Synthesis of lactone-fused pyrroles by ruthenium-catalyzed 1,2-carbon migration-cycloisomerization

Article abstract of DOI:10.1039/c9ob02363a

A ruthenium-catalyzed cycloisomerization of 3-amino-4-alkynyl-2H-chromen-2-ones via 1,2-carbon migration was developed. Various 1-arylchromeno[3,4-b]pyrrol-4(3H)-ones were synthesized in good to excellent yields. The reaction was applied to the formal total synthesis of marine natural products Ningalin B and Lamellarin H. The efficient synthesis of γ-butyrolactone-fused pyrrole derivatives was also achieved.

Full text of DOI:10.1039/c9ob02363a

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Synthesis of lactone-fused pyrroles by ruthenium-
catalyzed 1,2-carbon migration-cycloisomerization†
Cite this: Org. Biomol. Chem., 2020,
18, 81
Takuma Watanabe, Yuichiro Mutoh * and Shinichi Saito
*
Received 1st November 2019,
Accepted 22nd November 2019
A ruthenium-catalyzed cycloisomerization of 3-amino-4-alkynyl-2H-chromen-2-ones via 1,2-carbon
migration was developed. Various 1-arylchromeno[3,4-b]pyrrol-4(3H)-ones were synthesized in good to
excellent yields. The reaction was applied to the formal total synthesis of marine natural products Ningalin B
and Lamellarin H. The efficient synthesis of γ-butyrolactone-fused pyrrole derivatives was also achieved.
DOI: 10.1039/c9ob02363a
rsc.li/obc
nylchromeno[3,4-b]pyrrol-4(3H)-one can be synthesized by
applying the reaction. Considering the importance of the chro-
Introduction
1-Arylchromeno[3,4-b]pyrrol-4(3H)-one skeleton is found in meno[3,4-b]pyrrol-4(3H)-one skeleton in medicinal chemistry
natural products such as Ningalin B, Lamellarin H, and related and recent active studies related to the synthesis of Ningalin
compounds (Fig. 1).1 These alkaloids are isolated from marine and Lamellarin derivatives, the development of a new and
organisms and known to exhibit biological activities1 such as general method for the synthesis of chromeno[3,4-b]pyrrol-4
cytotoxicity,2 MDR reversal activity,2 HIV-1 integrase inhibition,3 (3H)-one derivatives would be highly desirable. In this paper,
and antitumor activity.4 Due to their promising pharmacological we report
potentials, these pyrrole-containing natural products have been 3-amino-4-alkynyl-2H-chromen-2-ones that leads to various
synthesized by various strategies over the years.1,5
1-arylchromeno[3,4-b]pyrrol-4(3H)-ones via 1,2-carbon
Recent examples for the synthesis of the chromeno[3,4-b] migration (Scheme 1c). This new methodology enabled the
pyrrol-4(3H)-one skeleton include palladium-catalyzed cycloiso- formal total synthesis of Ningalin and Lamellarin
a
ruthenium-catalyzed cycloisomerization of
B
merization,6 one-pot multistep synthesis from 4-chloro-3-nitro- H. Moreover, we describe the synthesis of rare γ-lactone-fused
coumarin,7 the functionalization of 2,3-diarylpyrrole,8 the cycliza- pyrrole derivatives by a similar ruthenium-catalyzed 1,2-carbon
tion of 3-nitrocoumarin and papaverine,9 and so on. Among these migration/cyclization strategy.
synthetic methods, the palladium-catalyzed cycloisomerization of
3-amino-4-alkynyl-2H-chromen-2-ones is a straightforward and
powerful method (Scheme 1a).6 The reaction proceeds via intra-
molecular nucleophilic amination of the π-activated alkyne, and
2-substituted chromeno[3,4-b]pyrrol-4(3H)-ones were isolated.
We have recently developed ruthenium-catalyzed cyclo-
isomerization reactions that involve the vinylidene rearrange-
ment of internal alkynes by 1,2-carbon migration and
cyclization.10–13 For example, in the presence of a cationic
ruthenium catalyst, various 2-alkynylanilides were converted
into the 3-substituted indoles in high yields (Scheme 1b).11
The mode of the reaction is different from other metal-cata-
lyzed cycloisomerization of 2-alkynylanilines, where no 1,2-
carbon migration was involved, and 2-substituted indoles were
isolated.14 In that study, we reported one example that 1-phe-
Results and discussion
We investigated the scope and limitation of the reaction using
various
3-amino-4-alkynyl-2H-chromen-2-one
derivatives
(1, Table 1). As previously reported, when a mixture of
Department of Chemistry, Faculty of Science Tokyo University of Science, 1-
3 Kagurazaka Shinjuku-ku, Tokyo 162-8601, Japan. E-mail: ymutoh@rs.tus.ac.jp,
ssaito@rs.kagu.tus.ac.jp
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. CCDC 1961068–1961070. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c9ob02363a
Fig. 1 Representative natural products and analogue containing 1-aryl-
chromeno[3,4-b]pyrrol-4(3H)-one skeleton.
