Letter pubs.acs.org/OrgLett
Synthesis of Spirocyclohexadienones through Radical Cascade Reactions Featuring 3‑Fold Carbon−Carbon Bond Formation Nina Hegmann, Lea Prusko, and Markus R. Heinrich* Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany S Supporting Information *
ABSTRACT: The radical 5-exo cyclization starting from 2-allyloxyphenyldiazonium ions can be employed for the diastereoselective synthesis of orthospirocyclohexadienones through a consecutive addition to alkynes. The spirocyclic systems are formed in a radical [2 + 2 + 1] cycloaddition comprising three carbon−carbon formations, of which the final one is an ipso attack onto the aromatic system at the original position of the diazoniumderived aryl radical.
S
cyclizations on electron-poor aromatic systems have also been reported.7 Radical induced spirocyclizations of aryl alkynes have so far been conducted with carbon-, sulfur-, and phosphoruscentered radicals (Scheme 1, reaction 3).8−10 Our interest in radical spirocyclizations arose from a recent work on Meerwein arylations11 proceeding via a 2-fold carbon− carbon bond formation.12,13 If the alkene that was originally used in combination with 2-allyloxyphenyldiazonium salts would be replaced by an alkyne, such cascade reactions could possibly be extended to an ipso attack onto the aromatic system and thus to a third carbon−carbon bond formation (Scheme 1, reaction 4). Compared to most known syntheses of spirocyclohexadienones (Scheme 1, reactions 1−3), such transformation would give an unusual ortho-spirocyclohexadienone14 and its intermolecular character regarding the alkyne15 might allow for structural diversity from readily available starting materials. In this letter, we now present a new type of [2 + 2 + 1] spirocyclization16 leading to ortho-spirocyclohexadienones via a highly diastereoselective cascade reaction with alkynes featuring three consecutive carbon−carbon bond formations. The general reaction conditions used for the optimization experiments are derived from earlier reports,17 in which iron(II)-mediated radical transformations in aqueous dimethyl sulfoxide had been particularly successful in reacting polar diazonium tetrafluoroborates with lipophilic alkenes. Selected results obtained from a series of optimization experiments with 2-allyloxyphenyldiazonium tetrafluoroborate (1a) and phenylacetylene (2a) are summarized in Table 1 (see Supporting Information (SI) for further results). Starting from standard conditions (entry 1), a less polar solvent mixture (entry 2) as well as a lower reaction temperature of 0 °C resulted in negative effects. Also, the yield of 3aa could not be increased through doubling the amount of alkene 2a (entry 4) or iron(II) sulfate (entry 5).
pirocyclohexadienones are present as substructures in many natural products, pharmaceuticals, and compounds for diverse other applications.1 Due to their increasing importance, a variety of synthetic methods have recently been developed to access structures of this type wherein the majority of reactions features an intramolecular dearomatization of phenols or other suitably substituted benzenes (Scheme 1).2 As precursors for Scheme 1. Reactions Leading to Spirocyclohexadienones
the ipso carbocyclization reactions, benzenes bearing alkene or alkyne side chains were found to be particularly useful, as these unsaturated units can be employed to introduce a broad range of atoms and functional groups. From such starting materials, spirocyclization can be achieved under transition metal catalysis using palladium, iridium, or gold catalysts (Scheme 1, reaction 1). 3,4 Alternatively, the triple bond may be attacked by electrophilic reagents such as iodine monochloride or N-bromo succinimde to trigger the cyclization onto the electron-rich aromatic system (Scheme 1, reaction 2).5,6 Complementary nucleophilic ipso © 2017 American Chemical Society
Received: March 6, 2017 Published: April 20, 2017 2222
DOI: 10.1021/acs.orglett.7b00676 Org. Lett. 2017, 19, 2222−2225
Letter
Organic Letters Table 1. Optimization of Reaction Conditions
Table 2. Evaluation of Substrate Scope and Limitations: Spirocyclization with Phenylacetylenes
entry
variation of standard conditionsa
yield 3aa (%)
1 2 3 4 5 6 7 8 9
− solvent mixture: DMSO/H2O = 10:1 reaction at 0 °C 2a (12 equiv) FeSO4 (6 equiv) argon atmosphere 15 min reaction time after addition of 1a FeSO4 (1.5 equiv) + 15 min reaction time add. over 10 min + 15 min reaction time
18b 8c 13c 13c 11c 18b 54b 34c 22b
a Standard conditions: Phenylacetylene (2a) (2.4 mmol) and FeSO4· 7H2O (1.2 mmol) in DMSO/H2O (5:2, 7 mL), slow addition of 1a (0.40 mmol) in DMSO/H2O (5:2, 3 mL) over 30 min at room temperature under air. b Yields after purification by column chromatography. cYields determined by 1H NMR using 1,3,5trimethoxybenzene as internal standard.
