Copper-Catalysed Conjugate Addition of Grignard Reagents to 2-Methylcyclopentenone and Sequential Enolate Alkylation

DOI: 10.1002/adsc.201400085

Copper-Catalysed Conjugate Addition of Grignard Reagents to2-Methylcyclopentenone and Sequential Enolate Alkylation

Beatriz C. Calvo,a Ashoka V. R. Madduri,a Syuzanna R. Harutyunyan,a

and Adriaan J. Minnaarda,*a Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands

E-mail : [email protected]

Received: January 23, 2014; Published online: && &&, 0000

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400085.

Abstract: The copper/Rev-JosiPhos-catalysed asym-metric conjugate addition of Grignard reagents to 2-methylcyclopentenone (1) provides 2,3-disubstitutedcyclopentanones in high yields and enantioselectivi-ties, and good diastereoselectivities. Reaction of thein situ formed enolate with various alkylating re-agents in the presence of 1,3-dimethyltetrahydropyri-midine-2(1H)-one (DMPU) affords the correspond-

ing products in a one-pot reaction. This procedurecreates two vicinal stereocentres, one of them quater-nary.

Keywords: asymmetric catalysis; conjugate addition;copper catalysis; 1,3-dimethyltetrahydropyrimidine-2(1H)-one (DMPU); DMPU; enolate alkylation;Grignard reagents

Introduction

The enantioselective copper-catalysed conjugate addi-tion of organometallic reagents has over the yearsbecome a well-established tool for asymmetric C�Cbond formation.[1–10] Various organometallic reagentsare employed in this transformation and the substratescope comprises a variety of Michael acceptors, bothcyclic and acyclic. In our recent work,[11–13] we focuson the use of Grignard reagents, because of theirstraightforward preparation from readily availablealkyl bromides. In the cyclic series, the use ofGrignard reagents in the copper-catalyzed asymmetricMichael addition has been reported for cyclopente-none,[14–16] cyclohexenone,[5,14,16–22] cycloheptenone,[14–17]

b-substituted cyclic enones,[22,23] and lactones.[15,17,18,24,25]

In these studies, however, a-substitution (2-substitu-tion) is lacking, a situation no different from reportswith other organometallic reagents. Until very recent-ly, the sole report in this field came from Vuagnoux-d’Augustin and Alexakis, and comprised the enantio-selective addition of Me3Al and Et3Al to 2-methylcy-clohexenone[23] (Scheme 1). This knowledge was sub-sequently used by Helmchen et al. in a synthesis ofpumiliotoxin C.[26] Neither the use of Grignard re-agents nor 2-methylcyclopentenone had been de-scribed until – during the preparation of this manu-script – Mauduit, Alexakis et al. reported the success-ful application of Cu(I)–N-heterocyclic carbene com-

plexes in the asymmetric addition of Grignard re-agents to 2-methylcyclopentenone and -hexenone.[27]

The resulting magnesium enolates were subsequentlyalkylated to provide a quaternary stereocentre vicinalto the initially formed tertiary stereocentre.

Here we report the asymmetric conjugate additionof Grignard reagents to 2-methylcyclopentenone witha copper catalyst based on Rev-JosiPhos (L1) and thesubsequent enolate alkylation with a variety of elec-trophiles.

Results and Discussion

As a starting point, 2-methylcyclohexenone (2) waschosen as the model substrate. Various copper salts,and chiral ligands (Table 1, Figure 1) were studied inthe conjugate addition of ethylmagnesium bromide.

The combination of L1 and CuBr·SMe2 resulted ina very high selectivity for the conjugate additionproduct 3, considerably higher than that of the reac-tion with just catalytic copper. A moderate but dis-tinct enantioselectivity was obtained as well (entry 2).With L2 only low enantioselectivity was obtainedwhereas L3 provided the racemate, as did L4–L7. No-tably, only when employing L3, no catalyst controlwas observed, while on the contrary, L5–L6 did pro-vide an excellent regioselectivity in favour of 3. L8provided a small enantioselectivity whereas L9 and

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L10 gave racemates, although with very high regiose-lectivity. With all ligands, the trans :cis ratio in 3varied as expected[23,28] between 60:40 and 80:20.

