Nucleofugal behavior of a β-shielded α-cyanovinyl carbanion

Introduction

A carbanionic fragment shows nucleofugal behavior on breaking its single-bond connection with a developing electrophilic center. Apart from deprotonation reactions or formation of a separated ion pair and other trivial examples, the (at least formally) heterolytic cleavage of C–C single bonds can provide cases of interest if it generates organometallic compounds under unusual conditions. The well-known cases of alkoxide fission [1-3] (top line of Scheme 1) may be viewed as a reversed formation of an alkoxide A¹M¹ from an organometallic C–M¹ and a carbonyl compound (R¹)₂C=O. Such a C–C fission (retro-addition reaction) can occur already near room temperature (rt) if the nucleofugal carbanion proves to be an electronically stabilized N≡C–CH₂^– [1] or allylic [2] species or a short-lived equilibrium component [3].

A cleavable alkoxide A¹M¹ can be employed in at least three ways: (a) its equilibrium component C–M¹ may be trapped by a different carbonyl compound (R²)₂C=O to give the new alkoxide A²M¹ (and from there the alcohol A²H) as evidence for the intermediacy of a short-lived species C–M¹. If A²M¹ is also cleavable, the two alkoxides A¹M¹ and A²M¹ may be obtained under thermodynamic control. (b) Trapping of the other equilibrium component (R¹)₂C=O by a nucleophile might accumulate the organometallic compound C–M¹. (c) A¹M¹ may be used to replace M¹ by M² with intent to study a different organometallic C–M² (bottom part of Scheme 1). For this purpose, A¹M¹ should be demetalated through work-up to give, for instance, the alcohol A¹H; the subsequent deprotonation of A¹H by an M²-containing base BM² must be complete before the generated alkoxide A¹M² begins to release C–M² that would otherwise be protonated by any unconsumed portion of A¹H. We had used this technique [3] to generate the short-lived, NMR-invisible pivaloylmetals (H₃C)₃C–COM from the overburdened alkoxides of tri-tert-butylacyloin that were readily cleaved with relief of internal strain as a driving force. We now report here on the above-mentioned options (a) and (c) with the focus on some nucleofugal traits of the carbanion unit of the stable [4], β-shielded α-metalated acrylonitriles.

Results and Discussion

The α-cyanoalkenyllithium 2Li (top line of Scheme 2) may be prepared [4] either by LDA-mediated deprotonation (LDA = iPr₂NLi) of the β-shielded acrylonitrile derivative 1 or by an Sn/Li transmetalation reaction of n-butyllithium (“n-BuLi”) with the α-stannyl derivative 3. Due to intermolecular LiN coordination, 2Li was deduced [4] to form a clustered ground state that showed no obvious rate anomaly with previously [4] studied electrophiles; this should also hold true here for pivalaldehyde t-BuCH=O (4, “t-Bu” = tert-butyl). The chiral adduct 7 of 4 exhibited four different NMR signals for the four methyl groups at the 1- and 3-positions. Analytically pure 7 was obtained only through distillation as a crystalline sample that decayed during an attempted recrystallization from methanol. A possible reason for this instability at a temperature far below the boiling point became clear on addition of some solid potassium tert-butoxide (KOt-Bu) to an NMR tube that contained purified 7 in DMSO at rt: After the immediate appearance of a yellow tint, the next ¹H NMR spectrum revealed that 7 was almost completely transformed into the acrylonitrile derivative 1 (bottom line of Scheme 2). This suggested that the nucleofugal carbanion unit of 2K had escaped from the potassium alkoxide 10 with formation of 2K (yellow tint) and t-BuCH=O, whereupon 2K was trapped by proton sources such as DMSO or unconsumed 7 to produce 1. As a consequence, the general procedure (GP) of adding carbonyl compounds to deprotonated 1 commends to use an acidic work-up and a strict exclusion of bases that are stronger than diluted aqueous NaHCO₃.

Benzaldehyde (5) and cyclopropanecarboxaldehyde (6) added also readily to 2Li with production of 8 and 9, respectively. As already reported above for 7, adducts 8 and 9 showed also four CH₃ NMR signals on account of the stereogenic carbon centers C–OH. The NMR AB-type interproton ³J splittings of the H–C–O–H moieties in 8 and 9 disclosed that intermolecular scrambling of the hydroxy protons was retarded through steric congestion.

