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. Author manuscript; available in PMC: 2018 Sep 15.
Published in final edited form as: European J Org Chem. 2017 Sep 14;2017(34):5147–5153. doi: 10.1002/ejoc.201700915

Cyclopentadienones via a tandem C-cyclopropylnitrone cyclization-cycloreversion sequence

Ihsan Erden [a],✉, Christian Gärtner [a], Jingxiang Ma [a], Gabriel Cabrera [a], Kate Markham [a], Saeed Azimi [a], Scott Gronert [b],✉
PMCID: PMC5708562  NIHMSID: NIHMS920223  PMID: 29200938

Abstract

Aldonitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and its benzo analog undergo a tandem uncatalyzed intramolecular cyclopropane-nitrone cyclization-5,6-dihydro-1,2-oxazine cycloreversion to give cyclopentadienones. Similarly, the NH-nitrone generated in situ from spiro[cyclopropane-1,1′-indene]carbaldehyde oxime leads to benzocyclopentadienone (1H-inden-1-one) by the same mechanism. DFT calculations are in favor of a concerted yet highly asynchronous pathway for the cyclizations. Control experiments with the dihydro and tetrahydro derivatives show that the spirocyclopentadiene unit is essential for the success of the reaction, invoking spiroconjugative effects for increased cyclopropane reactivity.

Keywords: spiroconjugation, C-cyclopropylnitrone, cycloaddition, cyclopentadienone, NH-nitrone

Graphical abstract

graphic file with name nihms920223u1.jpg

C-Cyclopropylnitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and its benzo analog undergo an unprecedented tandem cyclization-retro-Diels-Alder reaction of the 5,6-dihydro-1,2-oxazine intermediates to give the corresponding cyclopentadienones. Computational work indicates that the cyclization step is concerted but highly asynchronous.

Introduction

Nitrones are reactive dipoles1 that undergo 1,3-dipolar cycloadditions with alkenes and alkynes to give isoxazolidines or isoxazolines, respectively.2 Whereas the combination of nitrones with electron-deficient alkenes is quite common and is supported by favorable frontier orbital interactions,3 the corresponding reactions with electron-rich alkenes are considered as cycloadditions with inverse electron-demand4 and are enhanced by Lewis acids.5 Nitrone-alkene cycloadditions are of particular synthetic value since these can be employed in the synthesis of a variety of heterocycles6 and natural products,7 in particular the intramolecular variants. Also the synthetic utility of N-vinylnitrones has been explored.8 The nucleophilic character of nitrones has also been exploited in catalytic asymmetric nitrone-aldol reactions.9 Considerable synthetic and theoretical work has been done in this area shedding light on the regioselectivity and stereoselectivity aspects of these important cycloadditions.10

Cyclopropylnitrones have first been reported by Houk et al., and they do not exhibit divergent behavior, i.e., the cyclopropyl group with its π-conjugative ability does not engage the adjacent nitrone C=N in a conceivable intramolecular cyclization, similar to the cyclopropylimine→2-pyrroline cyclization.11

Recently, Kerr et al. reported the first intermolecular Lewis-acid [Yb(OTf)3] catalyzed “homo” (3+2) cycloadditions of nitrones with activated cyclopropanes -in particular 1,1-cyclopropane diesters- to give 1,2-oxazinanes.12 In the absence of the Lewis acid, the reaction is not observed; it is believed that the Lewis acid coordinates to the ester group, thus further polarizing the cyclopropane C-C-bond.13 Similar transformations of 1,1-cyclopropane diesters in the presence of Ni(ClO4)2 and chiral bisoxazoline ligands have been reported.14 Also (3+2)-cycloadditions of nitrocyclopropane carboxylates with nitrones, catalyzed by urea derivatives, were shown to give 1,2-oxazinane derivatives.15

The situation changes dramatically when a cyclopropyl group is placed in a bisected antiplanar conformation relative to a 1,1-divinyl group, as in spiro[2.4]hepta-4,6-diene (5). UV and NMR spectroscopic studies, theoretical calculations as well as photoelectron spectroscopy strongly support the existence of spiroconjugation in this system.16,17

The pseudoconjugation between the Walsh orbitals of cyclopropane and the LUMO of cyclopentadiene results in decreased bonding and manifests itself in considerable bond lengthening of C2-C3 and increased bonding and shortening of C3-C4 as well as C1-C2 in 5 as compared to dihydro analog spiro[2.4]hept-4-ene. Of all the spirocyclopropyl systems studied so far, spiro[2.4]hepta-4,6-diene exhibits the strongest delocalization of electrons by π and Walsh-orbital interactions (largest bond ellipticity).18 Based on these considerations, we decided to put the π-conjugative ability of cyclopropane to test by placing the cyclopropylnitrone unit onto a spiro[2.4]heptadiene framework in hopes of observing an intramolecular nitrone-cyclopropane cyclization resulting from this attempt.19