The situation improved when 2-methylcyclopente-none (1) was studied in the conjugate addition ofmethyl- and ethylmagnesium bromide, employing thecombination of CuBr·SMe2 and L1 as the most suc-cessful catalyst thus far (Scheme 2).

The addition of methylmagnesium bromide to (2)showed – like in the case of EtMgBr – a high selectiv-ity for the formation of the conjugate addition prod-uct, however without enantioselectivity. The same re-action with 2-methylcyclopentenone (1), however, re-sulted in a significant er (78:22). Rewarding resultswere obtained in the Cu/L1-catalyzed addition of

EtMgBr to 1; virtually full regioselectivity and an erof 92:8! Therefore we decided to focus on 1 as thesubstrate, and determine the scope of Grignard re-agents that could be added enantioselectively(Table 2).

Table 2 shows that high ers are obtained with a setof linear saturated and unsaturated Grignard re-agents. Substrates with linear alkyl and alkenyl sub-stituents, or substituents branched at the d-position,perform very well. This makes the catalyst systemhighly complementary to the aforementioned Maud-uit–Alexakis system that performs best with stericallymore hindered a-branched Grignard reagents. Un-fortunately, when the substrate was changed fora more sterically hindered one, 2-pentylcyclopente-

Scheme 1. Previous and current work.

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Table 1. Conjugate addition of ethylmagnesium bromide to (2); variation in copper salt and ligand.

Entry Ligand Copper salt Ratio 3 :3a[b] er (trans)[d,e]

1 – CuBr·SMe2 38:56 –2 L1 CuBr·SMe2 96:3 70:303 L2 CuI 73:26 60:4045[a]

67[a]

891011121314

L3L3L3L3L4L5L6L7L8L9L10

CuClCuClCuBr·SMe2

CuBr·SMe2

CuBr·SMe2

CuBr·SMe2

CuBr·SMe2

CuBr·SMe2

CuBr·SMe2

CuBr·SMe2

CuBr·SMe2

29:62[c]

42:56[c]

35:64[c]

21:79[c]

61:3794:591:965:3291:694:495:5

50:5050:5050:5050:5055:4552:4855:4554:4663:3952:4853:47

[a] Reactions were performed at �10 8C.[b] Selectivity determined by GC-MS.[c] No ee found for 3a.[d] Enantioselectivities determined by chiral GC, see the Supporting Information.[e] Diastereomeric ratios between 60:40 and 80:20.

Figure 1. Chiral ligands used in this study.

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FULL PAPERS Copper-Catalysed Conjugate Addition of Grignard Reagents


none, the conjugate addition resulted in very poorconversions. Conjugate addition to cyclic enones re-sults, in addition to a C�C bond and a stereocentre,also in regioselective formation of an enolate. Espe-cially in the current case, subsequent reaction witha carbon electrophile is attractive, as a second, quater-nary, stereocentre is formed. Reaction of in situformed enolates has been reported a number oftimes,[20,30–33] however, unlike lithium enolates, magne-sium enolates react only sluggishly and additives orco-solvents are mostly used to accelerate the reaction.

Protonation of the enolate formed gave alreadyreasonable diastereomeric ratios in the range of 6:4 to

8:2 in favour of the trans compound.[29] Benzyl bro-mide was selected to study the alkylation under vari-ous conditions[34] (Table 3). In the absence of additivesand co-solvents no reaction took place (entry 1).