The adduct 13 (Scheme 3) of adamantan-2-one (11) was formed (like the above aldehyde adducts) through addition at C-α (rather than at nitrogen), as shown by the δ values of the tetramethylindane part which were consistent with those of 7–9. Complete NMR assignments for the 2-hydroxyadamantan-2-yl part of 13 were achieved with the two-dimensional NOESY and HSQC techniques at rt. Except for the OH signal, all other resonances were changed only insignificantly on cooling to −60 °C. Cleavage of 13 via the lithium alkoxide 12 (top line of Scheme 3) was fast on the laboratory time scale at rt in the solvents THF, Et₂O, t-BuOMe, or toluene. As mentioned in the Introduction, the successful transfer of 2Li from 11 to 4 depends on the exclusion of proton sources (including the alcohol 13) that would protonate 2Li with formation of 1. Thus, the slow addition of 13 to a well-stirred solution of methyllithium (MeLi, 2 equiv) liberated gaseous CH₄ (1 equiv) so that 13 was completely consumed before the electrophile t-BuCH=O (4; 4 equiv) was introduced and furnished adduct 7 but no trace of 1. The worst case (with 1 as a preponderant product) may be encountered when the deprotonating base is added to the alcohol 13 either too slowly or in a less than stoichiometric amount. For instance (bottom line of Scheme 3), the heterogeneous, slow deprotonation of 13 in THF by the insoluble base potassium hydride (KH) afforded 11 and 1 as the only products via cleavage of the potassium alkoxide 14a and protonation of the emerging 2K by residual 13, so that the final introduction of pivalaldehyde (4) produced no adduct 7. However, the same result was also found when 13 was added to a homogeneous solution of PhCH₂K in THF; this suggested that 13 had transferred its proton to the emerging, thermally stable [4] cleavage product 2K faster than to the residual PhCH₂K (perhaps a problem of slow mixing). On the other hand, deprotonation of 13 by the Grignard reagent MeMgBr in THF was complete (quantitative CH₄ evolution) within 20 min at 0 °C; the subsequent cleavage reaction of the generated magnesium alkoxide 14b was very slow at rt, creating 2MgBr (Scheme 3) in the presence of t-BuCH=O (4) and therefrom 7 together with only a small amount of 1. This almost clean production of 7 agrees with the versatile [5] reactions of H₂C=C(CN)–MgBr with many electrophiles. In most of the above trapping experiments, a slow disproportionation of t-BuCH=O was observed to generate t-BuCH₂OH and t-BuCO₂Li as side-products.

The adduct 18 (Scheme 4) of fluoren-9-one (15) had again a triangular ligand-binding system at C-α, as shown by the completely assigned NMR resonances. As the only unexpected contrast to 7–9 and 13, the 3-CH₃ protons were observed to absorb at a higher δ value (1.98 ppm) than that of the 1-CH₃ protons, which amounts to an increase of 0.34 ppm relative to 3-CH₃ of 13. We ascribed this to a ring-current effect by the 9´-hydroxyfluoren-9´-yl substituent that can be expected to prefer a perpendicular conformation relative to the indane rings with the 9´-OH group pointing toward 3-CH₃. As a peculiar line-width effect, the NMR signals of 3-CH₃ (¹H and ¹³C) and of 4-H were significantly broadened at rt but had the usual narrow line widths at −45 °C. Formation of the primary lithium alkoxide 16 (Scheme 4) was shown to be readily reversible as follows. Without protolysis and work-up of the green-colored solution, 16 was kept in THF at rt for 30 min and then treated with t-BuCH=O (4; 1.5 equiv); after a further period of 2 hours at rt, the GP work-up furnished the adduct 7 of t-BuCH=O along with the co-product fluoren-9-one (15), some fluoren-9-ol [6], and a small amount of 1, but no 18 (would derive from residual 16). Thus, 16 had released the nucleofugal carbanion unit of 2Li which was trapped by 4 to give the alkoxide 17 of 7.