entrya
1: R1 =
2: R2, R3 =
yield 3 (%)b
1 2 3 4 5 6 7 8 9 10
1a: H 1a: H 1a: H 1a: H 1a: H 1b: Me 1b: Me 1b: Me 1b: Me 1b: Me
2a: H, H 2b: OMe, H 2c: F, H 2d: H, Me 2e: H, CO2Et 2a: H, H 2b: OMe, H 2c: F, H 2d: H, Me 2e: H, CO2Et
3aa (54) 3ab (28) 3ac (53) 3ad (19) 3ae (44) 3ba (71) 3bb (34) 3bc (57) 3bd (20) 3be (41)
a Reaction conditions: Acetylenes 2a−e (2.4 mmol) and FeSO4·7H2O (1.2 mmol) in DMSO/H2O (5:2, 7 mL), slow addition of 1 (0.40 mmol) in DMSO/H2O (5:2, 3 mL) over 30 min at room temperature under air. After completed addition, the reaction mixture is stirred for 15 min before workup. bYields after purification by column chromatography.
While the use of argon as a protecting gas did not have a remarkable influence (entry 6), a major advance could be made through prolongation of the reaction time after the slow addition of 1a had been finished.18 As radical generation from 1a can be considered to be fast due to the excess of iron(II) sulfate in the reaction mixture, the radical sequence is probably followed by a slower ionic step which requires additional time. Final variations including the reduction of the amount of iron(II) sulfate and a shortening of the addition time for 1a remained unsuccessful (entries 8 and 9). After the structure of spirocyclohexadienone 3aa had been unambiguously confirmed through 2D-NMR analysis and derivatization (see SI), we investigated the scope and limitations. The results obtained with two diazonium salts 1a,b and five phenylacetylenes 2a−e are summarized in Table 2. The 4-methylated diazonium salt 1b was chosen to gain insights into the stability of the resulting cyclohexadienones 3, which could be less sensitive to nucleophilic or radical attack with the additional methyl group in the β-position to the carbonyl. By comparing the two series based on 1a (entries 1−5) and 1b (entries 6−10), lower yields in each series were observed with 4-methoxyphenylacetylene (2b) (entries 2 and 7) and 1-phenyl-propyne (2d) (entries 4 and 9). These effects can be rationalized and will be discussed along with the underlying mechanism (see below). The regioselectivity of the reactions with ethyl phenylpropiolate (2e) were confirmed by 2D-NMR analysis of the spirocycles 3ae and 3be (entries 5 and 10, see SI). A clear trend concerning a possible effect of the additional methyl group in 1b did not become obvious. Attempts with diphenylacetylene remained unsuccessful due to insufficient solubility of this alkyne. Before investigating reactions with acetylenecarboxylates (Table 3), some additional optimization experiments were carried out with methyl acetylenecarboxylate (4a) (see SI). The best yield with this alkyne was achieved under conditions nearly identical to those used in Table 2, only with a prolonged reaction time of 30 min after addition of the diazonium salt 1 to the reaction mixture. Regarding the results
Table 3. Evaluation of Substrate Scope and Limitations: Spirocyclization with Acetylenecarboxylic Acid Esters
entrya
1: R1 =
4: R2, R3 =
yield 5 (%)b
1 2 3 4 5 6 7 8
1a: H 1a: H 1a: H 1a: H 1b: Me 1b: Me 1b: Me 1b: Me
4a: Me, H 4b: Et, Me 4c: tBu, H 4d: Me, CO2Me 4a: Me, H 4b: Et, Me 4c: tBu, H 4d: Me, CO2Me
5aa (48) 5ab (60) 5ac (50) 5ad (39) 5ba (79) 5bb (35) 5bc (70) 5bd (68)
a Reaction conditions: Acetylenes 4a−d (2.4 mmol) and FeSO4·7H2O (1.2 mmol) in DMSO/H2O (5:2, 7 mL), slow addition of 1 (0.4 mmol) in DMSO/H2O (5:2, 3 mL) over 30 min at room temperature under air. After completed addition, the reaction mixture is stirred for 30 min before workup. bYields after purification by column chromatography.
