Synthesis of quinolines from N-tosyl-1-azadienes

Article abstract of DOI:10.1080/00397911.2012.726388

A route to aryl-substituted quinolines from N-tosyl 1-azadienes is described. The key steps are a [4 + 2] cycloaddition with benzyne followed by base treatment of the 1,4-dihydroquinoline product. The N-tosyl 1-azadienes were prepared from readily accessible cinnamaldehyde and chalcone substrates by condensation with p-TsNH₂. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.726388

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Synthesis of Quinolines from N-Tosyl-1-
azadienes
Sean Stokes & Keith T. Mead a
a Department of Chemistry , Mississippi State University , Mississippi
State , Mississippi , USA
Published online: 26 Jun 2013.
To cite this article: Sean Stokes & Keith T. Mead (2013): Synthesis of Quinolines from N-Tosyl-1-
azadienes, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 43:19, 2627-2633
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Synthetic Communications1, 43: 2627–2633, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.726388
SYNTHESIS OF QUINOLINES FROM
N-TOSYL-1-AZADIENES
Sean Stokes and Keith T. Mead
Department of Chemistry, Mississippi State University, Mississippi State,
Mississippi, USA
GRAPHICAL ABSTRACT
Abstract A route to aryl-substituted quinolines from N-tosyl 1-azadienes is described. The
key steps are a [4 þ 2] cycloaddition with benzyne followed by base treatment of the
1,4-dihydroquinoline product. The N-tosyl 1-azadienes were prepared from readily access-
ible cinnamaldehyde and chalcone substrates by condensation with p-TsNH2.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords 1-Azadienes; benzyne; [4 þ 2] cycloaddition; quinoline synthesis
INTRODUCTION
The extraordinary contribution of quinoline synthesis to medicine and agricul-
ture has been extensively acknowledged and reviewed.[1,2] Despite these advances,
new synthetic method development in this area continues to be a focal point of high
interest.
Aryl-substituted quinolines represent a subclass of structures known for their
pharmacological properties, particularly those that are aryl substituted at the 2- or
4-position.[3] By contrast, routes to 2,4-diarylquinolines have received less attention.[4]
We recently reported a new route to 1,4-dihydroquinolines by reacting
N-substituted 1-azadienes with benzyne generated from benzene diazonium carbox-
ylate (BDC).[5] This provided a new entry into biologically active 4-arylquinoline-
2-one derivatives such as the fungal metabolite 3-O-methylviridicatin.[6] The purpose
Received July 23, 2012.
Address correspondence to Keith T. Mead, Department of Chemistry, Mississippi State University,
Mississippi State, MS 39762, USA. E-mail: kmead@chemistry.msstate.edu
2627

2628
S. STOKES AND K. T. MEAD
Scheme 1. Strategy for synthesizing quinolines from 1-azadienes.
of the current study was to see if N-tosyl-protected 1-azadienes could provide
an efficient route to aryl-substituted quinolines (Scheme 1). We reasoned that aroma-
tization of the cycloadduct could be achieved by either base-induced elimination of
p-toluenesulfinic acid[7] or tosyl group hydrolysis followed by air oxidation.[8–10]
RESULTS AND DISCUSSION
Initial studies focused on the synthesis of 4-arylquinolines, which required the
preparation of a series of N-tosyl 4-aryl-1-azadienes 2 (Scheme 2). This was achieved
by condensing cinnamaldehyde precursors 1 with p-TsNH2 following the method
described by Raghavan and Rajender.[11] Each azadiene derivative was then
subjected to our two-step protocol, which involved reaction with BDC at 130 ꢀC
followed by treatment of the 1,4-dihydroquinoline product 3 with NaOH in refluxing
MeOH.
BDC was synthesized from anthranilic acid using trichloroacetic acid (TCA)
and isoamyl nitrite according to known procedures.[12] However, some modifications
were made to ensure that both water and acid were excluded to avoid decomposition
of the azadiene in the cycloaddition step. First, a solution of TCA in tetrahydrofuran
(THF) was made and stored over molecular sieves for at least 24 h prior to use. Next,
when BDC precipitated out of solution, it was filtered and made into a suspension in
the reaction solvent (PhCl) and used as a slurry. This ensured that the BDC never
dried out and therefore did not pose an explosion risk. Finally, to remove trace
amounts of acid from this suspension, isobutylene oxide was added.
Cycloaddition reactions of derivatives 2 with benzyne generated under these
conditions proceeded in good to moderate yields when the azadiene aryl group
was either p-substituted (Table 1, entries 2, 3, and 6) or mono ortho-substituted
(Table 1, entry 5), but not ortho-disubstituted (Table 1, entry 4). With compound
2d, only slow decomposition of the imine was observed, as monitored by thin-layer
Scheme 2. Reagents and conditions: (a) TsNH2, BF3 ꢁ OEt2, benzene, Dean–Stark;(b) BDC, chloro-
benzene, reflux; (c) NaOH, MeOH, reflux.

