A palladium-catalyzed intramolecular carbonylative annulation reaction for the synthesis of 4,5-fused tricyclic 2-quinolones

Article abstract of DOI:10.1039/c6cc02600a

A concise and efficient synthetic route to 4,5-fused tricyclic 2-quinolones through the palladium-catalyzed carbonylative annulation of alkyne-tethered N-substituted o-iodoanilines has been developed. This reaction proceeds smoothly under mild reaction conditions and exhibits exceptional tolerance to a variety of functional groups. It has been successfully applied to the efficient synthesis of BI 224436, an HIV integrase inhibitor.

Full text of DOI:10.1039/c6cc02600a

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A palladium-catalyzed intramolecular carbonylative annulation reaction
to form 4,5-fused tricyclic 2-quinolones
Xiwu Zhang,‡ Haichao Liu,‡ and Yanxing Jia*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Figure 1 Selected biologically active 4,5-fused tricyclic 2-
quinolones and 4,5-fused tricyclic quinolines.
A concise and efficient synthetic route to 4,5-fused tricyclic 2-
quinolones through palladium-catalyzed carbonylative
a
annulation of alkyne-tethered N-substituted o-iodoanilines has
In 2004, Larock and Kadnikov reported a concise and efficient
55 synthetic route to 2-quinolones through a palladium-catalyzed
carbonylative annulation of N-substituted o-iodoanilines with
internal alkynes (Scheme 1, eqn (1)).4 The nature of the substituent
on the nitrogen is crucial for obtaining high yields of 2-quinolones,
and the nitrogen substituent is lost during the course of the reaction.
60 This multicomponent process is significant because it involves the
formation of two carbon-carbon and one carbon-nitrogen bonds.
During the course of our studies on the total synthesis of 3,4-fused
indole alkaloids, we have recently developed a new strategy for the
construction of 3,4-fused tricyclic indoles by intramolecular
65 Larock indolization of alkyne-tethered o-iodoanilines (Scheme 1,
eqn (2)).10 This general strategy can be widely applied to the total
synthesis of 3,4-fused alkaloids and related systems. Encouraged
by these results, we were curious whether an intramolecular
carbonylative annulation of alkyne-tethered o-iodoaniline
70 derivatives could be applied for the construction of 4,5-fused
tricyclic 2-quinolones (Scheme 1, eqn (3)). Herein, we report our
early results.
been developed. This reaction proceeds smoothly under mild
10 reaction conditions and exhibits exceptional tolerance to a
variety of functional groups. It has been successfully applied to
the efficient synthesis of BI 224436, an HIV integrase inhibitor.
The 2-quinolone nucleus is one of the most important heterocycles
since they are found in various natural products and
15 pharmaceutically active compounds.1,2 In addition, 2-quinolones
are also valuable synthetic intermediates that can be easily
converted into 2-haloquinoline derivatives, which could undergo
further modifications.3 Accordingly, a variety of well-documented
traditional and modern methods have been developed for the
20 construction of 2-quinolines.4-6 Among the members of the 2-
quinolone family, 4,5-fused tricyclic 2-quinolones have been
considered attractive synthetic targets because of their unique
molecular skeletons and potential pharmaceutical activities (Figure
1).7-9 For example, compound 1 exhibits highly specific inhibitory
25 activity toward apoptosis signal-regulating kinase 1 (ASK1) and
could be used for the treatment of cardiac and neurodegenerative
disorders.7a In addition, 4,5-fused tricyclic 2-quinolones have been
used as synthetic intermediates and converted into 4,5-fused
tricyclic 2-chloro- quinolines or 4,5-fused tricyclic quinolines.8
30 Moreover, the tricyclic quinoline derivatives have also been
reported to have interesting biological activities.8 Compound 3 (BI
224436) is the first noncatalytic site integrase inhibitor of HIV‑1
to undergo a phase Ia clinical trial.8a,b Compound 4 shows a
noticeable cytotoxic activity against HT-29 with an IC50 value of
35 0.16 µM.7d
Larock's work (ref 4):
R1
75
R1
I
NHCO2Et
R2
1. cat. Pd, CO
+
(1)
(2)
2. NaOH
N
O
R2
H
Our previous work (ref 10):
80
85
90
Y
Y
cat. Pd
4
3
I
R
40
R
N
H
NH2
This work:
Y
Y
1. cat. Pd, CO
5
45
4
R
O
I
(3)
2. NaOH
R
N
H
NHCO2Et
Scheme 1 Intramolecular annulation strategies for the synthesis of
4,5-fused tricyclic 2-quinolones.
50
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50 Table 2. Under our optimized reaction conditions, the reaction
Initially, compound 5a was chosen as a model substrate and
subjected to Larock’s 2-quinolone synthesis conditions [Pd(OAc)2
(0.1 equiv.), pyridine (2.0 equiv.), TBAC (1.0 equiv.) in DMF
(0.01 M) under 1 atm CO at 100 °C for 24 h]. The desired 4,5-
proceeded smoothly to yield a series of 4,5-fused tricyclic 2-
quinolones in moderate to excellent yields. DFOirIs:t1ly0.,10th3e9/eCl6eCctCro0n26ic00A