When HMPA was added, the reaction reachedalmost full conversion with high diastereoselectivity(entry 2), whereas with TMEDA the conversion de-creased dramatically (entry 3). The addition of coordi-nating solvents was also studied. The use of THF asa co-solvent did not improve the conversion althoughit afforded a nearly complete diastereoselectivity. Ad-dition of DME resulted in no reaction. In order to geta more complete picture, a set of additional electro-

Scheme 2. Cu/L1-catalyzed asymmetric conjugate addition reactions. The absolute configuration of 5, and in analogy that of6, was established by comparison of the optical rotation with the literature value.[29]

Table 2. Grignard reagent scope in the conjugate addition to 2-methylcyclopentenone 1.

Entry R Product Conversion[a] Yield er[c,d,e]

1 6 98% n.d.[b] 92:82 7 99% 95% 91:9

3 8 95% n.d.[b] 50:50

4 9 94% n.d.[b] 92:8

5 10 76% 70% 85:15

[a] Conversions determined by GC-MS.[b] Not determined due to the volatility of the product.[c] Enantioselectivities determined by chiral GC, see the Supporting Information.[d] er of the major trans diastereomer.[e] Diastereomeric ratios between 85:15 and 90:10.





philes was studied as well, under mostly identical con-ditions.

As in the benzylation, the allylation reaction withno additives showed no conversion (Table 4, entry 1).Remarkably, however, addition of HMPA now onlyshowed moderate improvement whereas DME in-creased the conversion to 93% (entry 7)! tert-Butylbromoacetate (Table 5), turned out to be rather un-reactive in this reaction and also the diastereomericratio dropped. Reaction with propargyl bromide gaveupon addition of 3 equiv. HMPA incomplete conver-sion (75%) and a dr of 85:15.

The picture that arose from this study is that al-though high conversion and diastereoselectivitiescould be obtained for most electrophiles (tert-butyl

bromoacetate being an exception), the optimal reac-tion conditions are highly dependent on the electro-phile. The addition of HMPA was in general most ef-fective but, on the other hand, it is toxic. DMPU [1,3-dimethyltetrahydropyrimidine-2(1H)-one] can oftenbe used as a versatile alternative, and is mostly ap-plied in somewhat larger amounts.[35] The addition of10 equiv. of DMPU was therefore studied (Scheme 3).We were pleased to see that this procedure gave con-sistently excellent conversions, good isolated yieldsand diastereomeric ratios for the various electro-philes.[36] Also tert-butyl bromoacetate performed wellnow, and also methyl iodide (not used earlier) gaveclose to complete conversion (Scheme 3). The diaste-reoselectivity is not strongly dependent on substitu-tion at the 3 position. The similar reaction sequencewith EtMgBr and benzyl bromide afforded a dr of84:16, whereas the combination of isobutylmagnesium

Table 3. Conjugate addition followed by benzylation.

Entry Additive (No. of equiv.) Co-solvent (MTBE:co-solvent) Conversion[a] dr[b]

1 – – – –2 HMPA (5) – 95% 90:103456

TMEDA (3)–HMPA (5)–

–THF (1:2)THF (2:3)DME (1:2)

20%20%51%–

89:1198:290:10–

[a] Conversions determined by GC-MS.[b] Diastereoselectivity determined by GC-MS. The absolute configuration was established by comparison of the optical ro-

tation with analogues in the literature.[27] The relative configuration was determined by NMR (NOESY), see the Support-ing Information.

Table 4. Conjugate addition followed by reaction with allyliodide.

Entry Additive(No. ofequiv.)

Co-solvent(MTBE:co-sol-vent)

Conversion[d] dr[e]

1[a] – – – –2[a] HMPA (3) – 40% 80:203[b]

4[c]

567

HMPA (5)HMPA (5)–HMPA (5)–

––THF (1:2)THF (2:3)DME (1:2)

65%43%60%89%93%

70:3070:3090:1080:2090:10

[a] Allyl bromide was used as electrophile.[b] Reaction performed at 42 8C.[c] Reaction performed at 70 8C.[d] Conversions determined by GC-MS.[e] Determined by GC-MS.

Table 5. Alkylation reaction followed by reaction with tert-butyl bromoacetate.

Entry Additive(No. ofequiv.)