QUINOLINES FROM AZADIENES
2629
Table 1. Results of the reactions shown in Scheme 2
Entry
1–4
R1
R2
R3
Yield of 2a (%)
Yield of 3a (%)
Yield of 4a (%)
1
2
3
4
5
6
a
b
c
d
e
f
H
H
H
MeO
NO2
H
H
77
67
80
62
88
60
57
90
93b
87
70
64
H
H
MeO
MeO
H
MeO
H
(CH3)2N
MeO
H
No Rxn
69
Not isolatedc
N=A
92
H
56
aIsolated yield.
bpreviously reported result.[5]
c[4 þ 2]reaction conditions gave the quinoline product directly.
chromatography (TLC). In contrast, the amine-containing 1-azadiene 2f gave a
quinoline product directly without isolation of the 1,4-dihydroquinoline intermedi-
ate (Table 1, entry 6). There are known examples of N-tosyl-1,2-dihydroquinolines
undergoing elimination reactions to produce quinolines in the presence of a nitrogen-
ous base.[7] It is possible that the dimethylamine functionality in 2f acted as a base,
causing the liberation of p-toluenesulfinate in 1,4-elimination.
Encouraged by our results, we next set out to extend this route to 2,4-diarylqui-
nolines. This required condensing p-TsNH2 with a series of chalcones 5, which were
prepared using the method of Ram and Khan[13] (Scheme 3). In every case, NMR
showed formation of the azadiene product as a single isomer. Moreover, several deri-
vatives crystallized, thereby allowing crystallographic analysis. The x-ray structure
of azadiene 6b revealed an E,E configuration for the diene with a preferred s-trans
conformation (Figure 1).
The condensation of 5i with p-TsNH2 produced a viscous, brown oil that
showed multiple products by TLC, and attempts at purification by column chroma-
tography and crystallization were unsuccessful. As a result, no cycloadduct was
observed for this derivative. In all other cases studied, however, our two-step proto-
col gave the expected 2,4-diarylquinoline product 8 (Table 2).
In summary, a two-step procedure for preparing aryl-substituted quinolines
from aryl-substituted N-tosyl1-azadienes has been demonstrated. Crucial to the suc-
cess of this approach is the elimination of trace amounts of water and TCA in the
cycloaddition step.
Scheme 3. Reagents and conditions: (a) TsNH2, TiCl4, Et3N, DCE, reflux; (b) BDC, chlorobenzene,
reflux;(c) NaOH, MeOH, reflux.