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Table 1 Scope of the ruthenium-catalyzed 1,2-carbon migration/cycli-
zation of 3-amino-4-ethynyl-2H-chromen-2-one derivatives (1)a,b
Scheme 1 Cycloisomerization of 3-amino-4-alkynyl-2H-chromen-2-
ones.
aminocoumarin 1a, [CpRuCl(dppe)] (Cp = η5-C5H5−; dppe =
Ph2PCH2CH2PPh2) (5 mol%), and NaBArF4·3H2O (ArF = 3,5-
(CF3)2C6H3) (6 mol%) was stirred at 145 °C for 2.5 h in chloro-
benzene, the desired 1,2-aryl migration product 3-phenylpyrrolo-
coumarin (2a) was formed in 95% yield.10,15 Isomeric 2-sub-
stituted pyrrole was not observed in the reaction mixture.
Although the reaction of 1a at 130 °C completed in 16 h at the
same catalyst loading, the yield of 2a was lower (82%).
[IndRuCl(dppe)] (Ind = η5-C9H7−) and [CpFeCl(dppe)] were
inactive catalysts for this reaction, and 2a was not formed.
We studied the impact of the aryl groups bound to the
ethynyl group (R1) on the reaction. Under the similar reaction
a Reaction conditions: 1 (0.25–0.5 mmol, [1]0 = 0.025–0.2 M in chloro-
benzene), [CpRuCl(dppe)] (1–10 mol%), NaBArF4·3H2O (1.2–12 mol%).
b Isolated yields are shown in parentheses except for 1j.
The scope of the reaction was further studied by introdu-
conditions described above, 4-methoxyphenyl pyrrole 2b was cing non-aromatic substituents as R1. The reactivity of benzoyl
obtained in 98% yield with lower catalyst loading. Electron- aminocoumarin 1i was similar to that of aryl-substituted amino-
withdrawing groups were tolerated for this reaction, and pyrro- coumarins, and the corresponding pyrrole 2i was prepared
locoumarins 2c (92% yield) and 2d (96% yield) were syn- in 89% yield. The reaction of 1j (R1 = Bu) did not proceed, and
thesized in the presence of 10 mol% [CpRuCl(dppe)]. The low the starting material was recovered. The low reactivity of 1j is
reactivity of the alkynes with electron-withdrawing groups (1c in contrast to our previous result: the cycloisomerization of a
and 1d) compared to the substrate with electron-donating 2-hexynylaniline derivative generated the corresponding
group (1b) was consistent with our previous studies on the 3-butylindole derivative.10 The reaction of 1j in the presence
ruthenium-catalyzed cycloisomerizations via 1,2-carbon of [CpRuCl(dppbz)] (dppbz
= 1,2-bis(diphenylphosphino)
migration10,11 and probably attributed to the rates of the for- benzene), which is a more effective catalyst for the synthesis of
mation of the disubstituted ruthenium vinylidene complex.16 alkylated indoles,10,17 also afforded no desired product. We
Pyrrolocoumarin 2e with 3,4-dimethoxyphenyl group was also assume that the decreased rate for the alkyne-to-vinylidene
formed from 1e in 81% yield. When the reaction of sterically rearrangement of electron-deficient and alkyl-substituted
congested amionocoumarin 1f bearing 1-naphthyl group at the acetylene16,18 could be the reason for this unsuccessful result.
alkyne terminus was examined in the presence of 5 mol% of
The effect of the substituents introduced to R2 and R3 on
the ruthenium catalyst, the progress of the reaction was slug- the coumarin moiety was explored. A methoxypyrrolcoumarin
gish. In the presence of an increased amount (25 mol%) of (2k, R2 = OMe, R3 = H) as well as a fluoropyrrolocoumarin
[CpRuCl(dppe)], however, the corresponding product 2f was (2l, R2 = H, R3 = F) were synthesized in high yields.
isolated in 89% yield. The compatibility of the substrates with
We further extended our study to the synthesis of a benzo-
heteroaryl groups was also evaluated, and 5-indolyl derivative fused pyrrolocoumarin derivative.19 The synthesis and
2g (96% yield) and thiophen-3-yl derivative 2h (90% yield) were ruthenium-catalyzed cycloisomerization of a benzochrome-
synthesized cleanly.
none derivative 1m was summarized in Scheme 2. When we
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Scheme 2 Preparation of 1m and the synthesis of 2m.
tried to synthesize 5 by the bromination of 3 20 with NBS in the
presence of a catalytic amount of NH4OAc at 0 °C,21 an unex-
pected product 4 was isolated in 59% yield. Since the corres-
ponding bromide was not isolated in the reaction of the bicyc-
lic 3-amino-2H-chromen-2-one under similar reaction con-
ditions,21 we assume that the presence of the C–H bond in the
proximity of the bromine atom inhibited the isomerization
reaction of 4 at 0 °C. Due to the steric hindrance, the rate of
the conversion of 4 to 5 should be lower compared to those of
other aminocoumarins. The isomerization of 4 smoothly pro-
ceeded at elevated temperature (70 °C), and compound 5 was
isolated in 79% yield. Subsequently, 1m was synthesized in
99% yield by Sonogashira reaction of 5 with 4-methoxyphenyl-
acetylene under modified Stoddart’s conditions.22 The reactiv-
ity of 1m was similar to that of sterically congested substrate
1f: the desired product 2m was isolated in 82% yield when a
larger amount (25 mol%) of the catalyst was employed.