Co-solvent(MTBE:co-sol-vent)

Conversion[c] dr[d]

1[a]

2[b]

34

HMPA (5)HMPA (5)HMPA (5)–

––THF (2:3)DME (1:2)

25%50%53%52%

60:4060:4050:5050:50

[a] Reaction performed at 42 8C.[b] Reaction performed at 70 8C.[c] Conversions determined by GC-MS.[d] Determined by GC-MS.





bromide and tert-butyl bromoacetate afforded a dr of85:15.

Conclusions

An efficient catalyst system has been identified forthe conjugate addition of Grignard reagents to 2-methylcyplopentenone (1). The products are obtainedin good yields, and in high enantioselectivities em-ploying CuBr·SMe2 and Rev-JosiPhos L1 in t-BuOMeat �78 8C. The method is nicely complementary withthe one recently reported by Mauduit and Alexakis.Linear Grignard reagents perform well, whereas withtheir reported Cu-NHC catalyst system, the per-formance of branched Grignard reagents is superior.A thorough study on the subsequent alkylation of theregioselectively formed enolate identified DMPU asan essential and superior additive. This sequential

conjugate addition–enolate alkylation leads in a one-pot reaction to the formation of two vicinal stereocen-tres one of which is quaternary. The products made inthis way are highly useful building blocks for the syn-thesis of natural products.

Experimental Section

General Experimental Details

All reactions were performed under a nitrogen atmosphere,using flame-dried glassware and dry solvents. t-BuOMe andTHF were taken from an MBraun solvent purificationsystem (SPS-800). All other reagents were purchased fromSigma–Aldrich or Acros Organics and were used withoutfurther purification. Racemic products were synthesized byreacting 1 with the corresponding Grignard reagent and1 equiv. of CuBr·SMe2 in MTBE at �78 8C. 1H NMR and13C NMR spectra were recorded on a Varian AMX400 (400

Scheme 3. Conjugate addition followed by a-alkylation in t-BuOMe/DMPU (3.5 equiv. of the electrophile and 10 equiv. ofDMPU were used).[37]





and 100.59 MHz, respectively) using CDCl3 as the solvent.Chemical shift values are reported in ppm with the solventresonance as the internal standard (CHCl3: d= 7.26 for 1 H,d= 77.0 for 13C). Data are reported as follows: chemicalshifts, multiplicity (s= singlet, d=doublet, t= triplet, q=quartet, br=broad, m= multiplet), coupling constants (Hz),and integration. High resolution mass spectra (HR-MS)were recorded on an AEI-MS-902 and FT-MS orbitrap(Thermo Fisher Scientific) mass spectrometers. Optical rota-tions were measured on a Schmidt +Haensch polarimeter(Polartronic MH8) with a 10 cm cell (c given in g/100 mL).Enantiomeric excesses were determined by capillary GCanalysis [Agilent Technologies 7890, CP-Chiralsil-Dex-CBcolumn (25 m� 25 mm� 25 mm)] using a flame ionisation de-tector. Progress and conversion of the reactions were deter-mined by GC-MS (GC, HP6890: MS HP5973) with an HP1or HP5 column (Agilent Technologies, Palo Alto, CA).Flash chromatography: Merck silica gel type 9385 230–400mesh. TLC: Merck silica gel 60, 0.25 mm. Compounds werevisualised by UV, Seebach�s reagent (phosphomolybdic acid,25 g; cerium sulfate, 7.5 g; H2O, 500 mL; H2SO4, 25 mL) andpotassium permanganate staining. Synthesised Grignard re-agents were titrated according to literature procedures.[38]

Typical Procedure for the Enantioselective ConjugateAddition: (+)-(2S,3R)-3-Pentyl-2-methylcyclo-pentanone (7)