2630
S. STOKES AND K. T. MEAD
Figure 1. X-ray structure of azadiene 6b. (Figure is provided in color online.)
Table 2. Results of the reactions shown in Scheme 3
Entry 5–8
R1
R2
R3
R4
R5
Yield of 6 (%) Yield of 7 (%) Yield of 8 (%)
1
2
a
b
c
d
e
f
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
63
58
67
63
90
96
3
MeO
MeO
MeO
MeO
H
67
68
62
58
88
92
4
MeO
Cl
5
51
56
56
71
94
92
6
F
7
g
h
i
MeO MeO MeO
47
61
55
63
90
90
8
MeO OBn
H
H
H
NO2
H
H
H
H
H
9
MeO
MeO
Br
H
H
H
No Rxn
59
66
N=A
62
N=A
88
10
11
j
NO2
H
k
MeO
65
91
EXPERIMENTAL
Synthesis of N-Tosyl 1-Azadiene (2a)
Cinnamaldehyde (1.32 g, 10 mmol) and para-toluenesulfonamide (1.71 g,
10 mmol) were dissolved in benzene (60 mL) and then BF3(OEt2(44 mL, 0.4 mmol)
was added. The mixture was refluxed using a Dean–Stark apparatus for 2 h. The
reaction was cooled to 0 ꢀC and then EtOAc was added. The organic mixture was
washed with cold 1 N NaOH, water, and brine and then dried over Na2SO4. The sol-
vent was removed under reduced pressure. The crude oil was mixed with petroleum
ether and stored in a ꢂ10 ꢀC freezer overnight. The resulting solid was recrystallized
1
in a mixture of hexane and EtOAc: 2.2 g (77%); white solid; mp 201–203 ꢀC; H
NMR (600 MHz, CDCl3): d 8.80 (d, J ¼ 9.4 Hz, 1H), 7.88 (d, J ¼ 8.2 Hz, 2H), 7.56
(d, J ¼ 7.6 Hz, 2H), 7.51 (d, J ¼ 15.8 Hz, 1H), 7.47–7.43 (m, 3H), 7.36 (d, J ¼ 8.0 Hz,
2H), 7.00 (dd, J ¼ 9.4 and; 15.8 Hz, 1H), 2.46 (s, 3H).

