The superacid induced condensation of quinolinecarboxaldehydes with arenes

Article abstract of DOI:10.1055/s-2000-6322

A variety of quinolinecarboxaldehydes have been reacted with arenes in the Bronsted superacid, CF₃SO₃H (triflic acid) to give condensation products in good to excellent yields (52-99%). The quinolinecarboxaldehydes are significantly

Full text of DOI:10.1055/s-2000-6322

PAPER
1117
The Superacid Induced Condensation of Quinolinecarboxaldehydes with
Arenes
Douglas A. Klumpp,* Andre Jones, Siufu Lau, Sarah de Leon, Manuel Garza
Department of Chemistry, California State Polytechnic University, 3801 West Temple Avenue, Pomona, California 91768, USA
Fax +1(909)8694396; E-mail: daklumpp@csupomona.edu
Received 18 February 2000
Table Results from the reaction of Quinolinecarboxaldehydes (1-
7) and Isoquinoline-carboxaldehyde (8) with Benzene in Triflic Acid
(CF3SO3H)
Abstract: A variety of quinolinecarboxaldehydes have been react-
ed with arenes in the Brönsted superacid, CF3SO3H (triflic acid) to
give condensation products in good to excellent yields (52-99%).
The quinolinecarboxaldehydes are significantly more reactive than
2-naphthalenecarboxaldehyde. It is proposed that the increased re-
activity is due to the formation of dicationic, electrophilic interme-
diates.
Quinoline
Product
Yield
C6H5
C6H5
H
N
CHO
CHO
N
Key words: heterocycles, aldehydes, electrophilic aromatic substi-
tutions, quinolines
96
1
9
C6H5
OH
OH
N
N
N
N
C6H5
H
In recent years, dicationic electrophilic species have been
the subject of many studies.1 We recently described the
condensation of 3-pyridinecarboxaldehyde with arenes in
the Brönsted superacid CF3SO3H (triflic acid, TfOH) to
give 3-(diarylmethyl)pyridines.2 These studies suggested
that 3-pyridinecarboxaldehyde is in equilibrium with
diprotonated species in superacidic solution (Scheme 1).
The pyridine ring has an easily protonated base-site, so
that upon subsequent protonation of the carbonyl group, a
reactive dicationic electrophile is formed. In a similar re-
spect, quinolinecarboxaldehydes possess well-defined
base-sites and should form reactive, diprotonated electro-
philes in superacid. These reactive electrophiles could be
useful in Friedel-Crafts type reactions to prepare substi-
tuted derivatives of quinoline. Because substituted quino-
lines have shown a wide array of biological activities,3
there has been a great amount of interest in synthetic
methodologies related to these heterocycles.4 In this pa-
per, we describe our studies of the superacid-catalyzed
condensations of quinolinecarboxaldehydes with arenes
and report an improved method for the preparation of (di-
arylmethyl)quinolines.
94
95
2
10
H
C6H5
CHO
C6H5
3
11
N
N
Cl
N
Cl
H
78
48
C6H5
CHO
C6H5
4
5
12
13
N
Cl
H
C6H5
Cl
CH3O
CH3O
CHO
C6H5
N
N
Cl
H
4
C6H5
HO
C6H5
14
N
73
C6H5
C6H5
H
CHO
N
6
15
Scheme 1
Ph
N
Ph
99
99
When quinolinecarboxaldehydes 1-7 are reacted with
benzene in TfOH,5 the condensation products 9-16 are
formed in good to excellent yields (Table). In the case of
aldehyde 5, condensation gives the expected product 13,
but a small amount of hydroxyquinoline product 14 is also
formed. Isoquinolinecarboxaldehyde (8) also gives the
product 17 from condensation with benzene. A typical
H
C6H5
CHO
N
7
8
C6H5
16
N
H
C6H5
CHO
C6H5
17
Synthesis 2000, No. 8, 1117–1120 ISSN 0039-7881 © Thieme Stuttgart · New York

1118
D. A. Klumpp et al.
PAPER
conversion can be accomplished in less than 1 hour at
25 °C. This is an improvement over earlier procedures us-
ing H2SO4.6 Sulfuric acid is up to 100 times weaker an
acid than TfOH.7 Consequently, the condensation reaction
of 1 with benzene in H2SO4 requires elevated tempera-
tures and longer reaction times.6
Reaction of 6 with toluene in TfOH at 25 °C gives the
condensation products in good yield, but several regioiso-
mers are formed. If the condensation is done at a low tem-
perature, then electrophilic attack occurs regioselectively
at the para-position of toluene and product 18 is formed.