To a flame-dried Schlenk tube, containing a magnetic stir-ring bar, CuBr·SMe2 (15 mmol, 3.08 mg), L1 (18 mmol,10.7 mg) and 3 mL of dry t-BuOMe were added. The mix-ture was left to stir for 15 min. After that, 2-methylcyclopen-tenone (1) (0.3 mmol, 28.8 mg) dissolved in 1 mL of dry t-BuOMe was added to the solution. The mixture was left tostir for 30 min at �78 8C. Pentylmagnesium bromide (2 M inEt2O,1.7 equiv., 0.25 mL) was then added dropwise over15 min and the reaction was left to stir for 3 to 4 h at�78 8C. The reaction was quenched with MeOH (2 mL), al-lowed to warm up to room temperature and diluted withEt2O. NH4Claq was added and the layers were separated.The aqueous layer was extracted with Et2O and the com-bined organic layers were dried over MgSO4, filtered, andconcentrated at reduced pressure to afford 7 as a yellowishoil after flash chromatography on SiO2, n-pentane:Et2O(92:8); yield: 95%; trans/cis 85/15; er (trans)=91:9, er (cis)=87:13; retention times on chiral GC: 13.5 min and 13.6 min(major trans diastereomer), 14.4 min and 14.6 min (minor cisdiastereomer). 1H NMR (400 MHz, CDCl3) (mixture of dia-stereomers): d=2.41–2.28 (m, 1 H), 2.20–2.02 (m, 2 H), 1.77–1.55 (m, 3 H), 1.40–1.23 (m, 8 H), 1.05 (d, J= 5.8 Hz, 3 H),0.90 (t, J=6.8 Hz, 3 H); 13C NMR (major trans ; 101 MHz,CDCl3): d=221.5, 50.5, 44.8, 37.4, 34.5, 32.0, 27.2, 26.7, 22.6,14.0, 12.6; [a]20

D: [a]D20 = ++ 27.7 (c=1.1, CHCl3). HR-MS

(ESI+): m/z=191.1406, calcd. for C11H20ONa [M+ Na]+:191.1406.

(+)-(2S,3R)-3-ethyl-2-methylcyclopentanone (6): 96%conversion; trans/cis 90/10; er (trans)= 92:8, er (cis)=91:9.The product was obtained as a colourless oil, the volatilityof the product did not allow complete removal of the sol-vents after column chromatography (SiO2, n-pentane:Et2O(90:10) hampering the determination of an accurate isolatedyield. Retention times on chiral GC: 8.8 min and 8.9 min

(major trans diastereomer), 9.9 min and 10.1 min (minor cisdiastereomer); 1H NMR (400 MHz, CDCl3) (mixture of dia-stereomers): d=2.23–2.11 (m, 1 H), 2.08–1.84 (m, 2 H), 1.67–1.47 (m, 2 H), 1.47–1.31 (m, 1 H), 1.29–1.08 (m, 2 H), 0.90 (d,J=6.9 Hz, 3 H), 0.83 (t, J=7.5 Hz, 3 H); 13C NMR(101 MHz, CDCl3; major trans): d=220.5, 49.9, 46.2, 37.0,26.8, 26.4, 12.3, 11.1; [a]20

D: + 84.1 (c= 2.5, CHCl3); HR-MS(ESI+): m/z:149.0937, calcd. for C8H14ONa [M+ Na]+:149.0936.

(+)-(2S,3R)-3-(But-3-en-1-yl)-2-methylcyclopentanone(9): 98% conversion; trans/cis 86/14; er (trans)=92:8. Theproduct was obtained as a colourless oil, the volatility of theproduct did not allow completele removal of the solventsafter column chromatography on SiO2, n-pentane:Et2O(90:10) hampering the determination of an accurate isolatedyield. Retention times on chiral GC for the major trans dia-stereomer 5.5 min and 5.7 min. 1H NMR (400 MHz, CDCl3;mixture of diastereomers): d=5.84–5.68 (m, 1 H), 4.98 (d,J=17.1 Hz, 1 H), 4.91 (d, J= 10.2 Hz, 1 H), 2.34–2.24 (m,1 H), 2.24–1.98 (m, 4 H), 1.81–1.69 (m, 1 H), 1.69–1.52 (m,2 H), 1.40–1.25 (m, 2 H), 1.01 (d, J= 6.6 Hz, 3 H); 13C NMR(101 MHz, CDCl3; major trans): d=220.8, 138.3, 114.7, 50.3,44.1, 37.3, 33.6, 31.2, 27.0; [a]20

D: +72.1 (c=2.7, CHCl3); HR-MS (ESI+): m/z= 175.1093, calcd. for C10H16ONa [M+Na]+:175.1093.

