Copper-catalysed conjugate addition of grignard reagents to 2-methylcyclopentenone and sequential enolate alkylation

Article abstract of DOI:10.1002/adsc.201400085

The copper/Rev-JosiPhos-catalysed asymmetric conjugate addition of Grignard reagents to 2-methylcyclopentenone (1) provides 2,3-disubstituted cyclopentanones in high yields and enantioselectivities, and good diastereoselectivities. Reaction of the in situ

Full text of DOI:10.1002/adsc.201400085

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DOI: 10.1002/adsc.201400085
Copper-Catalysed Conjugate Addition of Grignard Reagents to
2-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: a.j.minnaard@rug.nl
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- ing products in a one-pot reaction. This procedure
metric conjugate addition of Grignard reagents to 2- creates two vicinal stereocentres, one of them quater-
methylcyclopentenone (1) provides 2,3-disubstituted nary.
cyclopentanones in high yields and enantioselectivi-
ties, and good diastereoselectivities. Reaction of the Keywords: asymmetric catalysis; conjugate addition;
in situ formed enolate with various alkylating re- copper catalysis; 1,3-dimethyltetrahydropyrimidine-
agents in the presence of 1,3-dimethyltetrahydropyri- 2(1H)-one (DMPU); DMPU; enolate alkylation;
midine-2(1H)-one (DMPU) affords the correspond- Grignard reagents
Introduction
plexes in the asymmetric addition of Grignard re-
agents to 2-methylcyclopentenone and -hexenone.[27]
The enantioselective copper-catalysed conjugate addi- The resulting magnesium enolates were subsequently
tion of organometallic reagents has over the years alkylated to provide a quaternary stereocentre vicinal
À
become a well-established tool for asymmetric C C to the initially formed tertiary stereocentre.
bond formation.[1–10] Various organometallic reagents
Here we report the asymmetric conjugate addition
are employed in this transformation and the substrate of Grignard reagents to 2-methylcyclopentenone with
scope comprises a variety of Michael acceptors, both a copper catalyst based on Rev-JosiPhos (L1) and the
cyclic and acyclic. In our recent work,[11–13] we focus subsequent enolate alkylation with a variety of elec-
on the use of Grignard reagents, because of their trophiles.
straightforward preparation from readily available
alkyl bromides. In the cyclic series, the use of
Grignard reagents in the copper-catalyzed asymmetric Results and Discussion
Michael addition has been reported for cyclopente-
none,[14–16] cyclohexenone,[5,14,16–22] cycloheptenone,[14–17] As a starting point, 2-methylcyclohexenone (2) was
b-substituted cyclic enones,[22,23] and lactones.[15,17,18,24,25] chosen as the model substrate. Various copper salts,
In these studies, however, a-substitution (2-substitu- and chiral ligands (Table 1, Figure 1) were studied in
tion) is lacking, a situation no different from reports the conjugate addition of ethylmagnesium bromide.
with other organometallic reagents. Until very recent-
The combination of L1 and CuBr·SMe2 resulted in
ly, the sole report in this field came from Vuagnoux- a very high selectivity for the conjugate addition
d’Augustin and Alexakis, and comprised the enantio- product 3, considerably higher than that of the reac-
selective addition of Me3Al and Et3Al to 2-methylcy- tion with just catalytic copper. A moderate but dis-
clohexenone[23] (Scheme 1). This knowledge was sub- tinct enantioselectivity was obtained as well (entry 2).
sequently used by Helmchen et al. in a synthesis of With L2 only low enantioselectivity was obtained
pumiliotoxin C.[26] Neither the use of Grignard re- whereas L3 provided the racemate, as did L4–L7. No-
agents nor 2-methylcyclopentenone had been de- tably, only when employing L3, no catalyst control
scribed until – during the preparation of this manu- was observed, while on the contrary, L5–L6 did pro-
script – Mauduit, Alexakis et al. reported the success- vide an excellent regioselectivity in favour of 3. L8
ful application of Cu(I)–N-heterocyclic carbene com- provided a small enantioselectivity whereas L9 and
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Beatriz C. Calvo et al.
Scheme 1. Previous and current work.
L10 gave racemates, although with very high regiose- EtMgBr to 1; virtually full regioselectivity and an er
lectivity. With all ligands, the trans:cis ratio in 3 of 92:8! Therefore we decided to focus on 1 as the
varied as expected[23,28] between 60:40 and 80:20.
substrate, and determine the scope of Grignard re-