In view of the apparently modest spatial demand of the α-cyano substituent in the adducts of 2Li, it seemed surprising that the following ketones generated no (or no kinetically stable) C=O adducts at rt: t-Bu₂C=O, pivalophenone (t-Bu–C(O)–Ph), benzophenone (Ph₂C=O) [7], bis(1-methylcyclopropyl)ketone [8], and dicyclopropyl ketone (19). Instead of an adduct of 19 to 2Li, the carboxyalcohol 21 (a known [9] product of 19 with LDA) in Scheme 5 and the acrylonitrile derivative 1 were obtained from 19; this run was conducted in the absence of LDA with a sample of 2Li that had been prepared in Et₂O through an Sn/Li interchange reaction [4] of 3 with n-BuLi. Therefore, 2Li should have deprotonated 19 with formation of 20 that was trapped by 19 to give 21. But why was 21 not formed from 19 with the α-phenylalkenyllithium 22 (related to 2Li) that produced [10] the “normal” carbonyl adduct 23 of 19? This “normal” C=O addition reaction was obviously faster than the deprotonation of 19 and also apparently irreversible under the reaction conditions, whereas the unobserved C=O addition of 19 to 2Li might be possible yet quickly reversible with a terminating proton transfer from 19 to 2Li as shown in Scheme 5. Alternatively, carbonyl additions to 2Li might be generally retarded (relative to protonations) on account of the clustered [4] ground state structure of 2Li in solution.

Electrophilic cations (Li⁺ or K⁺) are not necessary (albeit perhaps helpful) for the addition of the carbanion unit of 2Li or 2K to carbonyl compounds: Generated through desilylation of 24 (Scheme 6) by tetrabutylammonium fluoride (Bu₄N⁺F⁻; ≤0.05 equiv), the ion pair 25 was trapped by pivalaldehyde (4) with formation of 7 along with a comparable amount of the alkene 1. However, the primary alkoxide product, as formed by 25 and 4, was supposedly blocked by FSiMe₃ and hence unsuitable for an analysis of the retro-addition reaction (see Supporting Information File 1).

Conclusion

(i) The nucleofugal carbanion (α-deprotonated 1) can escape with surprising ease from alkoxides, perhaps with some assistance by a metal cation if present. Conversely, metal cation assistance was not necessary for the rapid carbanion release from the α-silyl compound 24 in the presence of Bu₄N⁺F⁻ in catalytic amounts.

(ii) Most of the above alkoxide fission reactions were conducted in the presence of an electrophile for trapping the released nucleofugal carbanion; this provided a first evidence for the retro-addition process with an alkenylmetal intermediate. These fissions were slow in case of the magnesium alkoxide but rapid for the lithium or potassium alkoxides at ambient temperatures.

(iii) The alternative trapping [3] of the carbonyl component by means of a nucleophile was not tried here but might serve to accumulate the organometallic equilibrium component for the purpose of spectroscopic characterization or X-ray diffraction analyses.

(iv) Fission of the lithium alkoxide of the adduct 13 of adamantan-2-one appeared to be comparably fast on the laboratory time scale in the solvents THF, Et₂O, t-BuOMe, or toluene. A similarly weak solvent dependence had been observed [4] for the heterolytic cis/trans stereoinversion of 2Li.

(v) For more profound mechanistic investigations, one should be aware of the established [4] clustered ground state of 2Li and the possibility that clustered species might be the reactive components even in THF solutions, whereas the retro-addition processes may perhaps involve monomeric nucleofuges.

Experimental

General remarks. Stoichiometric formation of alkoxides through deprotonation of the alcohols was conveniently performed with methyllithium or methylmagnesium bromide and gas-volumetric control of the liberated methane (ca. 25 mL/mmol at 22 °C). All ¹H and ¹³C NMR shifts δ were referenced with internal Me₄Si. NMR abbreviations were as follows: d = doublet, m = multiplet, q = quartet, quat = quaternary, s = singlet, t = triplet.

