Stereospecific synthesis of alkylidenecyclopropanes via sequential cyclopropene carbomagnesation/1,3-carbon shift

Abstract

Alkylidenecyclopropanes can be synthesized from enantiomerically enriched cyclopropene derivatives with >99% stereotransfer and good to excellent yield. The protocol comprises the stereoselective reaction of Grignard reagents with 1-alkoxymethyl-3-hydroxymethyl cyclopropenes and a stereospecific [1,3] carbon shift reaction.

Alkylidenecyclopropanes have been the subject of considerable investigation because of their high strain energy and unique reactivity.¹ The utility of chiral alkylidenecyclopropanes is exemplified by stereospecific transformations that rapidly build stereochemical complexity through ring expansion,² cycloadditions³ or ring opening reactions⁴. While a number of methods for generating alkylidenecyclopropanes⁵ have been reported, access to enantiomerically enriched alkylidenecyclopropanes has been limited.⁶

An early approach to non-racemic alkylidene-cyclopropanes utilized the stereospecific, formal [1,3] carbon shift of Fiest’s ester, a methylenecyclopropane which is readily available in enantiomerically pure form.⁷ However, the preparative utility of such rearrangements of methylenecyclopropanes to alkylidenecyclopropanes is typically limited by the need for pyrolytic conditions.⁸ Studies by Gardner⁹, Creary¹⁰ and Nakamura¹¹ have shown that aryl¹⁰ or alkoxy^9,11 substituted methylenecyclopropanes rearrange to alkylidenecyclopropanes under mild conditions. However, the stereospecificity of the rearrangements of methylenecyclopropanes with stabilizing substitutents had not been tested. Moreover, there was no method to access enantiomerically enriched methylenecyclopropanes with substituents that facilitate the [1,3]-carbon shift reaction.

Our group had previously demonstrated that enantiomerically enriched methylenecyclopropanes (e.g. 2) can be obtained by addition of Grignard reagents to chiral cyclopropenes (e.g. 1) with allylic ether leaving groups (Scheme 1).¹² Contemporaneously, Marek reported Grignard reagent addition to resolved cyclopropenylcarbinols to form chiral alkylidenecyclopropanes.^6c–f We anticipated that the aromatic substitutent of methylenecyclopropenes 2 would facilitate the rearrangement to alkylidenecyclopropenes 3 under mild conditions. Cyclopropenylcarbinols with aromatic substituents (e.g. 1) are readily available with good levels of enantiomeric excess via Rh₂(S-DOSP)₄ catalyzed cyclopropenation.¹³ Accordingly, we envisioned a general methodology that would produce alkylidenecyclopropanes (3) upon sequential treatment of 1 with Grignard reagents and heat (Scheme 1).

Scheme 1.

Stereospecific synthesis of chiral alkylidenecyclopropanes (2) from cyclopropenes with allylic leaving groups

The rearrangements of methylenecyclopropanes 1 proceed in THF at reflux temperature (Scheme 2). For all of the reactions in Scheme 2, small amounts of starting material were recovered (5–10%). Prolonged heating did not result in higher conversion. Also, minor amounts of isomeric methylenecyclopropanes (4a–g) were observed. Compounds 4a–g resulted from epimerization of 2a–g.¹⁴ It was possible to separate 3g and 4g via preparative HPLC. When purified 3g was heated to reflux in THF for 16 h, compound 4g (3%) and trace 2g (~1%) were observed along with recovered 3g (96%). This result demonstrated that the reaction to form 3g is reversible.

Scheme 2.

Synthesis of alkylidenecyclopropanes from methylenecyclopropanes

^a cee = (product ee / starting material ee) × 100%

2a–g and 3a–g were all measured to be 82% ee (± 1% ee)

As anticipated,¹⁰ the aryl substituent on the methylenecyclopropane was necessary for reactions to take place under mild conditions. Thus, compounds 5–7 did not produce the alkylidenecyclopropanes after refluxing in THF for 16 h; only starting material was recovered (Figure 1). The formal [1,3] shifts of 5–7 did take place at higher temperature (toluene, reflux for 10 h). However, significant decomposition took place and only low yields of the alkylidenecyclopropanes (< 10% yield) were detected by ¹H NMR.

Figure 1.