Results and Discussion

The requisite spiro[2.4]hepta-4,6-diene-1-carbaldehyde (6) was prepared by a modified version of a procedure reported previously.20, 21 Upon treating 6 with N-methylhydroxylamine in water and extraction of the reaction mixture with EtOAc, a single product was isolated in 36% yield after purification on silica gel. It was identified as the endo-Diels-Alder dimer 10 of cyclopentadienone (8) 22 (Scheme 2). When the reaction was repeated in the presence of 1,3-cyclopentadiene (9), 8 was trapped as the corresponding Diels-Alder product 11.23

Scheme 2. Attempted nitrone formation from 6; trapping of cyclopentadienone 8 as Diels-Alder adducts.

Scheme 2

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Similarly, the benzo analog of 6 derived from indene (compound 12),24 gave under similar conditions the stable benzocyclopentadienone (inden-1-one, 14)25 in 68% isolated yield. In neither case could the nitrone intermediate 13 be detected. (Scheme 3).

Scheme 3. 1-Indenone formation via N-Methylnitrones 13/13′ derived from spiro(cyclopropane-1,1′-indene)-2-carbaldehyde (12/12′).

Scheme 3

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In the remarkable transformations shown in Schemes 2 and 3, the spirocyclopropanecarboxaldehyde moiety in 6 and 12 is replaced by a ring carbonyl group in a formal loss of acrolein N-methylimine (17), resulting in a net oxidation of the cyclopentadiene C-5. Compound 10 is obviously a secondary product formed by spontaneous Diels-Alder dimerization of the anti-aromatic cyclopentadienone 8, whereas the benzo analog 14 is stable as a monomer. A mechanism for these transformations consistent with the results shown in the above Schemes involves initial nitrone formation (acyclic aldonitrones exist as Z isomers)26 followed by a novel C-cyclopropylnitrone cyclization to give a 5,6-dihydro-1,2-oxazine 15 or 16 (benzo). The latter then undergoes a cycloreversion (formally a retro-Diels-Alder reaction), a process encouraged by favorable enthalpy of reaction of -11.5 kcal/mol and a low barrier of 23.0 kcal/mol (M062x/6-311+G** basis set) to give cyclopentadienone 8 (or its benzo analog 14) (Scheme 4). Moreover, inspection of the 1H NMR spectrum of the crude reaction mixture in the case of 13→14 clearly showed the presence of the fragmentation product 17.27

Scheme 4. Tandem intramolecular nitrone-cyclopropane cycloaddition-cycloreversion.

Scheme 4

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To our knowledge, these transformations represent the first intramolecular, uncatalyzed cyclopropane-nitrone cycloadditions. The ensuing fragmentation of the 5,6-dihydro-1,2-oxazines of the type 15 (16) is akin to similar fragmentations reported by Eschenmoser et al.28

The question whether an NH nitrone derived from the corresponding oximes would exhibit similar reactivity was addressed by converting the spirocyclopropylcarbaldehydes 6 and 12/12′ to the corresponding stable aldoximes, which were obtained as mixtures of Z and E isomers, respectively. Since aldoximes require temperatures in excess of 100 °C to undergo 1,2-prototropic shifts to NH nitrones,29, 30 and due to the fact that the dimer of cyclopentadienone decomposes near its melting point (97-98 °C),22a the thermolysis of the Z/E mixture of oximes 18a/18b was not expected to yield isolable quantities of 8. Indeed, thermolysis of the E, Z-oxime mixture 18a and b led to complete disappearance of the Z isomer via the NH-nitrone 18′a, leading to an intractable mixture, along with unreacted 18b (Scheme 5).

Scheme 5. Attempted generation of cyclopentadienone from 18a.

Scheme 5

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On the other hand, of the mixture of the oximes 19a, b+19′a, b, respectively,only 19a/19a′ (Scheme 6) reacted cleanly under the same conditions and yielded the stable inden-1-one (14). The progress of the reaction was monitored by 1H NMR (d8-toluene), and it was noted that the thermolysis proceeded cleanly; only the (Z) isomers were being converted to the product via 20a/20′a, while the E isomers remained intact.31 Upon complete conversion of the Z isomers to 14, the reaction was interrupted, the mixture consisting of 14 and the unreacted (E)- oximes 19b/19b′ separated by flash chromatography, and the products characterized by spectroscopy.

Scheme 6. 1-Indenone formation via the N-H nitrone (only the Z isomers 20a and 20′a react).

Scheme 6

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The process of converting 7 to 15 was explored computationally (M062x/6-311+G**).32 The reaction is concerted, but involves a very asynchronous path where the cyclopropane is fully cleaved and the new C-O bond has yet to form in the transition state (Figure 2).