from the whole series of experiments, only two reactions provided yields lower than 45%, namely those in entries 4 and 6. An additional experiment on a 2.5-fold reaction scale (1 mmol) led to 5aa in 52% yield (cf. entry 1, Table 3). A plausible reaction mechanism is depicted in Scheme 2. Triggered by the reduction of diazonium salt 1 to generate aryl radical 6, a rapid 5-exo cyclization19 provides the primary alkyl radical 7. Addition of 7 to 8 is in most cases (e.g., entries 4 and 9, Table 2), but not necessarily, complicated by disubstitution of the alkyne,20 as shown by the good yields of 5ab and 5bd (entries 2 and 8, Table 3). The ipso cyclization of vinyl radical 9 2223
DOI: 10.1021/acs.orglett.7b00676 Org. Lett. 2017, 19, 2222−2225
Letter
Organic Letters Scheme 2. Plausible Reaction Mechanism
Scheme 3. Extension to Sulfonamide and Further Transformation
to 10 is quite general,21 but it appears to suffer from donorsubsituted arenes as substituents R1. The additional methoxy group could thereby lead to an increased stabilization of radical 9, which is unfavorable for the cyclization step (entries 2 and 7, Table 2).22 Oxidation of radical 10 to the corresponding cation 11, nucleophilic attack of water to furnish hemiacetal 12, and final ring opening complete the formation of spirocycle 13. Regarding the oxidation of radical 10 to cation 11 in more detail, this step could be effected by iron(III) ions generated in the initial reduction of 1,23 by diazonium ions 1,24 or by an alternative oxidant related to oxygen from air. If radical 10 was oxidized by an iron(III) ion or a diazonium ion 1, the overall reaction could be run with catalytic amounts of iron(II) sulfate. Important hints to this question can be deduced from the results summarized in Table 1. First, oxygen from air is likely to play only a minor role since the reaction proceeded under argon without a decrease in yield (cf. entries 1 and 6, Table 1). Oxidation of 10 by diazonium ions, although basically possible,24 is probably also not the major pathway, since the excess of iron(II) sulfate in combination with the slow addition of 1 to the reaction mixture is deliberately applied to keep the concentration of the diazonium ions 1 very low. Higher concentrations of diazonium ions, as they are present when lower amounts of the reductant iron(II) are used or when the salt is added more quickly (cf. entries 7−9, Table 1), are known to lead to side reactions due to the fact that diazonium ions can not only act as radical sources but also as very effective radical scavengers.12,17a,d The remaining option, namely the oxidation of 10 by iron(III) ions, thus appears the most likely. This is supported by the observation that a larger excess of iron(II) sulfate (cf. entries 1 and 5, Table 1) leads to lower product yields, as the oxidation potential of the iron(II)/iron(III) system then decreases. Moreover, a time course experiment revealed that product formation becomes more efficient in a later stage of the reaction, which points to not only the critical importance of iron(III) but also at least some participation of other oxidants (see SI). Nevertheless, the basically attractive prospect of using iron(II) sulfate as a catalyst cannot easily be implemented due to the necessarily fast reduction of the diazonium ions 1. The additional reaction time after the addition of 1 to the reaction mixture is probably required to ensure the controlled ring opening of the tricyclic ring system 12 to give 13. An alternative pathway, in which 13 would be formed via the trapping of radical 10 by oxygen, appears less likely due to a missing differential effect under argon (cf. entries 1 and 6, Table 1). Final experiments demonstrated that the reaction principle can be extended to sulfonamides such as 14, which gave spirocycle 15 in a 45% yield (Scheme 3). Sodium borohydride reduction of 5aa selectively occurred at the more exposed
double bond of the cyclohexadienone system, and its increased conformational flexibility led to the formation of the hemiacetal substructure in the tricyclic product 16. Compounds similar to 16, which are structurally related to (+)-colletoic acid (17),25 have recently been evaluated as 11β-hydroxysteroid dehydrogenase type 1 inhibitors.26 In summary, it has been shown that ortho-spirocyclohexadienones are accessible via a, to date, unknown radical [2 + 2 + 1] cycloaddition comprising the consecutive formation of three carbon−carbon bonds. By starting from readily available aryldiazonium salts and alkynes, highly functionalized spirocyclic systems can be obtained under simple reaction conditions and with full diastereoselectivity.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00676. General experimental methods, characterization data, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Markus R. Heinrich: 0000-0001-7113-2025 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful for support by the Graduate School Molecular Science (N.H.) and would like to thank Antonia Leichs (Pharmaceutical Chemistry, FAU Erlangen-Nürnberg) for experimental assistance.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00676 Org. Lett. 2017, 19, 2222−2225
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