General procedure (GP) for carbonyl addition to α-lithio-α-(1,1,3,3-tetramethylindan-2-ylidene)acetonitrile (2Li). A dry Schlenk flask was charged with a magnetic stirring bar, anhydrous Et₂O or toluene (2 mL), and N,N-diisopropylamine (0.161 mL, 1.14 mmol). This solution was stirred at –30 °C under argon gas cover during the addition of n-BuLi (1.05 mmol) in hexane (0.47 mL). The created LDA (up to 1.05 mmol) solution was treated with the solid nitrile 1 (200 mg, 0.95 mmol) and stirred further at rt till 1 was completely dissolved, whereupon the carbonyl compound (1.24 mmol, neat or in a solvent) was added to the yellow solution of 2Li and stirred for another 30 min. The mixture was poured into aqueous HCl (2 M, 10 mmol) and extracted with Et₂O (3 × 20 mL). (Note that the product might decay in a non-acidic milieu.) The combined Et₂O extracts were shaken first with water (1 × 20 mL), then with diluted aqueous NaHCO₃, and again distilled water (2 × 20 mL), then dried over Na₂SO₄, filtered, and concentrated.

3´-Hydroxy-4´,4´-dimethyl-2´-(1,1,3,3-tetramethylindan-2-ylidene)pentanenitrile (7). The GP protocol was used to treat LDA (1.56 mmol) in toluene with the β-shielded acrylonitrile 1 (300 mg, 1.42 mmol), followed by pivalaldehyde (4, 0.200 mL, 1.84 mmol). After work-up, the crude material (401 mg) distilled at 120–130 °C (bath temp.)/0.03 mbar to give pure 7 (132 mg, 29%) with mp 108–112 °C; 7 would decay on recrystallization. ¹H NMR (CDCl₃, 400 MHz) δ 1.16 (s, 9H, t-Bu), 1.59 and 1.61 (2 s, 2 × 3H, 2 × 3-CH₃), 1.69 and 1.71 (2 s, 2 × 3H, 2 × 1-CH₃), 1.97 (broad s, 1H, OH), 4.71 (s, 1H, H–CO), 7.14 and 7.17 (2 m, 2 × 1H, 4-/7-H), 7.27 (m, 2H, 5-/6-H) ppm, assigned through comparison with 8; ¹³C NMR (CDCl₃, 100.6 MHz) δ 27.0 (q, Me₃C), 28.4 and 28.7 (2 q, 2 × 1-CH₃), 30.9 and 32.4 (2 q, 2 × 3-CH₃), 35.7 (quat, Me₃C), 49.42 (quat, C-3), 49.57 (quat, C-1), 74.6 (d, HCO), 110.9 (quat, C-α), 118.3 (quat, C≡N), 122.1 (d, C-4), 122.4 (d, C-7), 127.7 and 127.9 (2 d, C-5/-6), 147.6 (quat, C-7a), 148.0 (quat, C-3a), 180.6 ppm (quat, C-2); IR (KBr): 3475 (O–H), 2927, 2869, 2214 (s, C≡N), 1610, 1487, 1464, 1368, 1274, 1192, 1060, 1013, 762 cm⁻¹; anal. calcd for C₂₀H₂₇NO (297.4): C, 80.76; H, 9.15; N, 4.71; found: C, 81.15; H, 9.42; N, 4.76.

3´-Hydroxy-3´-phenyl-2´-(1,1,3,3-tetramethylindan-2-ylidene)propionitrile (8). A solution of LDA (1.14 mmol) in dry Et₂O was prepared according to the GP and treated with the acrylonitrile derivative 1 (200 mg, 0.95 mmol). The yellow solution (2Li, 0.95 mmol) was decolorized on the addition of benzaldehyde (5, 0.126 mL, 1.24 mmol). Warm-up (GP) afforded a colorless powder (262 mg, 87%); this almost pure material was recrystallized from toluene (5 mL) to furnish a powder (108 mg, 36%) with mp 190–192 °C; 8 was insoluble in CCl₄. ¹H NMR (CDCl₃, 400 MHz) δ 1.58 (s, 3H, 1 × 3-CH₃), 1.71 and 1.72 (2 s, 2 × 3H, 2 × 1-CH₃), 1.75 (s, 3H, 1 × 3-CH₃), 2.33 (d, ³J = 6.7 Hz, 1H, OH), 6.15 (d, ³J = 6.7 Hz, 1H, H–CO), 7.17 and 7.20 (2 m, 2 × 1H, 4-/7-H), 7.30 (m, 2H, 5-/6-H), 7.35 (t, ³J = 7.0 Hz, 1H, para-H), 7.42 (tm, ³J = 7.2 Hz, 2H, 2 × meta-H), 7.51 (dm, ³J = 7.4 Hz, 2H, 2 × ortho-H) ppm, assigned through comparison with 7; ¹³C NMR (CDCl₃, 100.6 MHz) δ 28.8 and 29.0 (2 q, 2 × 1-CH₃), 30.6 and 31.5 (2 q, 2 × 3-CH₃), 49.3 (quat, C-3), 49.5 (quat, C-1), 69.6 (d, HCO), 112.4 (quat, C-α), 116.9 (quat, C≡N), 122.1 (d, C-4), 122.5 (d, C-7), 126.1 (d, 2 × C-ortho), 127.9 and 128.0 (2 d, C-5/-6), 128.4 (d, C-para), 128.8 (d, 2 × C-meta), 140.0 (quat, C-ipso), 147.6 (quat, C-7a), 147.8 (quat, C-3a), 179.5 (quat, C-2) ppm, assigned through comparison with 7 and benzyl alcohol; IR (KBr): 3404 (O–H), 2971, 2228 (C≡N), 1487, 1458, 1368, 1052, 751, 716 cm⁻¹; anal. calcd for C₂₂H₂₃NO (317.4): C, 83.24; H, 7.30; N, 4.41; found: C, 83.39; H, 7.33; N, 4.48.