Figure 2. Transition state for transformation of 7 to 15 (M062x/6-311+G**).

Figure 2

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The pathway from reactants to transition state to products was confirmed with an intrinsic reaction coordinate calculation (IRC). The enthalpy of activation is computed to be 32.1 kcal/mol in the gas phase.

The fact that the spiro[2.4]hepta-4,6-diene unit was essential for a successful intramolecular cyclopropane-nitrone cycloaddition was confirmed by the following experiments: we removed one or both π-bonds in the cyclopentadiene ring via independent syntheses of the nitrones 25 and 29 (vide infra), respectively (Schemes 7 and 8).

Scheme 7. Synthesis of nitrone 25, the dihydro analog of 13.

Scheme 7

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a: N2CHCO2Et, Rh2(OAc)4, CH2Cl2, 74%; b: LiAlH4/THF, 97%; c: Dess-Martin, 66%; d: CH3NHOH·HCl, MgSO4, NaHCO3, CH2Cl2, 97%

Scheme 8. Synthesis of nitrone 29, the tetrahydro analog of 7.

Scheme 8

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a: LiALH4/THF, 87%; c: Swern, 83%; c: CH3NHOH·HCl, MgSO4, NaHCO3, CH2Cl2, 86%.

Though the synthesis of 21 was reported previously,33 we achieved a significant improvement in the yield (93%) of the Wittig reaction by using Ph3P+CH3Br-, KOt-Bu as base in ether,33c instead of n-BuLi (only 36%)33b. It is also noteworthy that of the two diastereomeric esters that were formed, 22a (1S, 2R) exhibits an ABX3 system in the 1H NMR spectrum for the diastereotopic ethoxy CH2 protons due to hindered rotation about the C-C=O group.

Nitrone 29 was synthesized starting from the known ester 2634 in an analogous manner. Neither nitrone 25a, b, nor 29 showed any tendency to undergo the intramolecular cycloaddition and remained intact even at elevated temperatures (∼60-70 °C).

Conclusions

We propose that the concerted intramolecular C-cyclopropylnitrone cyclization is unique to the cyclopentadienyl system (or its benzo analog) and is a consequence of the spiroconjugation effect that lengthens (and weakens) the C1-C3 bond in 7(13) and facilitates the ring opening component of the reaction pathway.

In addition to the fact that the tandem reaction sequence described herein represents the first uncatalyzed intramolecular C-cyclopropylnitrone cyclization, it also provides an excellent synthetic entry into cyclopentadienones since the spirocyclopropylcarbaldehyde precursors are readily available from the corresponding cyclopentadienes by base-promoted spiroannulation with epichlorohydrin.

Experimental Section

General

1H and 13C NMR spectra were recorded on a 500 MHz NMR spectrometer, using CDCl3 as solvent and TMS as internal standard, unless specified otherwise. Most column chromatographic separations were carried out on a flash chromatography system using 40-60 mm silica gel columns using ethyl acetate/n-hexane solvent mixtures. For preparative TLC, silica gel (grade 60 PF254) was used. All reactions were conducted under an atmosphere of dry nitrogen or argon. Non-deuterated solvents were dried and distilled prior to use. Exact masses of all new products by high resolution mass spectra (HRMS) were determined at the San Francisco State University Mass Spectrometry Facility.

Cyclopentadienone dimer 10 from spiro[2.4]hepta-4,6-diene-1-carbaldehyde (6) via the N-methylnitrone 7

To a solution of N-methylhydroxylamine (0.184 g, 2.2 mmol) and 0.46 g (3.4 mmol) of sodium acetate in 4 ml of H2O, a solution of 0.24 g (2 mmol) of 6 in 5 mL of ethanol was added dropwise with rapid stirring at room temperature. After 5 minutes all starting material was completely dissolved. Stirring was continued for 2 hours. Then the reaction mixture was extracted with 4×40 ml of ethyl acetate, the combined extracts dried over anhydrous Na2SO4, and the solvent rotovapped. The residue was purified by column chromatography in silica gel eluting with petroleum ether/ethyl acetate (1:1). Yield: 115 mg (36% yield) of 10. The NMR spectral data were identical in all respects to those reported in Reference 22.

Trapping of cyclopentadienone with cyclopentadiene. Synthesis of 10

In a 25 ml flask, MgSO4 (0.7 g, 0.01 mol), Na2CO3 (1.5 g, 0.01 mol) and N-methylhydroxylamine·HCl (1.312 g, 15.75 mmol) were combined, and CH2Cl2 (25 ml) was added, the solution was cooled to 0 °C, and aldehyde 6 (1.2 g, 0.01 mol) and freshly distilled cyclopentadiene (1 g, 1.5 mmol) were added. The mixture was allowed to warm up to room temperature and stirred for 2 h. The mixture was then concentrated, the crude mixture purified by flash chromatography (EtOAc/hexanes 1:4) to give 10 (0.55 g, 38%). The spectral data of 10 were identical to those reported in Reference 23.