Methylenecyclopropanes that do not rearrange efficiently to alkylidenecyclopropanes

To verify that the methylenecyclopropane to alkylidenecyclopropane rearrangement took place with net inversion of stereochemistry, the absolute configuration of methylenecyclopropane 2a and alkylidenecyclopropane 3a were assigned. Thus, enantiomerically enriched methylenecyclopropane 2a was prepared in 82% ee by the Rh₂(S-DOSP)₄ catalyzed reaction of methyl α-diazo-α-phenylacetate with methyl propargyl ether, followed by DIBAL reduction and reaction with MeMgBr (Scheme 3). The absolute configuration of intermediate 8 was assigned by conversion into (4S)-3-[(1S)-phenyl-2-(methoxymethyl) cycloprop-2-en-1-oyl]-4-phenyloxazolidinone [(S,S)-9]. The diastereomer (R,S)-9 had been prepared previously,¹⁵ and its absolute configuration has been established through X-ray crystallography (see supporting information). Thus Rh₂(SDOSP)₄ gives cyclopropane 8 with the (S)-configuration, and ultimately provided (R,R)-2a.

Scheme 3.

Assignment of absolute stereochemistry for 2a

The absolute configuration of 3a was assigned by Raney-Ni reduction, which gave separable diastereomers (S,S)-10 and 11. (Scheme 4). The opposite enantiomer of (S,S)-10 was produced upon reduction of the known compound 12, which was prepared as described by Davies. Davies had shown that 12 prepared from Rh₂(S-DOSP)₄ has the (1R,2R)-configuration.¹⁶ Thus, (1R,2R)-2a rearranges to give (S)-3a and a net inversion of stereochemistry at the pivot carbon is observed.¹⁷

Scheme 4.

Assignment of absolute configuration for 2a

The effect of varying the aromatic ring of the methylenecyclopropane was also studied. An electronically releasing p-methoxyphenyl group accelerated the rearrangement, whereas an electronically withdrawing p-fluorophenyl substituent decreased the reaction rate. Thus, the rearrangement of 2h to 3h (Ar = p-methoxyphenyl) reached 77% conversion after reflux for 1 h (94% conversion after 4 h). By contrast, only 50% of 2a to 3a (Ar = Ph) had converted after 1 h (90% conversion after 8 h). The rearrangement of 2i (Ar = p-fluorophenyl) reached only 36% conversion after 1 h (90% conversion after 8 h). The o-tolyl substituted methylenecyclopropane 2j (Ar = o-tolyl) lead only to traces (2% yield) of 3j upon prolonged heating in THF. At higher temperature (toluene, reflux 5 h) a 12% yield of 3j was observed (Scheme 5).

Scheme 5.

Substituent effects on methylenecyclopropane to alkylidenecyclopropane rearrangementa

^a All reactions were carried out in THF at reflux temperature

Excellent levels of chirality transfer [>99% conservation of enantiomeric excess (cee)] were observed for the transformations in Scheme 2. In prior studies on rearrangments of non-racemic methylenecyclopropanes, lower levels of chirality transfer were observed. Feist’s ester was shown to rearrange to a mixture of (E)- and (Z) methyl-carboxycyclopropylidene acetic acid^18a,19 with 93% cee and 47% cee, respectively.¹⁹ In studies on (S,S)-2,3-dimethylmethylenecyclopropane, high levels of chirality transfer were observed at low conversion (80% cee +/− 20%), but less efficient chirality transfer and partial racemization of starting material was observed at higher conversion.^8c

These observations are consistent with the accepted diradical mechanism for the methylenecyclopropane to alkylidenecyclopropane rearrangements.^10,18–20 Aromatic substituents have a dramatic stabilizing influence.¹⁰ A p-methoxy substituent accelerates the rate of the reaction and a p-fluoro substituent decreases the rate of the reaction, but the effect is only minor. However, the rate of rearrangement for 2j is severly reduced by the o-methyl substituent, which hampers co-planarity in a transition state with diradical character and axial chirality (Figure 2). The observation of isomeric products 4 (Scheme 2) is also in line with a diradical mechanism, in accord with earlier observations by Gajewski.^8c

Fig 2.

(a) diradical mechanism for the methylenecyclopropane to alkylidenecyclopropane rearrangements. (b) For the rearrangement of 2j, it is proposed that the o-methyl substituent hampers aromatic stabilization in a transition state with diradical character

Most conveniently, the rearrangement of methylenecyclopropanes to alkylidenecyclopropanes can be carried out in one pot from the cyclopropene precursor 1 (Scheme 6). The overall yields are comparable with the combined yields of separate Grignard addition and rearrangement reactions.

Scheme 6.

One pot reaction to form alkylidenecyclopropanes

In conclusion, a stereospecific method for preparing alkylidenecyclopropanes from enantiomerically enriched methylenecyclopropanes has been described. The reaction takes place under mild conditions, and takes place with excellent transfer of stereochemistry. This reaction can also be carried out in one pot from enantiomerically enriched cyclopropene precursors.