Scheme 3 Synthesis of the key intermediate 2n for the synthesis of
bioactive compounds.
Table 2 Synthesis of γ-butyrolactone-fused pyrrole derivativesa,b
Next, we applied this reaction to the formal total synthesis
of Ningalin B and Lamellarin H (Scheme 3). When 6 23,24 was
treated with methyl aminoacetate hydrochloride,25 aminocou-
marin 7 was obtained in 43% yield. The bromination of 7 pro-
ceeded at −35 °C to afford 8 in 80% yield. No α-bromoimine,
which was similar to 4, was isolated. Compound 1n was syn-
thesized in 92% yield by Sonogashira reaction. To our delight,
2n was obtained in quantitative yield in the presence of
5 mol% of the ruthenium catalyst. The structure of 2n was con-
firmed by an X-ray diffraction analysis.26 With the key inter-
mediate (2n) in hand, hexamethyl Ningalin B (9) was syn-
thesized in 96% yield by alkylation of 2n.7 The demethylation
of 9 to Ningalin B was reported by Boger and co-workers.2
Compound 9 is also the intermediate of Lamellarins, and the
conversion of 9 into Lamellarin G trimethyl ether27 and sub-
sequent transformation to Lamellarin H were reported.28
a Reaction conditions: 1 (0.25–0.4 mmol, [1]0 = 0.1–0.2 M in chloroben-
zene), [CpRuCl(dppe)] (3–5 mol%), NaBArF4·3H2O (3.6–6.0 mol%).
b Isolated yields are shown in parentheses.
Therefore, we achieved the formal total synthesis of natural synthesized a series of γ-butyrolactone-fused pyrroles by the
products, Ningalin B and Lamellarin H. ruthenium-catalyzed cycloisomerization of 3-amino-4-arylethy-
Furthermore, we examined the synthesis of γ-butyrolactone- nylfuranones. Under the established reaction conditions
fused pyrroles to exemplify the application of this reaction described for the reaction of 3-amino-4-alkynyl-2H-chromen-2-
(Table 2). In spite of the simplicity of the structure, only a one, the desired γ-butyrolactone-fused pyrroles 2o and 2p were
couple of γ-butyrolactone-fused pyrroles has been reported in isolated in 87% and 86% yields, respectively. The molecular
the literature,29,30 and a general method for the synthesis of structure of 2p was confirmed by a single-crystal X-ray diffrac-
these compounds has not been established. We successfully tion analysis. The reaction of aminobutenolide 1q with an
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ethoxycarbonyl group also afford the corresponding pyrrole 2q 10 T. Watanabe, Y. Mutoh and S. Saito, J. Am. Chem. Soc.,
in high yield. The reaction of 1r with 3,4-dimethoxyphenyl
group proceeded cleanly, and 2r was obtained in 86% yield.
2017, 139, 7749.
11 T. Watanabe, H. Abe, Y. Mutoh and S. Saito, Chem. – Eur. J.,
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12 For recent reviews on catalytic processes that involve vinyli-
dene intermediates, see: (a) J. A. Varela, C. González-
Rodríguez and C. Saá, Top. Organomet. Chem., 2014, 237;
(b) S. W. Roh, K. Choi and C. Lee, Chem. Rev., 2019, 119,
4293.
Conclusions
We have developed a synthetic method for various 1-arylchro-
meno[3,4-b]pyrrol-4(3H)-ones by ruthenium-catalyzed cyclo-
isomerization of 3-amino-4-ethynyl-2H-chromen-2-ones via 1,2- 13 For stoichiometric internal alkyne-to-vinylidene rearrange-
carbon migration. The formal total synthesis of Ningalin B
and Lamellarin H was achieved by employing this reaction.
Moreover, a general method for the synthesis of uncommon
γ-butyrolactone-fused pyrroles was established. Our studies
will contribute to the development of a new method for the
synthesis of heavily substituted pyrrole derivatives.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This research was supported in part by JSPS KAKENHI Grant
Number JP19J14232 (T. W.), as well as Taisho Pharmaceutical
Co., Ltd. Award in Synthetic Organic Chemistry, Japan (Y. M.),
the JGC-S Scholarship Foundation (Y. M.), and the Promotion
Expenses for Mid-term Research Strategic Plan by Tokyo
University of Science.
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