Reaction of 6 with chlorobenzene in TfOH gave the con-
densation product(s) 19 in 90% overall yield with three re-
gioisomers being produced [ratio of bis-(chlorophenyl)
products: 2% ortho,ortho; 38% ortho, para; 60% para,
para]. Despite a significant deactivation of o-dichlo-
robenzene toward electrophilic attack,8 product 20 is
formed in 75% yield by the reaction of 6 with o-dichlo-
robenzene in TfOH.
Figure GCMS analysis of the product mix from the reaction of al-
dehyde 6, alkylbenzenes, and CF3SO3H
tivation may be the result of inductive effects like that
observed with electron deficient aldehydes.
Since two arene molecules condense with the quinoline-
carboxaldehydes, the potential exists for the preparation
of molecular libraries through the use of combinatorial
synthesis.9 When 6 is reacted with toluene, ethylbenzene,
propylbenzene, and butylbenzene, in TfOH at low tem-
perature, all 10 expected products are formed and may be
identified by GC/MS (Figure). The product arising from
reaction with two molecules of butylbenzene is formed in
relatively small quantity. This may be due to a decrease in
solubility of the alkylbenzene in the acidic solution as the
alkyl chain increases in size. When aldehydes 6 and 7 are
reacted with the four alkylbenzenes, all 20 expected prod-
ucts may be observed by GC/MS.
Scheme 2
In summary, we have found that quinolinecarboxalde-
hydes react in good to excellent yields with arenes in
CF3SO3H to give diarylmethylquinolines. We propose
that these condensation reactions occur through dicationic
intermediates. The diprotonated quinolinecarboxalde-
hydes are capable of reacting with moderately deactivated
arenes.
The condensation of aldehydes or ketones with arenes is
known as the hydroxyalkylation reaction.10 In general, it
has been synthetically useful only when activated arenes
have been used (such as phenols), or when electron defi-
cient aldehydes or ketones are used (such as chloral or tri-
fluoromethyl ketones).11 In the case of quinoline-
carboxaldehydes 1-7 and 8, we propose that these com-
pounds are reactive due to their ability to form diprotonat-
ed, dicationic electrophiles. For example, 6 forms an
Triflic acid was purchased from 3M Company and distilled under
an inert atmosphere immediately prior to use. Quinolinecarboxalde-
equilibrium with 21 in strong acids and superacids, and hydes and the other aldehydes were purchased from commercial
suppliers and used as received. Compound 2 was prepared accord-
the dicationic electrophile is sufficiently electrophilic to
react with arenes like C6H6, C6H5Cl, or C6H4Cl2 (Scheme
2). When 2-naphthaldehyde is reacted with C6H5Cl in
ing to a published procedure.13 Compound 8 was prepared by the
oxidation of 3-methylisoquinoline with SeO2 in dioxane.14 Com-
bustion analyses were done by Galbraith Laboratories, Knoxville,
TfOH, no condensation reaction occurs despite the fact
Tennessee. Unless otherwise noted, recrystallizations of products
that the carbonyl group is extensively protonated.12 The
protonated heterocyclic ring appears to activate the car-
boxonium group in species like 21. This electrophilic ac-
were from CHCl3. 1H NMR spectra were recorded at 300 MHz and
13C NMR spectra were recorded at 125 MHz.
Synthesis 2000, No. 8, 1117–1120 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The Superacid Induced Condensation of Quinolinecarboxaldehydes with Arenes
1119
Reaction of Quinoline and Isoquinoline Aldehydes with Arenes;
General Procedure15
EI-MS: m/z = 329, 331 (M+).
