The Baylis–Hillman acetates in organic synthesis: Unprecedented sodium nitrite induced intramolecular Friedel–Crafts cyclization of secondary nitro compounds

Abstract

Unprecedented sodium nitrite mediated intramolecular Friedel–Crafts cyclization of alkyl (E)-2-arylidene-4-nitroalkanoates and (E)-3-arylidene-5-nitroalkan-2-ones derived from Baylis–Hillman acetates, providing a facile protocol for synthesis of naphthalenes, phenanthrenes, and carbazoles has been described.

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The nitro group is one of the key functional groups that plays a vital role in synthetic chemistry.¹ The high electron withdrawing ability of the nitro group has resulted in numerous applications of nitroalkanes as carbon nucleophiles in various carbon–carbon bond forming reactions.² The Nef reaction is yet another useful reaction which transforms the nitro group into the carbonyl group.³ It is very interesting to note the work of Kornblum who, as early as in 1956, reported an elegant conversion of aliphatic nitro compounds into ketones via the reaction with alkyl nitrite and sodium nitrite. The reaction is believed to proceed via nitrosation of aci-nitronate.⁴ Four decades later in 1997 Mioskowski has reported an interesting sodium nitrite mediated nitrosation of primary nitroalkanes leading to the formation of carboxylic acids.^5a In 2004 the research group of Mioskowski also described facile conversion of secondary nitroalkanes into ketones using sodium nitrite under neutral conditions (Scheme 1).^5b

Scheme 1 Formation of ketone from secondary nitroalkane

It needs to be mentioned here that there are a few reports in the literature on the application of aliphatic nitro compounds as electrophiles in the Friedel–Crafts (F–C) reaction in the presence of various acids.⁶ Kim and co-workers reported sulphuric acid mediated intramolecular F–C reaction of the aliphatic nitro compounds obtained from the Baylis–Hillman (BH) adducts producing naphthalene derivatives.^6d

Although the in situ generated transient (Kornblum–Mioskowski) species A, B and C in Scheme 1, look potential electrophiles for F–C reaction, to the best of our knowledge, there have been, so far, no such reports in the literature. Therefore we envisioned that secondary nitro-alkanes (3) obtained from the BH acetates (1) would be excellent synthons for intramolecular F–C cyclization using NaNO₂ as reagent to provide a simple protocol for obtaining naphthalenes (4a–p), phenanthrenes (4q–s) and carbazoles (4t, 4u) as shown in the retro synthetic strategy (Scheme 2). Accordingly, in continuation of ongoing research program⁷ on the BH reaction^8,9 we examined these reactions and were pleased to see NaNO₂ mediated intra-molecular F–C cyclization of secondary nitroalkanes (3) work reasonably well. These results are reported in this communication.

Scheme 2 Retro synthetic strategy.

We began our investigations with methyl (E)-2-(3-methoxy-benzylidene)-4-nitropentanoate (3a, R₁ = OMe, R₂ = Me, Ar = 3-MeOC₆H₄) which was easily obtained via alkylation of nitroethane 2a with the BH-acetate, methyl 3-acetoxy-3-(3-methoxyphenyl)-2-methylenepropanoate (1a, R₁ = OMe, Ar = 3-MeOC₆H₄).

We performed the reaction between methyl (E)-2-(3-methoxybenzylidene)-4-nitropentanoate (3a) (1 mmol) with sodium nitrite in the presence of various solvents and at different reaction conditions (entries 1–14, Table 1). In this direction, best results were obtained when a solution of 3a (1 mmol) and NaNO₂ (1 mmol) in DMF (4 mL) was heated at 100 °C for 8 h, thus providing methyl 5-methoxy-4-methylnaphthalene-2-carboxylate (ortho-4a) (ortho cyclized product) and methyl 7-methoxy-4-methylnaphthalene-2-carboxylate (para-4a) (para cyclized product) in 13% and 71% isolated yields respectively (Table 1, entry 11) after usual work up, followed by purification through silica gel column chromatography.¹⁰

