Synthesis of aryl-substituted 1,4-dihydroquinolines by [4+2] cycloaddition of benzyne with 1-azadienes

Article abstract of DOI:10.1055/s-0031-1290137

The synthesis of aryl-substituted 1,4-dihydroquinolines can be achieved using a [4+2] cycloaddition between benzyne and various aryl-substituted 1-azadienes. The conditions are tolerated by N-aryl-, alkyl-, tosyl-, and tert-butoxycarbonyl-protected 1-azad

Full text of DOI:10.1055/s-0031-1290137

LETTER
389
Synthesis of Aryl-Substituted 1,4-Dihydroquinolines by [4+2] Cycloaddition of
Benzyne with 1-Azadienes
[4+2]
C
ycload
e
ditions of
B
a
enzyne
w
i
n
th 1-Azadienes Stokes, Markondaiah Bekkam, Madeline Rupp, Keith T. Mead*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Fax +1(662)3251618; E-mail: kmead@chemistry.msstate.edu
Received 25 October 2011
enamines,12 b-amino carbonyls,13 and o-quinone me-
Abstract: The synthesis of aryl-substituted 1,4-dihydroquinolines
can be achieved using a [4+2] cycloaddition between benzyne and
various aryl-substituted 1-azadienes. The conditions are tolerated
by N-aryl-, alkyl-, tosyl-, and tert-butoxycarbonyl-protected 1-aza-
thides.14 To the best of our knowledge, reactions of arynes
with 1-azadienes have not been reported,15 and prior ex-
amples of reactions initiated by imine additions to arynes
dienes. A short synthesis of the fungal metabolite 3-O-methylviri- are rare.15–21 Singal and Kaur have reported that benzyne
dicatin is reported.
reacts with azomethines to give 1,2-diarylbenzazetidines
via [2+2] cycloaddition.16 However, Yoshida and co-
Key words: benzyne, dihydroquinolines, azadienes, cycloaddition,
3-O-methylviridicatin
workers were able to trap imine-generated aryl anions
with CO2, which led to the formation of benzo-1,3-ox-
azine-4-ones.17
Aryl-substituted quinolines and quinoline derivatives are
structural motifs common to a broad range of chemother-
apeutic agents, including HMG-CoA reductase inhibi-
tors,1 antimicrobials,2 cytotoxic compounds,3 and
antitumor agents.4 Not surprisingly, then, many groups
have been inspired to develop new methods for their syn-
thesis.5 We decided to investigate [4+2] cycloadditions of
1-azadienes with benzyne as a route to 1,4-dihydroquino-
lines that could be used to target derivatives that are aryl-
substituted at C-2 and/or C-4, depending on the azadiene
employed (Scheme 1). Previously, these derivatives have
been prepared by aryllithium and aryl Grignard additions
to quinolinium ions.6 Mild oxidation methods have been
used to convert 1,4-dihydroquinolines into quinolines.7
However, we saw other possibilities for further function-
alization of these products, including oxidative additions
to the enamine p-system.8 The requisite azadiene sub-
strates are conveniently accessible from chalcone or cin-
namaldehyde precursors by standard condensation
procedures.
Azadiene 1a was prepared by condensation of p-methoxy
cinnamaldehyde with aniline and reacted with excess ben-
zyne generated from benzenediazonium-2-carboxylate
(BDC) under different conditions (Table 1). In refluxing
DCE (Table 1, entry 1), the desired compound 2a was iso-
lated in 33% yield, along with two other products. The
first of these was identified as compound 3, the result of a
[2+2] cycloaddition of product 2a with benzyne. The oth-
er product was identified as compound 4, arising from a
[2+2] cycloaddition between the imine group of azadiene
1a and benzyne, as observed by Singal and Kaur.16 Fortu-
nately, by using chlorobenzene as the solvent and con-
ducting the reaction at higher temperature, we were able
to completely eradicate the formation of compound 4
(Table 1, entry 2). Moreover, the unwanted formation of
compound 3 was minimized by adding BDC in divided
doses (Table 1, entry 3). Thus, azadiene 1a was refluxed
overnight with three equivalents of BDC, and then an ad-
ditional three equivalents were added over three hours
with TLC monitoring. Under these conditions, we were
able to isolate compound 2a in 67% yield, 71% based on
recovered starting material. The only other significant
product was the benzyne dimer, but being very nonpolar
this was easily separable from the [4+2] product by col-
umn chromatography.
Ar
Ar
Ar
–
+
Ar
Ar
Ar
N
R
N
N
R
R
The use of fewer equivalents of BDC resulted in higher
amounts of recovered starting material. Inferior yields of
compound 2a were observed when benzyne was generat-
ed from 2-trimethylsilylphenyltriflate using CsF, MeCN
(45%), TBAF, THF (38%), and KF, THF, 18-crown-6
(30%). However, for optimum yields, steps had to be tak-
en to eliminate both moisture and acid from BDC.
Scheme 1 Proposed [4+2] route to aryl-substituted 1,4-dihydroquin-
olines
Several groups have previously reported [4+2] cycloaddi-
tion reactions of arynes with a variety of donor–acceptor
reagents. In addition to the voluminous work of the
Larock group,9 this includes 1,3-dienes,10 furans,11 N-acyl In an attempt to better understand the absence of ben-
zoazetidine 4 in the product mixture at high temperature,
this [2+2] product was heated under reflux in chloroben-
zene overnight to see if it was equilibrating to 2a. Howev-
er, the result was a 50% conversion to a compound
SYNLETT 2012, 23, 389–392
Advanced online publication: 19.01.2012
DOI: 10.1055/s-0031-1290137; Art ID: S59311ST
x
x.
x
x.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

