Stereoselective synthesis of medicinally relevant furo[2,3-d]pyrimidine framework by thermal rearrangement of spirocyclic barbiturates

Abstract

A new rearrangement of functionalised cyclopropanes was found: the thermally initiated transformation of substituted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octanes in DMSO at 100 °C results in the formation of furo[2,3-d]pyrimidines in 50–75% yields. Similar results were obtained using [BMim][BF₄] as a solvent. NMR and single-crystal X-ray diffraction analysis indicate stereoselective formation of (5R*,6R*) isomers by thermal rearrangement of 2-aryl-1-cyano-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1-carboxylates.

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Introduction

The cyclopropane subunit plays a prominent role in organic chemistry. Its distinctive reactivity is caused by its strained structure and unique bonding characteristics, which underlie a variety of chemical transformations available for three-membered cycloalkanes. Cyclopropane and its derivatives are efficient and powerful synthetic building blocks for the straightforward synthesis of diverse carbo- and heterocycles with molecular complexity.¹ Cyclopropanes with donor and acceptor substituents in the vicinal position (donor–acceptor cyclopropanes) are popular in organic synthesis nowadays as a source of 1,3-dipoles, generated from them in the presence of Lewis acids or upon heating.^1e–k,2

Among the different types of cyclopropane fragments, a spirocyclopropyl moiety joined with a heterocyclic counterpart has attracted particular attention due to its synthetic utility and wide number of pharmacological applications.³ In particular, fused spirocyclopropyl heterocycles have been recognized as α-L-fucosidase,^3a β-lactamase,^3b and HIV-1 non-nucleoside reverse transcriptase inhibitors, as well as diagnostic markers for the early detection of colorectal and hepatocellular cancers.^3c,d

Barbituric acid is a versatile molecule for designing potential bioactive agents. A large number of substituted barbituric acid derivatives have been reported to exhibit a broad spectrum of biological properties like anticonvulsant,^4a anaesthetic,^4b antiparkinsonian,^4c sedative and hypnotic.^4d,e Spirobarbiturates have attracted special attention in the organic and pharmaceutical communities due to their unique structural assembly and associated spectrum of biological activities.⁵

In a course of our studies on the electrocatalytic synthesis of cyclopropane derivatives,⁶ we recently reported an efficient stereoselective approach to the 4,6,8-trioxo-5,7-diazaspiro[2.5]octanes 1 and 2 (Scheme 1).⁷ The donor–acceptor cyclopropanes 1 and 2 were isolated by direct filtration of the reaction mixture and did not require any further purification.

Scheme 1 Stereoselective electrocatalytic synthesis of 4,6,8-trioxo-5,7-diazaspiro[2.5]octanes.

The ever-growing importance of thermal cyclopropane rearrangements in various synthetic applications attests to the uniqueness and convenience of this methodology, especially when the starting cyclopropane is more readily available than isomeric propene.^1a,8 Recently, we carried out the stereoselective thermal isomerization of bis(spiropyrazolone)cyclopropanes into (4Z)-4-[(pyrazol-4-yl)methylene]pyrazolones.⁹ A thorough literature search revealed that there are no precedents of thermal rearrangements of spirocyclic barbiturates containing a cyclopropane ring.

Results and discussion

In the present study we report our results for the thermal rearrangement of spirocyclic barbiturates 1 (Scheme 2, Tables 1 and 2) and 2 (Scheme 3, Table 3). In order to find optimal conditions, the thermal rearrangement of 5,7-dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 1a was selected as a model reaction (Table 1).

Table 1 Thermal rearrangement of 1a into 3a^a

Entry	Solvent	Temperature (°C)	Time (min)	Conv. of 1a^b (%)
a 1a (1 mmol), solvent (10 mL), heating.b Selective conversion into 3a, ^1H NMR data.c 0.5 mL of solvent.d 1 mmol of ionic liquid was used.
1	H2O	100	30	0
2	EtOH	78	30	0
3	n-PrOH	97	30	12
4	EtOAc	77	30	0
5	MeCN	82	30	12
6	Toluene	110	30	15
7	DMF^c	100	30	52
8	NMP^c	100	30	75
9	DMSO^c	100	30	84
10	[BMim]BF4^d	100	30	86
11	DMSO^c	100	15	50
12	DMSO^c	100	60	65
13	DMSO^c	50	30	0
14	DMSO^c	150	30	73

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The heating of 1a in water or ethanol under reflux for 30 min did not result in any conversion of the starting compound, probably due to its insolubility (Table 1, entries 1 and 2). After 30 min under reflux conditions in 1-propanol, 1a was selectively converted into 1,3-dimethyl-2,4-dioxo-6-phenyl-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidine-5,5(6H)-dicarbonitrile 3a in 12% yield (entry 3). As for aprotic solvents, a solution of 1a in ethyl acetate under reflux was unreactive, although in boiling acetonitrile or toluene the selective conversion into 3a was observed in 12% and 15% yield, respectively (entries 4–6). A dramatic improvement was achieved with high-boiling point polar aprotic solvents. Thus, heating 1a at 100 °C in DMF resulted in the formation of 3a in 52% yield (entry 7). The use of more polar solvents, such as NMP or DMSO, for 30 minutes at 100 °C resulted in 75% and 84% conversion of the starting compound, respectively, and only 1,3-dimethyl-2,4-dioxo-6-phenyl-1,2,3,4-tetrahydro-furo[2,3-d]pyrimidine-5,5(6H)-dicarbonitrile 3a was formed (entries 8 and 9). Moreover, these conditions allowed a 20-fold decrease in the required amount of solvent. The optimal conditions are 30 min heating in DMSO at 100 °C. Both an increase and decrease in temperature or time of procedure resulted in a drop in the yield of 3a (entries 11–14).