(Z)- and (E)-Spiro[2.4]hepta-4,6-diene-1-carbaldehyde oximes (18a and 18b)

In a round-bottomed flask, 0.4g (5.3 mmol) of Na2CO3 was added to a solution of hydroxylamine hydrochloride (0.52 g, 10.3 mmol) in 5 ml of water. Aldehyde 6, dissolved in 12.5 ml of EtOH was added to the hydroxylamine solution and the mixture stirred for 1 h at room temperature. The product was extracted with ethyl acetate, dried over anhydrous MgSO4 and the solvent rotovapped. According to the 1H NMR the product was >95% pure. According to the relative integrals in the 1H NMR spectrum of the mixture, the ratio of 18a/18b was 1.3:1.

1H NMR (CDCl3, 500 MHz) δ 8.1 (br s, 1H, NOH, 18b), 7.7 (br s, 1H, NOH, 18a); 7.4 (d, J= 8.5 Hz, 1H, CH=N, 18b); 6.6 (d, J= 8.5 Hz, 1H, CH=N, 18a); 6.58 (m, 1H, both isomers); 6.54 (m, 1H, both isomers); 6.25 (m, 1H, 18b); 6.22 (m, 1H, 18a); 6.14 (m, 1H, 18b); 6.11 (m, 1H, 18a); 3.49 (q, J= 8.5 Hz, 1H, 14b); 2.84 (q, J= 8.5 Hz, 1H, 18a); 2.1 (dd, J= 8.5, 5.0 Hz, 1H, 18b); 2.03 (d, J= 8.5 Hz, 2H, 18a); 1.9 (dd, J= 7.0, 5.0, 1H, 18b). 13C NMR (CDCl3, 175 MHz) δ 151.4, 151.2, 137.9, 137.7, 134.1, 133.7, 131.7, 131.5, 129.9, 129.7, 43.5, 25.5, 21.1, 17.8, 16.9 ppm. HRMS (ESI) m/z calcd for 136.0757 (M+H)+, found 136.0756.

1H-Inden-1-one (14) from spiro[cyclopropane-1,1′-indene]-2-carbaldehyde (12/12′) via the N-methylnitrones 13/13′

The same procedure described above for 6 was implemented for the nitrone formation from 12/12′. Thus, from 0.95 g (5.6 mmol) of 12/12′, there were obtained 0.5 g (68%) of bright yellow 14 after chromatography on silica gel (pet.ether/EtOAc, 1:1). The NMR spectra of the product so obtained were identical in all respects to those reported in Reference 13. The crude product spectrum contained both 14 and the other fragmentation product (E)-allylidenemethanamine (17) (spectral data, see below).

(E)- and (Z)-spiro[cyclopropane-1,1′-indene]-2-carbaldehyde oximes (19 a and 19 b) from (1S, 2R) aldehyde 12

The mixture of (1S, 2R) and (1S, 2S) aldehydes 12 and 12′, respectively, was carefully separated by flash chromatography, and the resulting product was practically pure (1S, 2R) isomer 12 (90%) (see spectral data below). To a stirred solution of 0.52 g (7.5 mmol) of hydroxylamine hydrochloride, 0.4 g (3.8 mmol) Na2CO3 in 5 ml of H20, 1,2 g (7 mmol) of aldehyde 12, dissolved in 12 ml of H2O was added dropwise. The mixture was stirred at room temperature for 1h. Then 10 ml of brine was added and the mixture extracted with 2×25 ml of CH2Cl2, the combined extracts dried over MgSO4, the solvent rotovapped and the residue purified by flash chromatography on silica gel, eluting with 40% EtOAc/hexanes to give a yellow oil to give 1.0 g (78%) of the oximes 19a (Z) and 19b (E) in a ratio of 1.8:1, and very small amounts of the corresponding oximes derived from (1S, 2S) aldehyde.