(+)-(2S,3R)-2-Methyl-3-(4-methylpent-3-en-1-yl)cyclopen-tanone (10): 76% conversion; 70% yield; trans/cis 84/16; er(trans)= 85:15; er (cis)= 83:17. The product was obtained asa colourless oil after column chromatography on SiO2, n-pentane:Et2O (92:8). Retention times on chiral GC:25.6 min and 26.0 min (major trans diastereomer), 30.0 minand 31.0 min (minor cis diastereomer). 1H NMR (400 MHz,CDCl3) (mixture of diastereomers) d=5.12 (t, J=7.1, 1 H),2.42–2.29 (m, 1 H), 2.27–1.92 (m, 5 H), 1.79–1.59 (m, 2 H),1.70 (s, 3 H), 1.62 (s, 3 H), 1.49–1.16 (m, 2 H), 1.07 (d, J= 6.7,3 H); 13C NMR (101 MHz, CDCl3; major trans): 13C NMR(101 MHz, CDCl3): d= 221.3, 131.8, 124.2, 50.5, 44.4, 37.4,34.6, 27.1, 25.7, 25.6, 17.7, 12.6; [a]20

D : +35.8 (c= 0.12,CHCl3); HR-MS (ESI+): m/z= 181.1587, calcd. for C12H21O[M+H]+ :181.1587.

Typical Procedure for the Enantioselective ConjugateAddition Followed by Trapping of the Enolate:(+)-tert-Butyl 2-[(1S,5R)-1-Methyl-2-oxo-5-pentyl-cyclopentyl]acetate (13)

To a flame-dried Schlenk tube, containing a magnetic stir-ring bar, CuBr·SMe2 (15 mmol, 3.08 mg), ligand L1 (18 mmol,10.7 mg) and 3 mL of dry t-BuOMe were added. The mix-ture was left to stir for 15 min. After that, 2-methylcyclopen-tenone (1) (0.3 mmol, 28.8 mg) dissolved in 1 mL of dry t-BuOMe was added to the solution. The mixture was left tostir for 30 min at �78 8C. Pentylmagnesium bromide (2 M inEt2O, 0.51 mmol, 0.25 mL) was added dropwise over 15 minand the reaction mixture was left to stir for 3 h at �78 8C.Dry DMPU (3 mmol, 0.36 mL) was added to the reactionmixture which was left to stir for 10 min at �78 8C. tert-Butyl 2-bromoacetate (1.05 mmol, 0.15 mL) was added, thereaction mixture was allowed to warm up to room tempera-ture and left to stir for 16 h. The mixture was diluted withEt2O, NH4Claq was added and the layers were separated.The aqueous layer was extracted with Et2O and the com-





bined organic layers were dried over MgSO4, filtered, andthe solvent was removed under reduced pressure. Com-pound 13 was obtained as a colorless oil after flash columnchromatography employing SiO2/n-pentane:Et2O (92:8);yield: 70%; trans/cis 80/20; er (trans)=90:10, er (cis)=87:13.Retention times on chiral GC: 13.5 min and 13.6 min (majortrans diastereomer), 14.4 min and 14.6 min (minor cis diaste-reomer). 1H NMR (400 MHz, CDCl3, mixture of diastereo-mers): d=2.68 (d, J=16.5 Hz, 1 H), 2.39–2.27 (m, 3 H), 2.30(d, J=16.5 Hz, 1 H), 2.26–2.08 (m, 2 H), 1.51–1.36 (m, 8 H),1.40 (s, 9 H), 0.89 (t, J= 6.6 Hz, 3 H), 0.79 (s, 3 H); 13C NMR(101 MHz, CDCl3; trans diastereomer): d=222.3, 170.6,80.7, 49.3, 42.4, 41.7, 37.1, 32.0, 29.8, 28.1, 27.4, 25.4, 22.6,17.6, 14.0; [a]20

D : + 18.1 (c= 0.11, CHCl3); HR-MS (ESI+):m/z= 305.2087, calcd. for C17H30O3Na [M+ Na]+: 305.2093.

