. V. Aksenov, D. V. Moiseev, I. V. Borovlev, and O. N. Nadein, Khim. Geterotsikl. Soedin., 1084
2000). [Chem. Heterocycl. Comp., 36, 948 (2000)].
A. V. Aksenov, O. N. Nadein, D. V. Moiseev, and Yu. I. Smushkevich, Khim. Geterotsikl. Soedin., 919
1999). [Chem. Heterocycl. Comp., 35, 804 (1999)].
1
1
1
2
7.
8.
9.
0.
1
(
(
(
9
78