1H NMR (CDCl3, 500 MHz): δ 8.5 (br s, =NOH, 1H, major Z oxime); 8.1 (br s, NOH, 1H, minor E oxime); 7.44 (d, J= 7.5 Hz, 1H, CH=N, E isomer); 7.43 (d, J= 7.0 Hz, 1H, aromatic H, Z isomer); 7.1-7.3 (m, 2H); 6.97-7.05 (two doublets, J= 7. Hz each, 2H); 6.98 (d, J= 5,5 Hz, 1H, major isomer); 6.96 (d, J= 5.5 Hz, 1H, minor isomer); 6.64 (d, J= 8.5 Hz, HC=N, Z isomer); 6.33 (d, J= 5.5 Hz, 1H, major Z isomer); 6.31 (d, J= 5.5 Hz, 1H, minor E isomer); 3.4 (dt, J= 8.5, 7.0 Hz, 1H, cyclopropyl CH-CH=N, major Z isomer); 2.7 (dt, J= 9.0, 7.5 Hz, 1H, cylopropyl CH-CH=N, minor isomer); 1.95-2.15 (two sets of multiplets, cylopropyl CH2, 2H, for each isomer). 13C NMR, both isomers, (CDCl3, 75 MHz) δ 151.8, 151.7, 146.9, 143.4, 136.1, 131.9, 131.6, 126.96, 126.90, 125.5, 125.4, 122.3, 118.4, 118.2, 40.1, 28.4, 24.2, 20.7, 19.6 ppm. HRMS (ESI) m/z calculated for C12H12NO (M+H)+ 186.0919, found 186.0913.

Thermolysis of 19a, b and and 19′a, b

A 1.8:1 mixture of 0.5g (2.7 mmol) of the oximes 19a,b and 19′a,b, respectively was dissolved in 4 ml of d8-toluene. The solution was placed into a cylindrical pressure vessel with a Teflon bushing and heated with stirring in an oil bath kept at 110 °C for 2h. The progress of the reaction was monitored by 1H NMR. After the reaction was complete, the mixture was subjected to flash chromatography on silica gel, using 40% EtOAc/hexanes. The bright yellow top fraction was shown to be indenone (160 mg, 71% based on the relative amount of 19a in the mixture) and a 3:1 mixture of 19b and the E oxime 19′b derived from the (1S, 2S) aldehyde (130 mg, 70% based on the relative amount of 19b in the mixture). Inden-1-one (14) was identified by comparing its 1H NMR spectrum with that described in Reference 25.

(E)-(1S, 2R)-Spiro[cyclopropane-1,1′—indene-2-carbaldehyde oxime (19b)

1H NMR (CDCl3, 500 MHz) δ 9.03 (br s, 1H, NOH); 7.4 (d, J= 7.5 Hz, 1H, HC=N); 7.36 (d, J= 7.0 Hz, 1H); 7.23 (t, J= 7 Hz, 1H); 7.14 (t, J= 7.0 Hz, 1H); 6.92 (d, J= 7.0 Hz, 1H); 6.9 (d, J= 5.5 Hz, 1H); 6.25 (d, J= 5.5 Hz, 1H); 2.7 (m, 1H), 1.99 (m, 1H); 1.92 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 151.2, 135.7, 131.0, 126.4, 125.0, 121.9, 117.8. Signals due to the minor isomer 19′b visible in the 13C NMR spectrum: 150.1, 139.7, 129.6, 126.4, 124.5, 122.1, 120.8, 25.4, 18.4 ppm.

1-Methylene-2,3-dihydro-1H-indene (21)

In a 250 ml round bottomed flask equipped with a reflux condenser and nitrogen inlet, 10.71g (30.0 mmol) of Ph3P+CH3Br- and 3.50g (30.60 mmol) of 98% KOt-Bu were placed in 60 ml of anhydrous diethyl ether. The mixture was refluxed under nitrogen for 2h. I was then cooled in an ice bath, and a solution of 3.97g (30.0 mmol) of 1-indanone in 4 ml of ether was added dropwise at 0 °C. Then the ice bath was removed and the mixture refluxed for 1h. After allowing the mixture to cool to room temperature, the solid was removed by filtration, the solution washed with H2O (30 ml), brine (30 ml), dried over anhydrous MgSO4 and the solvent rotovapped. The crude product was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (4:1) to give a 3.62g (93%) of a light yellow oil. The 1H NMR spectrum of 1-methylene-2,3-dihydro-1H-indene (21) so obtained was identical to that reported previously (see Reference 33).

(1S, 2R) and (1S, 2S)-Ethyl 2′3′-dihydrospiro[cyclopropane-1,1′-indene-2-carboxylate (22a,b)

1-Methylene-2,3-dihydro-1H-indene (21, 3.60, 27.7 mmol) was dissolved in 60 ml of CH2Cl2, 132 (0.30 mmol) mg of Rh2(OAc)4 was added, and a solution of ethyl diazoacetate (2.91 ml, 27.7 mmol) dissolved in 4 ml of CH2Cl2 was added dropwise through a syringe at room temperature. The mixture was stirred overnight and the green catalyst was removed by filtration through a short pad of silica gel. The solvent was rotovapped and the crude product was purified by flash chromatography on silica gel (hexane/ethyl acetate 6:1) to give 4.80 g (74% yield) of a colorless oil.