(+)-(2S,3R)-2-Benzyl-2-methyl-3-pentylcyclopentanone(11): yield: 90%; trans/cis 90/10; er (trans)=90:10, er (cis)=87:13. The product was obtained as a yellowish oil afterflash column chromatography on SiO2, n-pentane:Et2O(95:5). Retention times on chiral GC: 13.5 min and 13.6 min(major trans diastereomer), 14.4 min and 14.6 min (minor cisdiastereomer); 1H NMR (400 MHz, CDCl3; mixture of dia-stereomers): d=7.31–7.13 (m, 4 H), 7.05 (d, J= 7.6 Hz, 1 H),3.10 (d, J=13.6 Hz, 1 H), 2.52 (d, J=13.6 Hz, 1 H), 2.30 (dd,J=18.8, 7.9 Hz, 1 H), 2.02–1.93 (m, 1 H), 1.86–1.72 (m, 2 H),1.49–1.10 (m, 9 H), 0.92 (s, 3 H), 0.90 (t, J=7.2 Hz, 3 H);13C NMR (101 MHz, CDCl3): d=221.8, 137.5, 130.3, 128.0,126.5, 48.5, 37.8, 36.5, 32.3, 29.9, 29.6, 27.8, 24.4, 22.8, 20.6,14.2; [a]20

D : +30.8 (c=0.17, CHCl3); HR-MS (ESI+): m/z=281.1876, calcd. for C18H26ONa [M+ Na]+: 281.1881.

(+)-(2S,3R)-2-Allyl-2-methyl-3-pentylcyclopentanone(12): yielde: 75%; trans/cis 82/18, er (trans)=90:10, er(cis)=87:13. The product was isolated as a yellowish oilafter flash column chromatography on SiO2, n-pentane:Et2O(95:5). Retention times on chiral GC: 13.5 min and 13.6 min(major trans diastereomer), 14.4 min and 14.6 min (minor cisdiastereomer); 1H NMR (400 MHz, CDCl3; mixture of dia-stereomers): d=5.56 (m, 1 H), 4.99–4.90 (m, 2 H), 2.36–2.23(m, 2 H), 2.07–1.87 (m, 4 H), 1.45–1.29 (m, 3 H), 1.30–1.16(m, 6 H), 0.83 (t, J= 6.9, 3 H), 0.77 (s, 3 H); 13C NMR(101 MHz, CDCl3; major trans): d=223.5, 134.4, 117.9, 51.3,42.5, 40.4, 37.4, 32.1, 29.6, 27.3, 25.0, 22.6, 17.5, 14.0; [a]20

D :+61.4 (c=0.10, CHCl3); HR-MS (ESI+): m/z= 209.1899,calcd. for C14H25O [M+H]+: 209.1905.

(+)-(R)-2,2-Dimethyl-3-pentylcyclopentanone (16): yield:67%; er (trans)=90:10, er (cis)=87:13. The product was iso-lated as a colourless oil after flash column chromatographyon SiO2, n-pentane:Et2O (95:5). Retention times on chiralGC: 13.5 min and 13.6 min (major trans diastereomer),14.4 min and 14.6 min (minor cis diastereomer); 1H NMR(400 MHz, CDCl3; mixture of diastereomers): d=2.42–2.31(m, 1 H), 2.20–2.03 (m, 2 H), 1.76–1.65 (m, 1 H), 1.51–1.38(m, 3 H), 1.39–1.14 (m, 6 H), 1.02 (s, 3 H), 0.90 (t, J= 6.5 Hz,3 H), 0.81 (s, 3 H); 13C NMR (101 MHz, CDCl3; majortrans): d= 224.3, 47.9, 47.4, 36.4, 32.1, 29.7, 27.5, 25.0, 22.7,22.6, 17.9, 14.0; [a]20

D: +44.0 (c= 0.17, CHCl3); HR-MS(ESI+): m/z =183.1739, calcd. for C12H23O [M+H]+:183.1749.