Table 1 Optimization of reaction conditions^a

Entry	NaNO2 (eq.)	Solvent	Temp/°C	Time/h	Yield^b (%) o-4a/p-4a
a All reactions were carried out on 1 mmol scale of 3a in 4 mL of solvent.b Isolated yields based on 3a.c DMSO–H2O (3.5 : 0.5 mL).
1	1.0	DMSO–H2O^c	60	20	16/65
2	1.0	DMSO	60	20	14/68
3	1.0	DMF	RT	24	N.R
4	1.0	DMF	40	24	N.R
5	1.0	DMF	60	20	11/67
6	1.0	DMF	80	15	12/71
7	1.0	EtOH	78	24	N.R
8	1.0	1,4-dioxane	100	24	N.R
9	1.0	Water	100	24	N.R
10	1.0	DMSO	100	8	12/69
11	1.0	DMF	100	8	13/71
12	1.0	DMF	120	8	8/40
13	0.5	DMF	100	8	8/48
14	2.0	DMF	100	8	10/70

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With a view to further understand this strategy we have subjected the nitro compounds (3b and 3c) [prepared from the BH acetate (1a) and nitroalkanes (2b and 2c) (R₂ = Ph, Bn)] to the reaction with NaNO₂ which provided the required substituted naphthalenes 4b and 4c in overall 86 and 84% yields respectively [see Table 2 for composition of para (major) and ortho (minor) cyclized products]. We have also examined the F–C cyclization of the nitro compound (3d, R₁ = Me, R₂ = Ph, Ar = 3-MeOC₆H₄) with NaNO₂ which gave the desired naphthalene, para-4d in 70% yield along with ortho-4d in 14% yield (Table 2).

Table 2 Understanding the scope of reaction^a

a All reactions were carried out on 1 mmol scale of 3 with 1 equiv. of NaNO₂ in DMF (4 mL). The yields in parentheses are isolated yields based on 3.b The structure of this molecule was also confirmed by single crystal X-ray data analysis [see ESI¹].

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With a view to understand the generality of this reaction we have prepared representative arylidene secondary nitroalkane compounds (3e–u) (eqn (1)) and subjected them to Friedel–Crafts cyclization reaction under the influence of NaNO₂. The resulting naphthalene (4e–p), phenanthrene (4q–s) and carbazole (4t and 4u) derivatives were obtained in good to excellent yields as shown in Table 3.

Table 3 Scope of the reaction^a

a All reactions were carried out on 1 mmol scale of 3 with 1 equiv. of NaNO₂ in DMF (4 mL). The yields in parentheses are isolated yields based on nitro compounds 3.b The structures of these molecules were confirmed by single crystal X-ray data analysis (see ESI¹).

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With a view to understand the role of electron withdrawing group on aryl system in the F–C cyclization we have selected methyl 3-acetoxy-3-(2-nitrophenyl)-2-methylenepropanoate (1m) as a substrate for reaction with nitroethane (2a) in the presence of K₂CO₃ in DMF. In this case we did not observe formation of any arylidene secondary nitroalkane compound, but we have directly obtained methyl 4-methylnaphthalene-2-carboxylate (6) in 57% yield (Scheme 3). It should be mentioned here that a similar reaction is already reported by Horn and Perez.¹¹ We have examined alkylation of methyl 3-acetoxy-3-(3-nitrophenyl)-2-methylenepropanoate (1n) with nitroethane (2a) in the presence of K₂CO₃ and found that this reaction was not clean (Scheme 3). However alkylation of methyl 3-acetoxy-3-(4-nitrophenyl)-2-methylenepropanoate (1o) with nitroethane (2a) in the presence of K₂CO₃ provided the desired nitroarylidene secondary nitroalkane derivative (3v) in 45% yield. But, our attempts for intramolecular F–C reaction of 3v with NaNO₂ under similar conditions were not successful (Scheme 3).

Scheme 3 Towards understanding role of nitro group on aryl system.

Next we have studied the role of acids¹² (both Lewis and Brønsted) as additives on the NaNO₂ mediated F–C reaction of 3a. Since similar F–C reactions of arylidene secondary nitro compounds using conc. H₂SO₄ is already known in the literature^6d we did not use strong acids in our studies.¹² We have examined the applications of AlCl₃ and AcOH as additives in our studies (Table 4). From these studies it is clear that AcOH–DMF at 100 °C accelerates the rate of reaction to a reasonable extent (entry 8: Table 4) providing slightly inferior yields in comparison to our earlier result (entry 11: Table 1). The rate acceleration might be attributed to the possible stabilization of aci-nitronate with acid as mentioned in Scheme 1.