1H NMR (CDCl3, 500 MHz, two isomers) δ 7.1-7.25 (m, aromatic H's), 6.72 (m, 1H, aromatic); 4.19 (q, J= 7.0 Hz, 2H, major isomer); 4.04 (dq, A part of an ABX3 system, JAB= 10.5 Hz, JAX= 7.0 Hz, 1H, minor isomer); 3.97 (dq, B part of an ABX3 system, JAB= 10.5 Hz, JAX= 7.0 Hz, 1H, minor isomer); 2.85-3.15 (m, 2H, both isomers); 1.92-2.44 (several multiplets, 3H, both isomers); 1.89 and 1.68 (2 triplets for each isomer, J= 5 Hz in each, 1H); 1.44 (two overlapping multiplets, 1H, both isomers); 1.3 (t, J= 7.0 Hz, 3H, major isomer); 1.14 (t, J= 7.0 Hz, 3H, minor isomer). 13C NMR (CDCl3, 175 MHz, both isomers) δ 172.07, 170,68, 145.9, 145.8, 144.4, 141.7, 126.9, 127, 126.9, 125.9, 124.7, 124.2, 123.4, 118.9, 60.6, 60.5, 48.2, 38.1, 37.1, 31.5, 30.73, 30.68, 29.95, 29.69, 24.5, 18.5, 14.6, 14.4 ppm. HRMS (ESI) m/z calculated for C14H16O2: 216.1150, found 216.1148.

((1S, 2R)- and (1S, 2S)-2′,3′-dihydrospiro[cyclopropane-1,1-inden]2-yl)methanol (23a, b)

A mixture of the esters 22a and 22b (2.55g, 11.81 mmol) was dissolved in 50 ml of dry THF, and under nitrogen, at 0 °C, 23.6 ml of a 1M THF solution of LiALH4 (23.6 mmol) was added dropwise. After complete addition the mixture was stirred overnight at room temperature. Then it was cooled in an ice bath, and 50 ml of H2O was added dropwise, followed by 4 ml of 3N NaOHaq. The mixture was extracted with diethyl ether (3×30 ml), the combined ether extracts washed with H2O (30 ml), brine (30 ml), and dried over anhydrous MgSO4. The solvent was rotovapped and the residue purified by flash chromatography on silica gel (hexane/EtOAc 3:1) to 2g of give a colorless oil (97% yield).

1H NMR (CDCl3, 500 MHz, both isomers) δ 7.1-7.3 (m, 3H); 6.87 (m, 1H, major isomer); 6.7 (m, 1H, minor isomer); 3.8, 3.6 and 3.5 (multiplets, both isomers, 2H); 3.1, 2.9 (two multiplets, 2H); 2.4 and 2.3 (m, 1H); 2.1 and 1.9 (m, 1H); 1.5 (m, 1H); 1.4 (broad s, 1H, OH, minor isomer); 1.1 (m, 1H); 1.04, and 0.82 (m, 1H); 1.01 (broad s, 1H, OH, major isomer). 13C NMR (CDCl3, 175 MHz) δ 148.1, 145.8, 143.81, 143.5, 126.8, 126.4, 126.24, 126.17, 124.9, 124.5, 121.1, 118.6, 64.4, 62.5, 37.8, 32.2, 31.6, 31.1, 31.0, 30.5, 29.7, 28.6 ppm. HRMS (ESI) m/z calculated for C12H14O+Na+: 197.0937, found 197.0932.

(1S, 2R)- and (1S, 2S)-2′,3′-Dihydrospiro[cyclopropane-1,1′-indene]-2-carbaldehyde (24a,b)

To a solution of 348 mg (2.0 mmol) of the mixture of alcohols from the reaction described above in 10 ml of CH2Cl2, 5.0 ml (0.48 M 15 weight% in CH2Cl2, 2.4 mmol, 1.2 equivs.) of the Dess-Martin periodinane (DMP) was added dropwise at 0 °C. The the mixture was stirred at room temperature for 2h. Aqueous Na2S2O3 (10 ml, 0.5M) was added and the mixture stirred for 10 min, the aqueous layer separated, extracted with CH2Cl2 (2×10 ml), the combined extracts washed with each 10 ml of NaHCO3 and brine and dried over anhydrous MgSO4. The solvent was rotovapped and the crude product was purified by flash chromatography on silica gel (hexane/EtOAc 5:1).

