KOt-Bu/DMF promoted intramolecular cyclization of 1,1′-biphenyl aldehydes and ketones: an efficient synthesis of phenanthrenes

Abstract

A new synthesis of phenanthrene derivatives has been achieved through intramolecular cyclization of 1,1′-biphenyl aldehydes and ketones promoted by KOt-Bu/DMF. A free radical reaction pathway is proposed.

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Phenanthrenes have attracted great attention over the past years because of their important applications in biological studies¹ and materials science.² A number of synthetic methods of phenanthrenes have been developed.³ The classical methods such as carbocyclic ring expansion or cyclization of stilbenes, suffer from harsh conditions and limited substrate scope. In recent years, the cyclizations of biphenyl substrates have been widely used to synthesize phenanthrenes. Fabbri and co-workers reported the synthesis of phenanthrenes by ring-closing metathesis of 2,2′-divinylbiphenyls.⁴ Wang and co-workers found that TsNHNH₂ promotes the intramolecular cyclization of 2′-benzoyl-biphenyl-2-carbaldehyde to give phenanthrenes.⁵ The [4 + 2] cycloadditions of alkynes or bis(pinacolatoboryl)alkenes with biphenyl reactants including 2,2′-halogenated biphenyls,⁶ 2-biphenylmagnesium bromide,⁷ 2-phenylbenzoylchloride,⁸ biphenyl tosylhydrazones⁹ and biphenyldiazonium salts,¹⁰ were also used for the synthesis of phenanthrenes. Phenanthrenes can also be prepared by intramolecular cyclization of 2-alkynyl biphenyl compounds.¹¹ Koning and co-workers found that the combination of KOt-Bu/DMF and UV light irradiation could promote the intramolecular cyclization of 2-alkyl benzaldehydes to give naphthalenes and phenanthrenes.¹² In recent years, we developed a series of KOt-Bu/DMF promoted radical coupling reactions of tertiary amines, amides with alkenes, alkynes and ketones.¹³ In these reactions, KOt-Bu/DMF can readily initiate the formation of α-amino alkyl radicals without UV-light irradiation. We speculate that KOt-Bu/DMF also promotes the generation of diarylmethyl radicals. The subsequent reaction with carbonyl compounds will provide an attractive method for the synthesis of phenanthrenes. In this paper, we report an efficient synthesis of phenanthrenes via intramolecular cyclization of 1,1′-biphenyl aldehydes and ketones promoted by KOt-Bu/DMF.

Initially, we examined the reaction of 2′-benzyl-(1,1′-biphenyl)-2-carbaldehyde 1a and the results are summarized in Table 1. The expected phenanthrene 2a was obtained in a good yield when the reaction was carried out in DMF with 3.0 equivalents of KOt-Bu at 90 °C (Table 1, entry 1). The excellent yield was kept while the reaction temperature was decreased to room temperature (Table 1, entry 2). The reaction in DMSO gave 54% yield of 2a combined with 9-methyl-10-phenyl-phenanthrene (32% yield). This side product was generated via the further reaction of 2a with DMSO (Table 1, entry 3).¹⁴ The similar transformation was previously reported by Russell and Weiner.¹⁵ The replacement of DMF with DMA led to a lower yield (Table 1, entry 4). Other reaction solvents such as THF, dichloromethane, acetonitrile and dioxane are incompatible with the reaction (Table 1, entries 5–8). The complete decomposition of the substrate 1a was observed in these solvents, but no product 2a could be isolated from the reaction mixture. Other bases such as KOMe, NaOMe and KOH are also applicable, but lower yields were obtained (Table 1, entries 9–11). Weaker base such as K₂CO₃ is completely inefficient (Table 1, entry 12). The effect of KOt-Bu loading was also examined. The excellent yield was still kept even 1.0 equivalent of KOt-Bu was used (Table 1, entry 13). The further decrease of KOt-Bu loading led to a loss of yield (Table 1, entry 14). A control experiment in the dark was carried out. No substantial effect on the yield was observed (Table 1, entry 15).

Table 1 Intramolecular cyclization of 1a^a

Entry	Solvent	Base (equiv.)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), base, solvent (2.0 mL), room temperature, argon atmosphere, 1 h.b Isolated yields.c Reaction was carried out at 90 °C.d Reaction was carried out in the dark.
1^c	DMF	KOt-Bu (3.0)	93
2	DMF	KOt-Bu (3.0)	92
3	DMSO	KOt-Bu (3.0)	54
4	DMA	KOt-Bu (3.0)	82
5	THF	KOt-Bu (3.0)	0
6	CH2Cl2	KOt-Bu (3.0)	0
7	CH3CN	KOt-Bu (3.0)	0
8	Dioxane	KOt-Bu (3.0)	0
9	DMF	KOMe (3.0)	90
10	DMF	NaOMe (3.0)	87
11	DMF	KOH (3.0)	89
12	DMF	K2CO3 (3.0)	0
13	DMF	KOt-Bu (1.0)	93
14	DMF	KOt-Bu (0.5)	85
15^d	DMF	KOt-Bu (1.0)	89

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With the optimal reaction conditions in hand, a number of 1,1′-biphenyl-2-carbaldehyde derivatives were examined and the results are summarized in Table 2. The substitution at the 2′-benzyl group with 2-methyl, 3-methyl, 4-methoxy and 4-fluoro is tolerable, but lower yields were obtained (Table 2, entries 2–5). The replacement of phenyl with vinyl, amino, and benzoxy are also acceptable. The products 2f–2h were obtained in moderate yields (Table 2, entries 6–8). The replacement with methoxy group led to a low yield (Table 2, entry 9). The reaction of 2′-methyl-biphenyl-2-carbaldehyde 2j gave phenanthrene in a poor yield (Table 2, entry 10).¹² The results implicate that the activation of benzyl position with aryl or heteroatom substitution is crucial. On the other hand, the substitution at the phenyl ring with 5-methyl, 4-methoxy and 4-chloro led to the slight loss of yield (Table 2, entries 11–13). The reaction of 2-naphthyl derived benzaldehyde 1n provided the expected product 2n in an excellent yield (Table 2, entry 14). The substrates 1o–1p with heteroaryl backbones are also applicable. The corresponding products were obtained in moderate yields (Table 2, entries 15–16).