Anal. calcd for C22H16ClN: C, 80.10; H, 4.89. Found: C, 80.27; H,
5.02.
The heterocyclic aldehyde (0.2 g) was dissolved in benzene (1 mL)
or the corresponding arene (1 mL, for 19 and 20) and CF3SO3H (2
mL) and the mixture was stirred at r.t. for 3 h. The mixture was then
poured over ice and the resulting solution was made basic by slow
addition of aq 50% NaOH solution. The products were then extract-
ed into CHCl3, the organic phase was washed with H2O then brine,
dried (MgSO4), and the product was isolated by removal of solvent
from under vacuum.
2-Chloro-3-(diphenylmethyl)-6-methoxyquinoline (13)
Mp 209-213 °C.
1H NMR (CDCl3/TMS): d = 3.84 (s, 3 H), 5.98 (s, 1 H), 6.89 (d, 1
H, J = 3.0 Hz), 7.08-7.10 (m, 4 H), 7.24-7.33 (m, 7 H), 7.50 (s, 1
H), 7.88 (d, 1 H, J = 8.7 Hz).
13C NMR (CDCl3/TMS): d = 53.6, 55.6, 105.0, 122.9, 126.9, 128.2,
128.6, 129.5, 129.5, 136.3, 137.8, 141.6, 142.5, 149.0, 158.1.
EI-MS: m/z = 359, 361 (M+).
Combinatorial Preparations
The alkylbenzenes (ca. 0.25 mL each) was combined with
CF3SO3H and mixed with CH2Cl2 (2 mL). The resulting solution
was then cooled to -50 °C. The heterocyclic aldehyde(s) (0.05 to
0.1 g) was dissolved in CH2Cl2 (2 mL) and the aldehyde solution
was then added to the CF3SO3H/alkylbenzene solution. After stir-
ring for 8 h, the mixture was poured over several grams of ice. The
aqueous phase was extracted with hexanes to remove the excess
alkylbenzenes, and then it was made basic by slow addition of aq
50% NaOH solution. The products were then extracted into CHCl3,
the organic phase was washed with H2O then brine, dried (MgSO4),
and the product mixture was analyzed by GC/MS (DB-5 capillary
column).
Anal. calcd for C23H18ClNO: C, 76.77; H, 5.04. Found: C, 76.36; H,
5.05.
2-Chloro-3-(diphenylmethyl)-6-hydroxyquinoline (14)
Mp 250-254 °C.
1H NMR (CDCl3/TMS): d 5.76 (s, 1 H), 6.95 (d, 1 H, J = 3.0 Hz),
7.06-7.09 (m, 4 H), 7.25-7.34 (m, 11 H), 7.45 (s, 1 H), 7.88 (d, 1
H, J = 9.0 Hz).
13C NMR (CDCl3/TMS): d, 53.6, 109.0, 120.6, 122.0, 126.9, 128.3,
128.6, 129.5, 129.7, 136.5, 137.7, 141.5, 142.1, 149.2, 154.4.
EI-MS: m/z = 345, 347 (M+).16
2-(Diphenylmethyl)quinoline (9)
Mp 105-107 °C.
1H NMR (CDCl3/TMS): d = 5.91 (s, 1 H), 7.20-7.31 (m, 12 H) 7.49
(m, 1 H), 7.67 (m, 1 H), 7.75 (d, 1 H, J = 7.8 Hz), 8.14 (m, 1 H).
13C NMR (CDCl3/TMS): d = 60.2, 122.0, 126.3, 126.7, 126.9,
127.5, 128.5, 129.4, 129.5, 132.9, 136.4, 142.7, 148.0, 162.3.
EI-MS: m/z = 295 (M+).
4-(Diphenylmethyl)quinoline (15)
Mp 137-141 °C.
1H NMR(CDCl3/TMS): d = 6.24 (s, 1 H), 6.87 (d, 1 H, J = 4.8 Hz),
7.08-7.12 (m, 4 H), 7.27-7.33 (m, 6 H), 7.44 (m, 1 H), 7.66 (m, 1
H), 7.96 (d, 1 H, J = 7.8 Hz), 8.12 (d, 1 H, J = 8.7 Hz), 8.80 (d, 1 H,
J = 4.8 Hz).