1H NMR (CDCl3, 500 MHz) δ 9.54 (d, J= 4.5 Hz, 1H, CHO, minor isomer); 9.29 (d, J= 5.0 Hz, 1H, CHO, major isomer); 7.15-7.3 (m, 3H, ArH, both isomers); 7.07 (m, 1H, major isomer); 6.76 (m, 1H, minor isomer); 2.0-3.2 (overlapping multiplets, 2H), 2.46 (m, 1H, major isomer); 2.3 (m, 2H, minor isomer); 2.24 (m, 1H, major isomer); 2.19 (t, J= 5.5 Hz, 1H, major isomer); 1.96 (ddd, J= 13.0, 8.0, 1.5 Hz, 1H, major isomer), 1.91 (t, J= 5.0 Hz, 1H, minor isomer); 1.65 (m, 1H, both isomers isomers). 13C NMR (CDCl3, 175 MHz) d 199.9, 1997, 145.7, 145.1, 143.9, 141.2, 127.33, 127.30, 127.0, 126.2, 124.9, 124.8, 122.3, 118.9, 40.8, 40.3, 39.2, 38.5, 37.7, 30.9, 30.7, 29.7, 23.1, 18.7 ppm. HRMS (ESI) m/z calculated for C13H13O (M+H+): 173.0962, found 173.0963.

N-Methylnitrones 25a and 25b

A mixture of 300 mg (2.5 mmol) of anyhdrous MgSO4, 420 mg (5.00 mmol) of NaHCO3, 209 mg (2.5 mmol) of N-methylhydroxylamine hydrochloride was placed in 10 ml of CH2Cl2. To this mixture, a solution of aldehydes 24a,b in 2 ml of CH2Cl2 was added with stirring. The mixture was stirred overnight at room temperature. Then 20 ml of H2O was added, the layers were separated, the aquesous layer was extracted once with 20 ml of CH2Cl2. The combined methylene chloride extracts were washed with 20 ml of brine, dried over MgSO4 and the solvent rotovapped. Due to the sensitivity of nitrones 25a and 25b toward silica gel, it was not further purified. The product was >98% pure by 1H NMR. Yield: 195 mg (97%).

1H NMR (CDCl3, 500 MHz) δ 7.1-7.2 (m, 3H), 6.8 (m, 1H, major isomer); 6.75 (m, 1H, minor isomer), 6.4 (d, J= 8.5 Hz, CH=N, major isomer); 6.34 (d, J= 8.5 Hz, CH=N, minor isomer); 3.71 (s, 3H, NMe, major isomer); 3.56 (s, NMe, minor isomer); 3.07 (m, 2H, major isomer); 3.042 and 2.92 (2 multiplets, 2H, minor isomer), 2.8 (m, 1H, major isomer), 2,7 (m, 1H, minor isomer); 2.4 (m, 1H. minor isomer); 2.2 (m, 1H, major isomer); 2.1 (m, 1H, major isomer); 2.0 (m, 1H, minor isomer); 1.6 (overlapping multiplets, 1H, both isomers); 1.46 (t, J= 5.5 Hz, 1H, minor isomer); 1.23 (t, J= 5.5 Hz, 1H, major isomer). 13C NMR (CDCl3, 175 MHz), major isomer, δ 145.7, 143.3, 139.7, 126.9, 126.8, 124.4, 119.2, 52.6, 36.8, 35.7, 30.9, 30.8, 24.9, 23.6 ppm; minor isomer, d 146.1, 142.7, 139.5, 126.9, 126.2, 125.3, 120.5, 52.6, 33.0, 36.5, 30.9, 25.8, 19.1 ppm. HRMS (ESI) m/z calculated for C13H16NO (M+H+): 202.1227, found 202.1227.

Spiro[2.4]heptan-1-ylmethanol (27)

To a solution of ethyl spiro[2.4]heptane-1-carboxylate2 (2.44 g, 14.5 mmol) in THF (50 ml) at 0 °C, LiAlH4 (1.0 M in THF, 29.0 ml, 29.0 mmol) was added dropwise. The mixture was stirred overnight at room temperature. After addition of water (50 ml) at 0 °C, 3 N NaOHaq (4 ml) was added. The aqeous layer was extracted with diethyl ether (3 × 20 ml), the combined organic layers were washed with water (50 ml), brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was rotovapped and the product was purified by flash chromatography on silica gel (hexane/EtOAc 3:1) to give 21 as a colorless oil (1.587 g, 12.6 mmol, 87%).

1H NMR (CDCl3, 500 MHz) δ 3.6 (dd, J= 11, 6.5 Hz, 1H); 3.5 (dd, J= 11.0, 8.0 Hz, 1H); 1.64-1.76 (m, 4H); 1.6 (m, 2H); 1.45 (m, 2H); 1.37 (broad s, 1H, OH); 1.09 (m, 1H); 0.64 (dd, J= 8.5, 4.5 Hz, 1H); 0.27 (t, J= 5.0 Hz, 1H). 13C NMR (CDCl3, 175 MHz) δ 65.2, 37.4, 30.5, 27.4, 26.7, 26.1, 25.6, 18.6 ppm. HRMS (ESI) m/z calcd for C8H15O (M+H+) 127.1118, found 127.1119.