(+)-(2S,3R)-2-Benzyl-3-ethyl-2-methylcyclopentanone(17): 95% conversion; 54% yield; trans/cis 84/16; er(trans)= 92:8, er (cis)= 91:9. The product was isolated asa colourless oil after flash column chromatography on SiO2,

n-pentane:Et2O (95:5). Retention times on chiral GC:8.8 min and 8.9 min (major trans diastereomer), 9.9 min and10.1 min (minor cis diastereomer); 1H NMR (400 MHz,CDCl3, mixture of diastereomers): d=7.27–7.14 (m, 4 H),7.06 (d, J=6.7 Hz, 1 H), 3.10 (d, J=13.5 Hz, 1 H), 2.53 (d,J=13.5, 3.2 Hz, 1 H), 2.30 (dd, J= 18.7, 7.8 Hz, 1 H), 2.05–1.95 (m, 1 H), 1.85–1.68 (m, 2 H), 1.58–1.46 (m, 1 H), 1.40–1.23 (m, 2 H), 0.92 (s, 3 H), 0.92 (t, 3 H); 13C NMR(101 MHz, CDCl3, major trans): d=223.6, 138.3, 130.2,128.1, 126.2, 53.2, 43.2, 41.6, 37.8, 24.5, 22.5, 18.4, 12.2; [a]20

D :+60.7 (c=0.14, CHCl3); HR-MS (ESI+): m/z= 217.1587,calcd. for C15H21O [M+H]+: 217.1592.

(+)-(2S,3R)-2-Methyl-3-pentyl-2-(prop-2-yn-1-yl)cyclo-pentanone (15): 95% conversion; 60% yield; trans/cis 82/18;er (trans)= 90:10, er (cis)= 87:13. The product was isolatedas a colourless oil after flash column chromatography onSiO2, n-pentane:Et2O (95:5). Retention times on chiral GC:13.5 min and 13.6 min (major trans diastereomer), 14.4 minand 14.6 min (minor cis diastereomer); 1H NMR (400 MHz,CDCl3; mixture of diastereomers): d= 2.47 (dd, J= 16.9,2.5 Hz, 1 H), 2.43–2.34 (m, 2 H), 2.22 (dd, J=17.1, 2.5 Hz,1 H), 2.33–2.04 (m, 5 H), 1.95 (t, J= 2.5 Hz, 1 H), 1.61–1.37(m, 6 H), 0.90 (t, J=6.1 Hz, 3 H), 0.85 (s, 3 H); 13C NMR(101 MHz, CDCl3; major trans) d=221.8, 81.1, 70.4, 50.8,43.0, 37.1, 32.1, 29.8, 27.3, 25.6, 25.1, 22.6, 16.8, 14.0; [a]20

D :+39.0 (c=0.10, CHCl3); HR-MS (ESI+): m/z= 229.1562,calcd. for C14H22ONa [M+Na]+: 229.1568.

Acknowledgements

Financial support from The Netherlands Organization forScientific Research (NWO-CW) is acknowledged. T. D. Tie-mersma-Wegman (Stratingh Institute for Chemistry) is ac-knowledged for high resolution mass spectrometry support.

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10 Copper-Catalysed Conjugate Addition of GrignardReagents to 2-Methylcyclopentenone and SequentialEnolate Alkylation

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Copper-Catalysed Conjugate Addition of Grignard Reagents to 2-Methylcyclopentenone and Sequential Enolate Alkylation