Table 2 Intramolecular cyclization of substrates 1a–1p^a

Entry	R^1	R^2	Product	Yield^b (%)
a Reaction conditions: 1a–1p (0.2 mmol), KOt-Bu (0.2 mmol), DMF (2.0 mL), argon atmosphere, room temperature, 1 h.b Isolated yields.c Reaction was carried out at 80 °C for 2 h.d Yield determined by ^1H NMR.
1	Ph	H	2a	93
2	2-Me–Ph	H	2b	70
3	3-Me–Ph	H	2c	81
4	4-MeO–Ph	H	2d	73
5	4-F–Ph	H	2e	87
6			2f	50
7			2g	70
8			2h	65
9^c	MeO	H	2i	33
10^d	H	H	2j	21
11	Ph	5-Me	2k	83
12	Ph	4-MeO	2l	86
13	Ph	4-Cl	2m	80
14			2n	94
15			2o	68
16			2p	50

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The reaction of 1,1′-biphenyl derived ketones were also examined at an elevated reaction temperature and the results are summarized in Table 3. To our delight, various diaryl ketones and aryl alkyl ketones are suitable substrates. The expected phenanthrenes 4a–4g were obtained in good yields (Table 3, entries 1–7). Methoxy substituted ketones 3h provided the product in a moderate yield (Table 3, entry 8). The reaction of pyrrolidin-2-one derived substrate 3i gave the product 4i in a good yield (Table 3, entry 9). α,β-Unsaturated ketone is also applicable. The 10-styrylphenanthrene 4j was obtained in a moderate yield (Table 3, entry 10). The reaction of substrate 3k did not afford the expected 1,2-diphenyl-naphthalene (Table 3, entry 11). The 1,1′-biphenyl backbone seems to be necessary for the reaction.

Table 3 Intramolecular cyclization of substrates 3a–3k^a

Entry	R^3	R^4	Product	Yield^b (%)
a Reaction conditions: 3a–3k (0.2 mmol), KOt-Bu (0.2 mmol), DMF (2.0 mL), argon atmosphere, 80 °C, 1 h.b Isolated yields.
1	Ph	Ph	4a	91
2	Ph	2-Me–Ph	4b	88
3	Ph	4-F–Ph	4c	80
4	Ph	4-MeO–Ph	4d	86
5	Ph	4-CF3–Ph	4e	94
6	Ph	Me	4f	90
7	Ph	Cyclo-Pr	4g	84
8	MeO	Ph	4h	65
9			4i	81
10			4j	63
11			4k	0

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In 2009, Sliwka and co-workers reported that the observation of radical intermediates in the basic DMF and DMSO solution via the EPR analysis.¹⁶ We examined the reaction of 1a in the presence of radical scavengers BQ (benzoquinone) and DPPH (1,1-diphenyl-2-picrylhydrazyl radical). The reaction was found to be inhibited significantly (Scheme 1). To further explore the reaction mechanism, the EPR analysis of the solutions of KOt-Bu/DMF, 1a in KOt-Bu/DMF and triphenylmethane in KOt-Bu/DMF, were carried out respectively (Fig. 1). Weak EPR signal was observed in the solution of KOt-Bu/DMF. Strong signal was observed in the solution of 1a in KOt-Bu/DMF. More intensive signal was found in the solution of triphenylmethane in KOt-Bu/DMF. The results approve the possible generations of DMF radical, diphenylmethyl radical from substrate 1a, and highly stable triphenylmethyl radical.

Scheme 1 Controlled experiments with radical scavengers.

Fig. 1 EPR spectra, (a) KOt-Bu/DMF; (b) 1a in KOt-Bu/DMF; (c) triphenylmethane in KOt-Bu/DMF.

Based on our previous studies,¹³ a tentative reaction mechanism is proposed in Scheme 2. DMF is deprotonated by KOt-Bu to give the carbamoyl anion. After a single-electron transfer (SET) step, the carbamoyl radical A is generated. The radical A abstracts a hydrogen from substrate 1a to generate diphenylmethyl radical C. An intramolecular radical addition gives the oxygen radical D. After the abstraction of a hydrogen from DMF or 1a, the primary product E is formed. The subsequent dehydration provides the final product 2a.¹⁷

Scheme 2 Tentative reaction mechanism.

Conclusions

In summary, we have developed an efficient intramolecular cyclization of 1,1′-biphenyl aldehydes or ketones promoted by KOt-Bu/DMF. The reaction could be carried out under mild reaction conditions. A number of phenanthrenes were prepared in moderate to good yields. A radical reaction pathway is proposed. This finding provides a practical synthesis of phenanthrenes from 1,1′-biphenyl aldehydes or ketones.

Acknowledgements

We thank the National Natural Science Foundation of China (nos 21202208, 21172270, 21472248), Guangdong Engineering Research Center of Chiral Drugs, and Major Scientific and Technological Project of Guangdong Province (no. 2011A080300001) for the financial support of this study. We also thank Mr Gu-ping Hu at the department of chemistry, Sun Yat-sen university for carrying out the EPR analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra07188g

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