It was also found that the rearrangement of 1a into 3a occurred with high selectivity (86%) using 1-butyl-3-methylimidazolium tetrafluoroborate [BMim]BF₄ as a solvent. The recovery and reuse of the ionic liquid was examined. The reaction was then attempted in recovered ionic liquid. A marginal loss in the yield of 3a was observed within five cycles (Fig. 1).

Fig. 1 Reusability of ionic liquid [BMim]BF₄.

Under the optimal conditions (0.5 mL of DMSO, as a cheaper reagent than [BMim]BF₄, at 100 °C for 30 min) the thermal rearrangement of 2-aryl-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles 1a–g afforded the corresponding 6-aryl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-furo[2,3-d]pyrimidine-5,5(6H)-dicarbonitriles 3a–g in 50–66% yield (Scheme 2, Table 2).

Scheme 2 Thermal rearrangement of 2-aryl-5,7-dialkyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles 1.

Table 2 Thermal rearrangement of spirocyclopropylbarbiturates 1a–g to 5,6-dihydrofuro[2,3-d]pyrimidines 3a–g^a

Entry	R^1	R^2	Product	Yield of 3^b (%)
a 1 (1 mmol), DMSO (0.5 mL), 100 °C.b Yield of isolated product.
1	Me	H	3a	66
2	H	H	3b	52
3	Et	H	3c	61
4	Me	4-tBu	3d	58
5	Me	4-Me	3e	66
6	Me	4-Cl	3f	50
7	Me	3-Br	3g	62

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Furo[2,3-d]pyrimidines possess important biological activities, which are:

(1) Classical antifolate activity towards dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS), as well as antitumor activity;¹⁰

(2) Multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity;¹¹

(3) RTK and dihydrofolate reductase (DHFR) inhibitory activity in single molecules, as potential cytostatic and cytotoxic agents with antitumor activity.¹²

Also, furo[2,3-d]pyrimidines are potent inhibitors of RIP1 (receptor interacting protein 1) kinase¹³ and show anti-HCMV (human cytomegalovirus) activity.¹⁴

To widen the scope of the discovered method and evaluate its stereoselectivity aspects, the thermal rearrangement of alkyl (1R*,2S*)-1-cyano-5,7-dimethyl-4,6,8-trioxo-2-phenyl-5,7-diaza-spiro[2.5]octane-1-carboxylates 2a–g was studied. Under the optimal conditions (0.5 mL of DMSO at 100 °C for 30 min), the thermal rearrangement of 2a–g afforded the corresponding alkyl 6-aryl-5-cyano-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6-hexahydrofuro[2,3-d]pyrimidine-5-carboxylates 4a–g in 51–75% yields (Scheme 3, Table 3).

Scheme 3 Stereoselective thermal rearrangement of alkyl (1R*,2S*)-1-cyano-2-aryl-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1-carboxylates 2.

Table 3 Stereoselective thermal rearrangement of spirocyclopropylbarbiturates 2a–g to 1,2,3,4,5,6-hexahydrofuro[2,3-d]pyrimidine-5-carboxylates 4a–g^a

Entry	R^1	R^2	Product	Yield of 4^b (%)
a 2 (1 mmol), DMSO (0.5 mL), 100 °C.b Yield of isolated product.
1	H	Me	4a	59
2	H	Et	4b	51
3	4-tBu	Et	4c	55
4	4-Me	Me	4d	70
5	3-Br	Me	4e	73
6	4-Cl	Et	4f	75
7	4-F	Me	4g	56

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It should be mentioned that the obtained furo[2,3-d]pyrimidines 4a–g could exist as pairs of diastereoisomers with (5R*,6R*) or (5R*,6S*) configuration of the aryl and carbomethoxy substituents. However, in the NMR spectra of 4a–g, only a single set of signals was present, indicating the stereoselective formation of individual diastereoisomers in the developed thermal rearrangement. The structure of furo[2,3-d]pyrimidine 4a was further confirmed by a single-crystal X-ray diffraction study (Fig. 2). The X-ray diffraction data unambiguously support the (5R*,6R*) configuration for 4a. Considering the facts given above, compounds 4a–g should also possess the (5R*,6R*) configuration.

Fig. 2 X-ray crystal structure of 4a.†

A probable mechanism involved in the formation of the products is outlined in Scheme 4. We guess that the scission of the cyclopropane bond upon heating in polar DMSO takes place in a concerted fashion, followed by the furan ring closure.

Scheme 4 Probable mechanistic pathway for the synthesis of furo[2,3-d]pyrimidines 3 and 4.

Conclusions

In conclusion, we have developed an efficient approach to substituted furo[2,3-d]pyrimidines by thermal rearrangement of readily accessible spirocyclic barbiturates. The isomerization proceeds simply upon heating in DMSO, does not require any additional reagents or catalysts, and affords the 1,3-dimethyl-2,4-dioxo-6-phenyl-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidine-5,5(6H)-dicarbonitriles and individual diastereoisomers of alkyl (5R*,6R*)-5-aryl-6-cyano-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6-hexahydrofuro[2,3-d]pyrimidine-6-carboxylates in good yields. The products are isolated by water-assisted precipitation directly from the reaction mixture.

Acknowledgements

The reported study was funded by RFBR, according to the research project No. 15-33-20168.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1423220. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra19169f

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