390
S. Stokes et al.
LETTER
Table 1 Effects of Solvent and Temperature on Reaction Outcome
OMe
OMe
OMe
OMe
+
N2
–
CO2
(6 equiv)
+
+
N
N
N
Ph
N
Ph
3
Ph
Ph
1a
2a
4
Entry
Solvent
Temp (°C)
84
Yield of 2a (%)
Yield of 3 (%)
Yield of 4 (%)
1
2
3
DCE
PhCl
PhCl
33
52
67
8
13
<5
19
–
130a
130b
–
a BDC added in a single dose.
b BDC added in stages.
1
showing a similar, but clearly nonidentical, H NMR To test whether cycloadditions of 1-azadienes are actually
spectrum to that of 2a. Based on well-established litera- occurring via benzyne formation and not a 2-carboxyphe-
ture precedent of related benzoazetidines,22 we identified nyl cation intermediate generated from stepwise decom-
this structure as the 1,2-diaryl-1,2-dihydroquinoline 5 position of BDC,23 azadiene 1a was reacted with the
presumably formed by electrocyclic ring opening of 4 fol- arenediazonium carboxylate derived from 2-amino-3-me-
lowed by intramolecular [4+2] cycloaddition of the aza- thylbenzoic acid to see if we would observe scrambling of
xylylene intermediate (Scheme 2). This result strongly the methyl group in the product. Indeed, in refluxing chlo-
suggests that at 130 °C, a [4+2] cycloaddition of 1a occurs robenzene an inseparable 1:1 mixture of regioisomeric
to the exclusion of the [2+2] path, given the absence of 1,4-dihydroquinolines resulted (Scheme 3), consistent
compound 5 in the product mixture.
with aryne formation.
The generality of this reaction was investigated by vary-
ing the substitution pattern on the azadiene (Table 2).
Overall, yields of [4+2] products were good to moderate,
and in most cases a small amount of starting material was
recovered. As expected, 2,4-diaryl-substituted derivatives
were accessible (see Table 2, entries 2 and 12), although
additional electron donation at the 2-position did not
translate to a higher yield (Table 2, compare entries 1 and
2). For the synthesis of N-aryl products, reactions tended
to be cleaner when the azadiene was N-substituted with an
electron-withdrawing group (Table 2, compare entries 3
and 4). When this electron demand was reversed, slow ad-
dition of BDC was necessary to avoid further reaction of
the 1,4-dihydroquinoline product with benzyne. Surpris-
ingly, additional methoxy groups on the C4-aryl ring did
not improve yields (Table 2, compare entries 4 and 5),
perhaps due to steric influences. By comparison, N-benzyl
azadienes were found to be less stable than their N-aryl
counterparts, and were often prone to decomposition.
Compound 2g, for example, was eventually prepared in
acceptable yield only when all traces of acid and moisture
were excluded from the reaction. In contrast, both N-Boc-
and N-tosyl-protected azadienes were more stable to the
conditions employed, and gave the expected products
2h–l without noticeable decomposition.
OMe
130 °C
N
N
Ph
4
Ph
OMe
N
Ph
OMe
5 50%
Scheme 2 Formation of 1,2-dihydroquinolines from benzoazeti-
dines
OMe
OMe
OMe
+
N2
–
CO2
+
PhCl, 130 °C
57%
N
N
N
Ph
1a
Ph
Ph
To illustrate an application of this method, 3-O-methylvir-
idicatin (9) was chosen as a suitable target (Scheme 4).
This is one of several 4-arylquinolin-2(1H)-ones which
Scheme 3 Evidence for aryne formation
Synlett 2012, 23, 389–392
© Thieme Stuttgart · New York