effects of aryl groups attached to the internal alkyne were first
examined (Table 2, 5c-7c). We found that there was no significant
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5
fused tricyclic 2-quinolone 6a was obtained in only 25% yield 55 electronic effect of aryl groups on the internal alkyne. To explore
accompanied with a recovery of 53% starting material 5a (Table 1,
entry 1). Interestingly, replacement of additive TBAC with LiCl
gave better result and the unprotected product 7a was also obtained
the substituent effects of internal alkyne, a variety of internal
alkynes bearing TES, alkyl, alkene, aryl and heteroaryl groups
were examined (Table 2, 7c-7h). They all gave the expected
products in moderate to good yields. These results indicated that
10 in 34% yield, which was generated in situ by deprotection of the
nitrogen substituent (Table 1, entry 2). Considering the low 60 the substituents did not affect the reactivity of this transformation.
boiling point of pyridine and its diluted concentration, the amount
of pyridine was increased to 5 equivalents. To our delight, the yield
of 6a was increased to 69% and the yield of 7a was 21% (Table 1,
15 entry 3). Next, the effect of reaction temperature was examined.
The substrates leading to 7- and 8-membered ring fused 2-
quinolones were then examined and gave the desired products in
good yields (Table 2, 7i-7k). In addition, o-methyl substituent on
the o-iodoaniline was well tolerated, giving corresponding product
When the temperature was decreased to 80 °C, the reaction was 65 in 60% yield (Table 2, 7l).
notably slower. 6a was obtained in 60% yield accompanied with a
recovery of 28% starting material 5a, and no 7a was generated
(Table 1, entry 4). Increasing the temperature to 120 °C led to the
20 completely consume of 5a, but the yields of 6a and 7a were only
30% and 39%, respectively (Table 1, entry 5). Finally, we found
that the phosphine ligand was effective for this process. When 0.2
equivalent of PPh3 was added, the desired product was obtained in
95% overall yield (Table 1, entry 6), although the exact role of
25 PPh3 is not clear.11 Thus, the optimized conditions is: 10 mol %
Pd(OAc)2, 5 equivalent of pyridine, 1 equivalent of LiCl, and 0.2
equivalent of PPh3 in DMF at 100 °C for 24 h.
Table 2 Substrate scope for the formation of 4,5-fused tricyclic 2-
quinolonesa
70
75
Table 1 Optimization of reaction conditionsa
30
80
35
85
Yield (%) of
Equiv. of
Entry Additive
Temp.
6a, 7a, and
pyridine
90
recovery of 5a
1
2
3
4
5
6 b
TBAC
LiCl
LiCl
LiCl
LiCl
LiCl
2
2
5
5
5
5
100 °C
100 °C
100 °C
80 °C
120 °C
100 °C
25:0:53
33:34:28
69:21:5
60:0:28
30:39:0
70:25:0
95
a
40 Reaction conditions: 5a (0.3 mmol), Pd(OAc)2 (10 mmol%),
pyridine (as indicated), additive (as indicated) in DMF (30 mL)
under 1 atm CO for 24 h. b 0.2 equiv of PPh3 was added.
100
a
Reaction conditions: 5a (0.3 mmol), Pd(OAc)2 (10 mmol%),
Under the optimized reaction conditions, we next examined the
45 substrate scope of this reaction. Considering that most substrates
afforded the cyclized products 6 and 7 as a mixture in different
ratios, the crude products were treated with 1 M ethanolic NaOH
for 1 h at room temperature to hydrolyze 6 completely and the yield
of 7 was obtained. The results of this study are summarized in
pyridine (5 equiv.), additive (2 equiv.), and PPh3 (20 mmol%) in
DMF (30 mL) under 1 atm CO for 24 h.
105
The utility of this new process was demonstrated by a rapid
formal synthesis of compound 3, a HIV integrase inhibitor
2
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TES
O
NBS, CH2Cl2, 0 °C, 2 h
32% (90% brsm)
TES
O
N
H
N
H
7h
Br
8
O
N
O
POCl3, MeCN
75 °C, 6 h
Me
[8a]
Me
N
O
Me
70%
N
Cl
CO2H
Br
Me
9
3 (BI 224436)
Scheme 2 Formal synthesis of compound 3 (BI 224436).
7
10
In summary, we developed a novel and efficient strategy for the
construction of 4,5-fused tricyclic 2-quinolones via palladium-
catalyzed intramolecular carbonylative annulation of alkyne-
tethered N-substituted o-iodoanilines. A variety of 4,5-fused
tricyclic 2-quinolones have been successfully prepared. Its utility
15 has been demonstrated with the rapid synthesis of BI 224436. We
expect that this intramolecular protocol will find use in broad
chemical synthesis.
8
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Acknowledgements
This research was supported by the National Natural Science
20 Foundation of China (Nos. 21372017, 21290183, and 21572008).
Notes and references
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing
100191, China; Fax: 86-10-82805166; Tel: 86-10-82805166; E-mail:
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‡ These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: Experimental
details and spectroscopic characterization. See DOI: 10.1039/b000000x/
30
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