Table 4 Role of acid additive on NaNO₂ mediated F–C reaction^a

Entry	Additive	Solvent	Temp/°C	Time/h	Yield^b (%) o-4a/p-4a
a All reactions were carried out on 1 mmol scale of 3a in 4 mL of solvent.b Isolated yields based on 3a.
1	AlCl3	DCE	RT	24	N.R
2	AlCl3	DCE	80	12	N.R
3	AlCl3	DMF	RT	24	N.R
4	AlCl3	DMF	100	12	Trace
5	AcOH	DCE	RT	24	N.R
6	AcOH (excess)		RT	24	N.R
7	AcOH	DMF	RT	24	5/21
8	AcOH	DMF	100	4	14/66

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A plausible mechanism for NaNO₂ mediated intramolecular F–C reaction is illustrated in Scheme 4 taking the nitro compound 3a as a model case and assuming that transient species oxaziridine (B) as the reactive electrophile. However we cannot rule out the involvement of any other similar reactive electrophiles. In fact, we have also considered the possibility of generation of in situ ketone (D as in Scheme 1) which might cyclize in the presence of NaNO₂. Even though we are not sure of such possibility, with a view to confirm our understanding we made the ketone¹³ [methyl (E)-2-(3-methoxybenzylidene)-4-oxopentanoate (5a)] via Nef reaction of 3a which then was treated with NaNO₂ in DMF at 100 °C for longer times (upto 20 h). We did not notice formation of any Friedel–Crafts product. This result unequivocally confirms that the ketone (5a) is not the key intermediate and further confirms that the electrophile is the Kornblum–Mioskowski transient oxaziridine species (B) or related transient such as A or C as shown in Scheme 1. It is believed that the formation of heterocyclic compound (4t) from 3t follows a similar mechanism as in the formation of 4a from 3a as described in Scheme 4.

Scheme 4 Plausible mechanism.

It should be mentioned here the importance of polycyclic aromatic compounds, especially substituted naphthalenes, phenanthrenes and carbazoles as these structural frameworks are present in several biologically active molecules¹⁴ and natural products.^14d,15 Also these compounds are extensively used as building blocks for the synthesis of biologically active molecules¹⁴ and polycyclic aromatic materials.¹⁶ Therefore, development of facile strategies for obtaining these molecules has been and continues to be a challenging endeavor in synthetic chemistry.^17,9j,18 The present methodology indeed constitutes another important strategy for obtaining these structurally important frameworks using NaNO₂ as a mild reagent.

In summary, we have, for the first time, described novel sodium nitrite mediated intramolecular Friedel–Crafts alkylation of secondary nitroalkanes derived from Baylis–Hillman adducts under neutral conditions. This reaction provides a facile methodology for the synthesis of naphthalene, phenanthrene and carbazole derivatives that are of tremendous importance in medicinal and material chemistry. Since this methodology describes the Friedel–Crafts reaction under neutral conditions we believe this protocol will find extensive applications in synthetic chemistry.

Acknowledgements

We thank the DST (New Delhi) for funding this project. DMR thanks CSIR and DST (New Delhi) for his research fellowships. We thank the UGC (New Delhi) for support and providing some instrumental facilities. We are grateful to the National Single-Crystal X-ray and HRMS facilities funded by the DST. We also thank Professor S. Pal, School of Chemistry, and University of Hyderabad for helpful discussions regarding X-ray data analysis.

Notes and references

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10. As suggested by one of the referees, we have also performed the reaction with NaNO₃ instead of NaNO₂. In this case (using NaNO₃) we did not notice formation of any F–C product and compound 3a was intact. We thank this referee for the suggestion.
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12. As suggested by one of the referee, we have examined the role of acid additives in the F–C reactions. We thank this referee for the suggestion.
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Footnote

† Electronic supplementary information (ESI) available: Representative experimental procedure with spectral data of 3a–v, 4a–u, 5a, 6 and ¹H and ¹³C NMR spectra of 4a–u and 6, crystal data (CCDC 982203, 982204, 982657 and 982658) and ORTEP diagrams of ortho-4c, 4r–t. See DOI: 10.1039/c4ra03573a

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