13C NMR (CDCl3/TMS): d = 52.7, 122.1, 124.2, 126.6, 126.9,
127.2, 128.6, 128.9, 129.4, 130.2, 142.0, 148.4, 149.5, 150.1.
EI-MS: m/z = 295 (M+).
Anal. calcd for C22H17N: C, 89.46, H, 5.80. Found: C, 88.72, H,
5.89.
2-(Diphenylmethyl)-8-hydroxyquinoline (10)
Mp 250-254 °C.
1H NMR (CDCl3/TMS):: d = 5.85 (s, 1 H), 7.13 (m, 1 H), 7.19-7.34
(m, 12 H), 7.40 (m, 1 H), 8.06 (d, 1 H, J = 8.4 Hz).
13C NMR (CDCl3/TMS): d = 59.5, 110.0, 117.5, 123.0, 126.7,
126.9, 127.4, 128.5, 129.4, 136.5, 137.5, 142.3, 152.0, 160.8.
EI-MS: m/z = 311 (M+).
Anal. calcd for C22H17N: C, 89.46; H, 5.80. Found: C, 89.58; H,
5.89.
4-(Diphenylmethyl)-3-phenylquinoline (16)
Mp 148-151 °C.
1H NMR (CDCl3/TMS): d = 6.31 (s, 1 H), 7.16-7.52 (m, 16 H),
6.73 (m, 1 H), 7.98 (m, 2 H), 8.22 (d, 1 H, J = 8.7 Hz).
13C NMR (CDCl3/TMS): d = 52.9, 119.9, 120.0, 124.0, 126.2,
126.3, 126.9, 127.4, 127.6, 128.6, 129.2, 129.5, 130.4, 139.7, 142.1,
148.6, 150.1, 156.8.
Anal. calcd for C22H17NO: C, 84.86, H, 5.50. Found: C, 83.84, H,
5.65.
EI-MS: m/z = 371 (M+).
3-(Diphenylmethyl)quinoline (11)
Mp 123-126 °C.
Anal. calcd for C28H21N: C, 90.53, H, 5.70. Found: C, 91.00, H,
5.76.
1H NMR (CDCl3/TMS): d = 5.76 (s, 1 H), 7.17 (m, 4 H), 7.24-7.38
(m, 6 H), 7.51 (m, 1 H), 7.65-7.72 (m, 3 H), 8.09 (d, 1 H, J = 8.4
Hz), 8.79 (d, 4 H, J = 2.1 Hz,).
13C NMR (CDCl3/TMS): d = 54.4, 126.7, 126.8, 127.7, 127.8,
128.6, 129.1, 129.2, 129.4, 135.3, 136.9, 142.5, 146.8, 152.5.
3-(Diphenylmethyl)isoquinoline (17)
Mp 146-149 °C.
1H NMR (CDCl3/TMS): d = 5.85 (s, 1 H), 7.17-7.31 (m, 11 H),
7.52 (m, 1 H), 7.61 (m, 1 H), 7.65 (m, 1 H), 7.91 (d, J = 8.1 Hz, 1
H), 9.22 (s, 1 H).
EI-MS: m/z = 295 (M+).
13C NMR (CDCl3/TMS): d = 59.0, 119.6, 126.5, 126.5, 126.8,
127.1, 127.4, 128.4, 129.5, 130.3, 136.2, 142.9, 152.4, 156.8.
Anal. calcd for C22H17N: C, 89.46; H, 5.80. Found: C, 89.58; H,
5.89.
EI-MS: m/z = 295 (M+).
2-Chloro-3-(diphenylmethyl)quinoline (12)
Mp 199-202 °C.
Anal. Calcd. for C22H17N: C, 89.46%, H, 5.80%. Found: C, 88.97%,
H, 5.87%.
1H NMR(CDCl3/TMS): d = 5.76 (s, 1 H), 7.14-7.17 (m, 4 H), 7.26-
7.36 (m, 6 H), 7.51 (m, 1 H), 7.66-7.71 (m, 2 H), 8.09 (d, 1 H,
J = 8.4 Hz), 8.78 (s, 1 H).