3´-Cyclopropyl-3´-hydroxy-2´-(1,1,3,3-tetramethylindan-2-ylidene)propionitrile (9). Using the GP protocol, the acrylonitrile derivative 1 (200 mg, 0.95 mmol) was deprotonated with LDA (1.05 mmol) in Et₂O to generate 2Li which was treated with cyclopropanecarboxaldehyde (6, 0.092 mL, 1.24 mmol). The crude product (259 mg) was crystallized from ethanol (2 mL) to give colorless 9 (126 mg, 47%) with mp 146–149 °C. ¹H NMR (CDCl₃, 400 MHz) δ 0.39 (m, 1H of cyclopropyl-CH₂ cis to HCO), 0.65 (m, 2 × trans-H), 0.76 (m, 1 cis-H), 1.41 (m, 1H, tert-CH of cyclopropyl), 1.49 and 1.57 (2 s, 2 × 3H, 2 × 3-CH₃), 1.69 and 1.71 (2 s, 2 × 3H, 2 × 1-CH₃), 1.98 (d, ³J = 4.6 Hz, 1H, exchangeable with D₂O, OH), 4.35 (dd, ³J = 7.7 and 4.6 Hz, 1H, H–CO), 7.14 and 7.18 (2 m, 2 × 1H, 4-/7-H), 7.27 (m, 2H, 5-/6-H) ppm, assigned through comparison with 7; ¹³C NMR (CDCl₃, 100.6 MHz) δ 2.8 and 3.8 (2 t, 2 diastereotopic cylopropyl-CH₂), 16.4 (d, tert-C of cyclopropyl), 28.83 and 28.88 (2 q, 2 × 1-CH₃), 30.3 and 32.0 (2 q, 2 × 3-CH₃), 49.11 and 49.16 (2 quat, C-3 and C-1), 71.2 (d, HCO), 112.3 (quat, C-α), 117.4 (quat, C≡N), 122.1 (d, C-4), 122.5 (d, C-7), 127.76 and 127.87 (2 d, C-5/-6), 147.71 (quat, C-7a), 147.92 (quat, C-3a), 178.6 (quat, C-2) ppm, assigned as above; IR (KBr): 3471 (O–H), 2993, 2961, 2928, 2214 (s, C≡N), 1629, 1487, 1461, 1039, 759 cm⁻¹; anal. calcd for C₁₉H₂₃NO (281.4): C, 81.10; H, 8.24; N, 4.98; found: C, 80.92; H, 8.11; N, 4.97.