LETTER
[4+2] Cycloadditions of Benzyne with 1-Azadienes
391
Table 2 Synthesis of 1,4-Dihydroquinolines from Azadienesa
R3
R3
+
N2
PhCl
+
–
reflux
N
R2
CO2
N
R2
R1
2a–l
R1
1a–l
Entry
1
Azadiene
R1
Ph
Ph
R2
R3
Product
2a
Yield (%)
1a
1b
1c
1d
1e
1f
H
4-MeO
4-MeO
4-MeO
4-MeO
2,4,6-(MeO)3
2,4,6-(MeO)3
4-MeO
4-MeO
H
67b (71)c
63b
2
4-MeOC6H4
2b
2c
3
4-O2NC6H4
H
H
H
H
H
H
H
H
H
Ph
73b
4
4-MeOC6H4
4-MeOC6H4
2d
2e
55b (64)c
48b (58)c
58b (72)c
64b
5
6
3,4,5-(MeO)3C6H2
2f
7
1g
1h
1i
Bn
Boc
Ts
2g
8
2h
2i
53b
9
41b (57)c
61b (70)c
64b
10
11
12
1j
Ts
4-MeO
4-O2N
H
2j
1k
Ts
2k
2l
1l
Ts
59b (67)c
a Reaction conditions: 1 (0.4 mmol), BDC (3–6 equiv), PhCl (3 mL), 130 °C, 12–18 h.
b Yield of isolated product.
c Yield based on recovered starting material.
have attractive considerable attention in recent years for of 8 gave the desired product 9 in 59% overall yield from
their biological activities.24 Isolated as a fungal metabolite 2i.
in 1964,25 3-O-methylviridicatin was shown to inhibit the
Finally, N-tosylated products of cycloaddition provided
additional confirmation of structure assignments. Base
treatment of 2j, for example, gave the quinoline 10
(Scheme 5) which correlated with the spectral data of the
replication of HIV induced by tumor necrosis factor-a.26
Working on the hypothesis that it functions by inhibiting
the signaling of NF-kB, Désaubry and colleagues recently
designed analogues of this natural product that showed
known compound.28
promise as potential anti-inflammatory agent.27 Com-
pound 2i was oxidized to the 2,3-diol 6 and then to the cor-
responding dione which tautomerized to 7. Following
near-quantitative methylation of 7, standard detosylation
OMe
OMe
Ph
Ph
Ph
NaOH, MeOH
reflux, 90%
OH
OH
OH
O
OsO4
TPAP
N
N
CH2Cl2
NMO
84%
N
N
N
Ts
90%
2j
Ts
Ts
Ts
10
2i
6
7
Scheme 5 Synthesis of quinolines from N-tosyl-protected products
Ph
Ph
of [4+2] cycloaddition
OMe
O
OMe
Me2SO4, DMF
Na naphth.
Cs2CO3
98%
THF, DME
80%
N
N
H
O
In summary, the [4+2] cycloaddition of benzyne with aza-
dienes has been shown to be a useful route to aryl-substi-
tuted 1,4-dihydroquinolines. The oxidation of these
products to biologically active 4-arylquinoline-2-ones and
Ts
8
9
Scheme 4 Synthesis of 3-O-methylviridicatin
© Thieme Stuttgart · New York
Synlett 2012, 23, 389–392

392
S. Stokes et al.
LETTER
Roca, T.; Monerris, M.; García-Díaz, D. Tetrahedron Lett.
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General Method for Preparing the Aryl-Substituted 1,4-Dihy-
droquinolines
Anthranilic acid (165 mg, 1.2 mmol) and TCA (1 mL, 0.03 mmol,
0.03 M in THF dried over crushed 4 Å MS) were dissolved in THF
(2 mL) and cooled to 0 °C. Isopentyl nitrite (321 mL, 2.4 mmol) was
added and stirred at 0 °C for 15 min then warmed to r.t. and stirred
for 45 min. The precipitate was filtered and washed with chloroben-
zene (Caution: use a plastic spatula when handling the diazonium
salt). The diazonium salt was added to chlorobenzene (3 mL) and
1,2-epoxy-2-methylpropane (213 mL, 2.4 mmol) and stirred for 15
min. This suspension was slowly added to a refluxing mixture of
azadiene (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 peri-
odically over several hours. Once TLC showed that significant
amounts of product had formed, the reaction was cooled to r.t., and
the solvent was removed under reduced pressure. The crude oil was
subjected to flash gradient column chromatography on neutral alu-
mina using hexane–EtOAc mixtures as the eluting solvents.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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[4+2] cycloadditions of arynes with benzylidene amines.
See: González, C.; Guitián, E.; Castedo, L. Tetrahedron
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Acknowledgment
We thank the National Institutes of Health through Grant No. 1 R15
GM088780-01 for financial support of this research.
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Synlett 2012, 23, 389–392
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