QUINOLINES FROM AZADIENES
2631
Synthesis of N-Tosyl-1,4-dihydroquinoline (3a)
Anthranilic acid (165 mg, 1.2 mmol) and trichloroacetic acid (1 mL, 0.03 mmol,
˚
0.03 M in THF dried over crushed 4 A molecular sieves) were dissolved in THF
(2 mL) and cooled to 0 ꢀC. Isopentyl nitrite (321 mL, 2.4 mmol) was added, stirred
at 0 ꢀC for 15 min, warmed to room temperature, and stirred for 45 min. The precipi-
tate was filtered and washed with chlorobenzene (caution: use a plastic spatula when
handling the diazonium salt). The diazonium salt was added to chlorobenzene
(3 mL) and isobutylene oxide (213 mL, 2.4 mmol) and stirred for 15 min. This suspen-
sion was slowly added to a refluxing mixture of azadiene 2a (114 mg, 0.4 mmol) in
chlorobenzene (3 mL) (caution: use a teflon-coated needle and plastic syringe to
add suspension). The solution was refluxed overnight. TLC was used to determine
when the reaction was complete. If the azadiene was still present, another batch of
diazonium salt in suspension was created and added periodically over several hours.
Once TLC showed that significant amounts of product had formed, the reaction was
cooled to room temperature and the solvent was removed under reduced pressure.
The crude oil was subjected to flash gradient column chromatography on neutral
alumina using hexane=EtOAc mixtures as the eluting solvents: 82 mg (57%); orange
oil; 1H NMR (600 MHz, CDCl3): d 8.08 (dd, J ¼ 0.9 and 8.4 Hz, 1H), 7.56 (d,
J ¼ 8.3 Hz, 2H), 7.20–7.17 (m, 3H), 7.12–7.01 (m, 4H), 6.96 (dd, J ¼ 1.1 and
7.9 Hz, 1H), 6.78 (d, J ¼ 7.6 Hz, 1H), 6.61 (dd, J ¼ 1.2 and 7.7 Hz, 2H), 5.39 (dd,
J ¼ 4.4 and 7.9 Hz, 1H), 4.35 (d, J ¼ 4.3 Hz, 1H), 2.41 (s, 3H).
Synthesis of Quinoline (4a)
N-Tosyl-1,4-dihydroquinoline 3a (51 mg, 0.14 mmol) was dissolved in MeOH
(10 mL) and then NaOH (17 mg, 0.42 mmol) was added. The solution was refluxed
overnight and then cooled to room temperature. The mixture was diluted with
EtOAc and H2O and then separated. The organic solution was washed with H2O
and brine and then dried over MgSO4. The solvent was removed under reduced
pressure and the crude oil was subjected to column chromatography: 26 mg (90%);
orange oil; 1H NMR (600 MHz, CDCl3): d 8.96 (d, J ¼ 4.4 Hz, 1H), 8.18 (d,
J ¼ 8.4 Hz, 1H), 7.93 (dd, J ¼ 1.1 and 8.4 Hz, 1H), 7.77–7.71 (m, 1H), 7.55–7.49
(m, 6H), 7.35 (d, J ¼ 4.4 Hz, 1H).
Synthesis of N-Tosyl 1-Azadiene (6a)
p-Toluenesulonamide (0.86 g, 5 mmol) and trans-chalcone (1.04 g, 5 mmol)
were dissolved in DCE (20 mL) and then TiCl4 (2.5 mL, 2.5 mmol, 1 M in DCM)
was added, followed by Et3N (1.4 mL, 10 mmol). The mixture was refluxed overnight
and then cooled to room temperature. The organic solution was washed with dilute
HCl, saturated NaHCO3, water, and brine and then dried over Na2SO4. The solvent
was removed and the brown syrup was left to crystallize overnight. The solid was
recrystallized from a mixture of hexane and EtOAc: 1.14 g (63%); yellow solid; mp
149–151 ꢀC; 1H NMR (600 MHz, CDCl3): d 8.04–7.45 (m, 13H), 7.34 (d, J ¼ 7.9 Hz,
Hz, 2H), 7.10 (d, J ¼ 16.0 Hz, 1H), 2.45 (s, 3H).

2632
S. STOKES AND K. T. MEAD
Crystal Data for 6b
C26H24NO2S, FW ¼ 414.52, crystal size: 0.23 mm ꢃ 0.27 mm ꢃ 0.30 mm, crystal
˚
˚
system: triclinic, space group: ꢀ P -1, a ¼ 8.8684(8) A, b ¼ 10.0584(9) A,
ꢀ
ꢀ
˚
c ¼ 11.4737(11) A, a ¼ 89.6940(10) , b ¼ 80.7440(10) , c ¼ 89.5130(10) , V ¼ 1010.
3
˚
˚
11(16) A , Z ¼ 2, T ¼ 100(2) K, reflections collected 12475 (0.74 A resolution),
4766 independent (Rint ¼ 0.0218), R1 ¼ 0.0371, wR2 ¼ 0.0985. The crystallographic
data was deposited with the Cambridge Crystallographic Data Centre (deposition
number CCDC 886372). The data can be obtained free of charge from www.ccdc.
cam.ac.uk.
SUPPORTING INFORMATION
1
Full experimental details, H and 13C NMR spectra, and HRMS data for all
new compounds can be found via the Supplementary Content section of this article’s
Web page.
ACKNOWLEDGMENTS
We thank the National Institutes of Health through Grant No. 1 R15
GM088780-01 for financial support of this research. The NMR data were made
possible through NSF CRIF Award 0840220, which supported the acquisition of
a 600-MHz NMR. We also thank Jonathan R. Frisch and the X-ray Crystallo-
graphic Laboratory at Mississippi State University for the structure of azadiene 6b.
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