α-(2´-Hydroxyadamantan-2´-yl)-α-(1,1,3,3-tetramethylindan-2-ylidene)acetonitrile (13). The technique of the GP was used to generate 2Li in Et₂O from LDA (1.05 mmol) and acrylonitrile derivative 1 (200 mg, 0.95 mmol). After continued stirring till 1 was completely dissolved, a solution of adamantan-2-one (11, 186 mg, 1.24 mmol) in dry Et₂O (4 mL) was added slowly (1 drop per s) at rt, whereupon the mixture was stirred for 30 min and then worked up (GP). The crude material (321 mg after drying in presence of solid KOH) was recrystallized from CCl₄ (5 mL) to give colorless platelets 13 (141 mg, 41%) with mp 179–180.5 °C. ¹H NMR (CDCl₃, 400 MHz, 25 °C) δ 1.64 (s, 6H, 2 × 3-CH₃), 1.68 (dm. ²J = 12.5 Hz, 2H, 1 × 4´-H and 1 × 9´-H), 1.74 (broadened t, ³J ≈ 2 Hz, 2H, 2 × enantiotopic 6´-H), 1.79 (s, 6H, 2 × 1-CH₃), 1.83 (m, ³J ≈ 2.5 Hz, 1H, 5´-H), 1.85 (dm, ²J obscured, 2H, 1 × 8´-H and 1 × 10´-H), 1.86 (s, 1H, OH, δ = 2.30 ppm at –60 °C), 1.89 (m, ³J = 2.8 Hz, 1H, 7´-H), 1.96 (broadened d, ²J = 13 Hz, 2H, 1 × 8´-H and 1 × 10´-H), 2.33 (broadened d, ²J = 12.5 Hz, 2H, 1 × 4´-H and 1 × 9´-H), 2.70 (broad, 2H, 1´-/3´-H), 7.12 (m, 1H, 4-H), 7.17 (m, 1H, 7-H), 7.26 (m, 2H, 6-/5-H) ppm, assigned through the NOESY correlations 4-H ↔ 3-CH₃ ↔ 1´-/3´-H ↔ all four 4´-/9´-H ↔ 5´-H ↔ 2 × 6´-H ↔ 7´-H ↔ 8´-/10´-H ↔ 1´-/3´-H ↔ OH, and 7-H ↔ 1-CH₃ (this without any cross-peaks to the adamantane protons); ¹³C NMR (CDCl₃, 100.6 MHz) δ 25.9 (d, CH-5´), 26.5 (d, CH-7´), 28.8 (q, 2 × 1-CH₃), 30.0 (q, 2 × 3-CH₃), 32.9 (t, CH₂-4´-/9´), 35.6 (t, CH₂-8´-/10´), 37.0 (t, CH₂-6´), 37.4 (d, CH-1´-/3´), 50.5 (quat, C-3), 51.5 (quat, C-1), 77.1 (quat, C-2´), 118.2 and 119.4 (2 × quat, C-α or C≡N), 121.9 (d, C-4), 122.5 (d, C-7), 127.45 and 127.57 (2 d, C-5/-6), 147.4 (quat, C-7a), 149.2 (quat, C-3a), 182.6 (quat, C-2) ppm, assigned through DEPT, HSQC, and comparison with 7–9, no other significant changes at −60 °C; IR (KBr): 3471 (sharp, O–H), 2855, 2201 (sharp, C≡N), 1602 (w), 1488, 1453, 1353, 1020, 760 (s) cm⁻¹; anal. calcd for C₂₅H₃₁NO (361.53): C, 83.06; H, 8.64; N, 3.87; found: C, 82.90; H, 8.50; N, 3.61.