Spiro[2.4]heptane-1-carbaldehyde (28)

To a solution of oxalyl chloride (0.655 ml, 7.5 mmol) in CH2Cl2 (20 ml) kept at -78 °C, DMSO (1.065 ml, 15.0 mmol) was added dropwise. After 15 min at -78 °C, a solution of spiro[2.4]heptan-1-ylmethanol (0.63 g, 5.0 mmol) in 4 ml of CH2Cl2 was added. The mixture was stirred at -78 °C for 30 min. After the addition of NEt3 (2.087 ml, 15.0 mmol) at -78 °C, the resulting solution was stirred at -78 °C for 30 min, then for 60 min at room temperature. After adding H2O (20 ml) the organic layer was separated and the aqueous layer extracted with CH2Cl2 (2 × 20 ml). The combined organic extracts were washed with water (20 ml), brine (20 ml), and dried over anhydrous MgSO4. After removal of solvent under reduced pressure the residue was purified by column chromatography on silica gel (hexane /OEtAc = 6:1) to give 28 as a colourless oil (0.512 mg, 83%).

1H NMR (CDCl3, 500 MHz) δ 9.2 (d, J= 5.5 Hz, 1H, CHO); 1.87 (dt, J= J= 8.0, 5.5 Hz, 1H); 1.81 (m, 1H); 1.63-1.77 (m, 6H), 1.58 (m, 1H); 1.4 (t, J= 4.5Hz, 1H); 1.23 (dd, J= 8.0, 4.5 Hz, 1H). 13C NMR (CDCl3, 175 MHz) δ 201.6, 42.6, 37.1, 35.8, 30.9, 26.5, 2. HRMS (ESI) m/z calculated for C8H13O (M+H+) 125.0961, found 125.0951.

N-Methylnitrone of spiro[2.4]heptane-1-carbaldehyde (29)

To a suspension of MgSO4 (600 mg, 5.0 mmol), NaHCO3 (840 mg, 10.0 mmol) and N-methylhydroxylamine hydrochloride (418 mg, 5.0 mmol) in 10 ml of CH2Cl2, spiro[2.4]heptane-1-carbaldehyde (248 mg, 2.0 mmol) was added, the resulting mixture stirred overnight at room temperature. The white solid was removed by filtration, and washed with CH2Cl2 (30 ml). The organic solution was washed with water (20 ml), brine (20 ml), and dried over MgSO4. After removal of solvent under reduced pressure, the product was obtained as colorless oil (262 mg, 86%).

1H NMR (CDCl3, 500 MHz) δ 6.23 (d, J= 8.5 Hz, 1H, CH=N); 3.7 (s, 3H, NCH3); 2.4 (dt, J= 8.5, 4.5 Hz, 1H); 1.6-1.8 (m, 6H), 1.56 (m, 1H); 1.47 (m, 1H); 1.2 (dd, J= 8.5, 4.5 Hz, 1H); 0.8 (t, 4.5 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 142.0 (C=N); 52.4 (NMe), 37.4, 36.8, 32.0, 26.6, 25.8, 22.9, 21.8 ppm. HRMS (ESI) m/z calculated for 154.1227 (M+H)+, found 154.1226.

Supplementary Material

Supporting Information

Figure 1. Spiroconjugative effects in 5.

Figure 1

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Figure 3.

Figure 3

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Relative enthalpy profile for the conversion of 7 to 8 at the M062x6-311+G** level. Barriers are posted for transition states. For species 8, the enthalpy of the associated retro Diels-Alder product is included.

Scheme 1. Yb(OTf)3 catalyzed intermolecular nitrone-activated cyclopropane homo [3+2] cycloaddition.

Scheme 1

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Acknowledgments

I. Erden acknowledges financial support of this work by funds from the National Institutes of Health (Grant No. SC1 GM082340). S. Gronert acknowledges support from the National Science Foundation (CHE-1565852). The mass spectrometry work at SFSU was in part supported by a grant from the National Science Foundation (CHE-1228656) and is gratefully acknowledged. Mr. G. Cabrera acknowledges an NIH MS/PhD Bridge fellowship (R25-GM04897). We thank Ms. Lourdes Adame for technical support.

Footnotes

Dedicated to Professor Edwin L. Motell on the occasion of his 85th birthday

Supporting Information. Supporting information (1H and 13C NMR spectra of 10, 11, 12, 12′, 14/17, 18a, b, 19/19′, 19b/19′b′, 22a ,b, 23a, b, 24a, b, 25a, b, 27, 28, 29; complete reference 32, as well as all computational data) associated with this article can be found in the online version at

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Supplementary Materials

Supporting Information
NIHMS920223-supplement-Supporting_Information.pdf (1.9MB, pdf)

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