13C NMR (CDCl3/TMS): d = 54.4, 126.7, 126.8, 127.7, 127.8,
128.6, 129.0, 129.1, 129.4, 135.3, 142.5, 146.7, 152.5.
4-[(Bis-4-tolyl)]methylquinoline (18)
1H NMR (CDCl3/TMS): d = 2.33 (s, 6 H), 6.18 (s, 1 H), 6.90 (d, 1
H, J = 4.8 Hz), 6.99 (d, 4 H, J = 8.1 Hz), 7.11 (d, 4 H, J = 8.1 Hz),
7.44 (m, 1 H), 7.65 (m, 1 H), 7.98 (d, 1 H, J = 8.7 Hz), 8.13 (d, 1 H,
J = 8.4 Hz), 8.80 (d, 1 H, J = 4.2 Hz).
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D. A. Klumpp et al.
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13C NMR (CDCl3/TMS): d = 21.3, 52.2, 122.0, 122.6, 126.7, 129.3,
Soc. 1994, 116, 2312.
129.8, 130.4, 136.6, 139.6, 148.6, 150.2, 150.3, 150.6.
(n) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1993, 32, 767.
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(b) Eicher, T.; Hauptman, S. The Chemistry of Heterocycles;
Thieme: Stuttgart, 1995; pp 334-336.
(4) (a) Greenhill, J. V. in Quinolines, part III; Jones, G., Ed.;
Wiley, New York, NY, 1990; pp 2-8.
EI-MS: m/z = 323 (M+).
Anal. calcd for C24H21N: C, 89.12; H, 6.54. Found: C, 88.48; H,
6.86.
4-[Bis(3,4-dichlorophenyl)]methylquinoline (20)
Viscous oil.
1H NMR (CDCl3/TMS): d = 6.11 (s, 1 H), 6.80 (d, 1 H, J = 4.8 Hz),
6.88 (dd, 2 H, J = 2.1, 8.4 Hz), 7.15 (d, 2 H, J = 2.1 Hz), 7.37 (d, 2
H, J = 8.4 Hz), 7.47 (m, 1 H), 7.69 (m, 1 H), 7.79 (d, 1 H, J = 8.7
Hz), 8.14 (d, 1 H, J = 8.4 Hz), 8.82 (d, 1 H, J = 4.5 Hz).
13C NMR (CDCl3/TMS): d = 50.83, 121.8, 123.4, 126.5, 127.2,
128.6, 129.5, 130.5, 130.8, 131.1, 131.7, 133.2, 141.1, 146.9, 148.5,
150.1.
(b) Comprehensive Heterocyclic Chemistry, vol. 2, part 2a;
Katritzky, A. R.; Rees, C. W.; Boulton, A. J.; McKillop, A.,
Eds.; Pergamon: Oxford, 1985.
(5) (a) For a review of TfOH chemistry see: Stang, P. J.; White,
M. R. Aldrichimica Acta 1983, 16, 15.
(b) TfOH may be quantitatively recycled; for a procedure see:
Booth, B. L.; El-Fekky, T. A. J. Chem. Soc., Perkin Trans. 1
1979, 2441.
EI-MS: m/z = 433 (M+).
(6) Mathes, W.; Wolf, A. German Patent 1198366 (1965); Chem.
Abstr. 1965, 63, 14825.
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Pharm. Bull. 1991, 39, 2718.
Anal. calcd for C22H13Cl4N: C, 61.00; H, 3.03. Found: C, 63.44; H,
4.05.
(b) Superacids Olah, G. A.; Prakash, G. K. S.; Sommer, J.;
Wiley: New York, NY, 1985.
Acknowledgement
(8) (a) Taylor, R. Electrophilic Aromatic Substitution; Wiley:
New York, 1990; Chapter 2.
The support of the NIH (SO6GM53933-0251) is gratefully acknow-
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Article Identifier:
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Synthesis 2000, No. 8, 1117–1120 ISSN 0039-7881 © Thieme Stuttgart · New York