α-(9´-Hydroxyfluoren-9´-yl)-α-(1,1,3,3-tetramethylindan-2-ylidene)acetonitrile (18). Using the GP protocol, the solid acrylonitrile derivative 1 (200 mg, 0.95 mmol) was added to a solution of LDA (1.05 mmol) in dry Et₂O, followed by fluoren-9-one (15, 223 mg, 1.24 mmol) which changed the color of the mixture from yellow to dark green. The crude material (406 mg) obtained after work-up (GP) was recrystallized from toluene (9 mL) to afford colorless 18 (147 mg, 40%) with mp 243–245 °C. ¹H NMR (CDCl₃, 400 MHz, 25 °C) δ 1.66 (sharp s, 6H, 2 × 1-CH₃), 1.98 (broadened s, 6H, 2 × 3-CH₃), 2.35 (s, 1H, OH), 7.15 (dm, 1H, 7-H), 7.22 (broadened d, 1H, 4-H, narrowed at −45 °C), 7.25 (td, 1H, 5-H), 7.28 (td, 1H, 6-H), 7.33 (td, ³J = 7.5 Hz, 2H, 2´-/7´-H), 7.42 (td, ³J = 7.0 Hz, 2H, 3´-/6´-H), 7.48 (d, ³J = 7.6 Hz, 2H, 1´-/8´-H), 7.69 (d, ³J = 7.5 Hz, 2H, 4´-/5´-H) ppm, assigned through comparison with 13 and the NOESY correlations 3-CH₃ ↔ 1´-/8´-H ↔ 1-CH₃ (weaker) ↔ 7-H ↔ 6-H, and 1´-/8´-H ↔ 2´-/7´-H ↔ 3´-/6´-H ↔ 4´-/5´-H; ¹H NMR (CDCl₃, 400 MHz, −45 °C) δ 1.65, 1.98, 2.39, 7.20, 7.27, 7.30, 7.33, 7.37, 7.46, 7.49, 7.69 ppm; ¹³C NMR (CDCl₃, 100.6 MHz) δ 29.1 (qq, ¹J = 128 Hz, ³J = 4.5 Hz, 2 × 1-CH₃), 31.7 (broadened qq, sharp at −45 °C, ¹J = 128 Hz, ³J = ca. 4.5 Hz, 2 × 3-CH₃), 50.1 (unresolved m, C-3), 51.0 (unresolved m, C-1), 85.7 (m, C-9´), 111.1 (very weak d, stronger at −45 °C, ³J = 8.5 Hz to OH, C-α), 117.9 (sharp s, C≡N), 120.6 (dd, ¹J = 160 Hz, ³J = 8 Hz, CH-4´/-5´), 122.3 and 122.4 (2 dd, ¹J = 159 Hz, ³J = 8 Hz, CH-7/-4), 124.1 (dd, ¹J = 160 Hz, ³J = 8 Hz, CH-1´/-8´), 127.2 and 127.5 (2 dd, ¹J = 160 Hz, ³J = 7.5 Hz, CH-5/-6), 128.8 (dd, ¹J = 162 Hz, ³J = 7.3 Hz, CH-2´/-7´), 130.1 (dd, ¹J = 159 Hz, ³J = 7.2 Hz, CH-3´/-6´), 139.9 (broadened t, ³J = 7 Hz, C-4a´/4b´), 147.4 (m, C-7a), 147.9 (t, ³J = 7.2 Hz, C-8a´/9a´), 149.6 (unresolved m, C-3a), 179.4 (m, C-2) ppm, assigned through comparison with 7, 8, 9, and fluoren-9-one → HETCOR → COLOCS(7 Hz); COLOCS cross-peaks of ³J: 1-CH₃ → C-2 and C-7a, 3-CH₃ → C-2 and C-3a, OH → C-α, 4-H → C-6, 5-H → C-7, 6-H → C-4, 7-H → C-5, 1´-H → C-3´ and C-4a´, 2´-H → C-4´ and C-9a´, 3´-H → C-1´ and C-4a´, 4´-H → C-2´ and C-9a´; IR (KBr): 3525 (w). 3417 (s), 3022, 2959, 2925, 2215 (sharp, C≡N), 1607, 1488, 1451, 1366, 1207, 771, 761, 754, 735 cm⁻¹; anal. calcd for C₂₈H₂₅NO (391.5): C, 85.90; H, 6.44; N, 3.58; found: C, 86.13; H, 6.04; N, 3.60.

Cyclopropyl 1-[α,α-(dicyclopropyl)hydroxymethyl]cyclopropyl ketone (21) [9]. ¹H NMR (CDCl₃, 400 MHz) δ 0.27 (m, 4H), 0.49 (m, 4H), 0.80 (m, 2H), 0.86 (m, 4H), 0.98 (m, 2H), 1.27 (m, 2H), 1.46 (m, 1 tert-H), 4.3 (broadened s, 1H, OH) ppm; ¹³C NMR (CDCl₃, 100.6 MHz) δ 0.28 (2 × CH₂), 0.39 (2 × CH₂), 11.1 (2 × CH₂), 11.3 (2 × CH₂), 15.7 (1 × CH), 17.6 (2 × CH), 39.8 (1 × quat C), 70.7 (1 × quat, C–O), 212.9 (1 × quat, C=O) ppm.