Experimental Section

Representative Procedure for the [1,3] carbon shift reaction: (S,E)-2-Hydroxymethyl-2-phenylethylidenecyclopropane (3a)

To a 100 mL round bottomed flask was added a solution of 2a (52 mg, 0.30 mmol) in THF (15 mL). The reaction mixture was heated to reflux temperature for 16 h. Subsequently, the mixture was allowed to cool and concentrated under reduced pressure. Purification by silica gel chromatography (10% ethyl acetate in hexane) gave 37 mg (0.21 mmol, 71% yield) of 3a as a pale yellow oil. A similar experiment that began with 46 mg of 2a gave 3a in 70% yield. Small peaks attributable to 4a (7%) were detected in the ¹H NMR spectrum at 5.74, 5.57, 4.00, 3.58, 1.77 and 0.84 ppm and in the ¹³C NMR at 129.9, 126.9 ppm. HPLC analysis showed the material to be of 82% ee (using a Chiral OD column, flow rate of 1 mL/min, 1% IPA in hexanes). [α]²⁰_D −76° (c 0.28, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.40 (m, 2H), 7.28-7.34 (m, 2H), 7.20-7.25 (m, 1H), 6.09-6.15 (m, 1H), 3.87 (dd, J = 11.3, 6.1 Hz, 1H), 3.72 (dd, J = 11.2, 6.6 Hz, 1H), 1.86 (dt, J = 6.5, 1.7 Hz, 3H), 1.51-1.55 (m, 1H), 1.41-1.45 (m, 1H), 1.37-1.40 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 141.4 (C), 128.4 (CH), 128.2 (C), 128.0 (CH), 126.7 (CH), 114.7 (CH), 68.8 (CH₂), 31.0 (C), 16.9 (CH₃), 15.6 (CH₃); IR (neat, cm⁻¹): 3351, 3083, 3059, 3028, 2957, 2924, 2855, 1602, 1495, 1464, 1416, 1378, 1303, 1222, 1176, 1029, 905, 760, 732, 699, 562, 542; HRMS-CI (M+NH₄) m/z, calcd for C₁₂H₁₈NO, 192.1388; found, 192.1380.

Representative procedure for the one pot Grignard addition/rearrangement to alkylidenecclopropanes: (S,E)-2-Hydroxymethyl-2-phenyl-heptylidenecyclopropane (3c)

To a 50 mL round bottomed flask was added a solution of 3-hydroxymethyl-1-methoxyethoxymethoxymethyl-3-phenylcyclopropene (63 mg, 0.24 mmol) in THF (5 mL). The mixture was stirred with a magnetic stir bar and hexylmagnesium bromide (2.4 mmol, 1.2 mL of a 2.0 M solution in diethyl ether) was slowly added via syringe. The resulting mixture was allowed to stir at r.t. for 12 h and then heated to reflux for 5 h. The reaction was quenched with saturated NH₄Cl. The aqueous layer was extracted with ethyl acetate (5 mL) three times and the combined organic layers were washed with brine and dried over anhydrous MgSO₄. The solvent was removed and the crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give 37 mg (0.15 mmol, 64% yield) of 3c as a pale yellow oil. A similar experiment that began with 55 mg of 1 gave 3c in 59% yield. Small peaks attributable to 4c (3%) were detected in the ¹H NMR spectrum at 5.73, 5.57, 4.03 and 3.58 ppm. HPLC analysis showed the material to be of 82% ee (using a chiral OD column, flow rate of 1 mL/min, 1% IPA in hexanes. [α]²⁰_D −47° (c 0.34, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.40 (m, 2H), 7.28-7.33 (m, 2H), 7.20-7.24 (m, 1H), 6.07-6.12 (m, 1H), 3.88 (dd, J = 11.3, 6.1 Hz, 1H), 3.72 (dd, J = 11.3, 6.8 Hz, 1H), 2.19-2.25 (m, 2H), 1.24-1.56 (m, 11H), 0.88 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 141.5 (C), 128.4 (CH), 127.9 (CH), 127.3 (C), 126.6 (CH), 120.2 (CH), 68.8 (CH₂), 31.7 (CH₂), 31.6 (CH₂), 30.4 (C), 29.1 (CH₂), 29.0 (CH₂), 22.7 (CH₂), 16.1 (CH₂), 14.1 (CH₃); IR(neat, cm⁻¹): 2924, 2854, 2360, 2341, 1494, 1024, 764, 697, 502; HRMS-CI (M+NH₄) m/z calcd for C₁₇H₂₈NO, 262.2171; found, 262.2175.