The situation improved when 2-methylcyclopente- agents that could be added enantioselectively
none (1) was studied in the conjugate addition of (Table 2).
methyl- and ethylmagnesium bromide, employing the
combination of CuBr·SMe2 and L1 as the most suc- of linear saturated and unsaturated Grignard re-
cessful catalyst thus far (Scheme 2). agents. Substrates with linear alkyl and alkenyl sub-
Table 2 shows that high ers are obtained with a set
The addition of methylmagnesium bromide to (2) stituents, or substituents branched at the d-position,
showed – like in the case of EtMgBr – a high selectiv- perform very well. This makes the catalyst system
ity for the formation of the conjugate addition prod- highly complementary to the aforementioned Maud-
uct, however without enantioselectivity. The same re- uit–Alexakis system that performs best with sterically
action with 2-methylcyclopentenone (1), however, re- more hindered a-branched Grignard reagents. Un-
sulted in a significant er (78:22). Rewarding results fortunately, when the substrate was changed for
were obtained in the Cu/L1-catalyzed addition of a more sterically hindered one, 2-pentylcyclopente-
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Copper-Catalysed Conjugate Addition of Grignard Reagents
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
2
3
–
CuBr·SMe2
CuBr·SMe2
CuI
CuCl
CuCl
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
38:56
96:3
–
L1
L2
L3
L3
L3
L3
L4
L5
L6
L7
L8
L9
L10
70:30
60:40
50:50
50:50
50:50
50:50
55:45
52:48
55:45
54:46
63:39
52:48
53:47
73:26
29:62[c]
42:56[c]
35:64[c]
21:79[c]
61:37
94:5
91:9
65:32
91:6
4
5[a]
6
7[a]
8
9
10
11
12
13
14
94:4
95:5
[a]
Reactions were performed at À108C.
Selectivity determined by GC-MS.
No ee found for 3a.
Enantioselectivities determined by chiral GC, see the Supporting Information.
Diastereomeric ratios between 60:40 and 80:20.
[b]
[c]
[d]
[e]
Figure 1. Chiral ligands used in this study.
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Beatriz C. Calvo et al.
Scheme 2. Cu/L1-catalyzed asymmetric conjugate addition reactions. The absolute configuration of 5, and in analogy that of
6, 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
2
6
7
98%
99%
n.d.[b]
95%
92:8
91:9
3
4
5
8
95%
94%
76%
n.d.[b]
n.d.[b]
70%
50:50
92:8
9
10
85:15
[a]
Conversions determined by GC-MS.
Not determined due to the volatility of the product.
Enantioselectivities determined by chiral GC, see the Supporting Information.
er of the major trans diastereomer.
Diastereomeric ratios between 85:15 and 90:10.
[b]
[c]
[d]
[e]
none, the conjugate addition resulted in very poor 8:2 in favour of the trans compound.[29] Benzyl bro-
conversions. Conjugate addition to cyclic enones re- mide was selected to study the alkylation under vari-
sults, in addition to a C C bond and a stereocentre, ous conditions[34] (Table 3). In the absence of additives
À
also in regioselective formation of an enolate. Espe- and co-solvents no reaction took place (entry 1).
cially in the current case, subsequent reaction with
When HMPA was added, the reaction reached
a carbon electrophile is attractive, as a second, quater- almost full conversion with high diastereoselectivity
nary, stereocentre is formed. Reaction of in situ (entry 2), whereas with TMEDA the conversion de-
formed enolates has been reported a number of creased dramatically (entry 3). The addition of coordi-
times,[20,30–33] however, unlike lithium enolates, magne- nating solvents was also studied. The use of THF as
sium enolates react only sluggishly and additives or a co-solvent did not improve the conversion although
co-solvents are mostly used to accelerate the reaction. it afforded a nearly complete diastereoselectivity. Ad-
Protonation of the enolate formed gave already dition of DME resulted in no reaction. In order to get
reasonable diastereomeric ratios in the range of 6:4 to a more complete picture, a set of additional electro-
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Copper-Catalysed Conjugate Addition of Grignard Reagents
Table 3. Conjugate addition followed by benzylation.
Entry
Additive (No. of equiv.)
Co-solvent (MTBE:co-solvent)
Conversion[a]
dr[b]
1
2
3
4
5
6
–
–
–
–
–
–
HMPA (5)
TMEDA (3)
–
HMPA (5)
–
95%
20%
20%
51%
–
90:10
89:11
98:2
90:10
–
THF (1:2)
THF (2:3)
DME (1:2)
[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 allyl
iodide.
Table 5. Alkylation reaction followed by reaction with tert-
butyl bromoacetate.
Entry Additive
(No. of
Co-solvent
(MTBE:co-sol-
vent)
Conversion[d] dr[e]
Entry Additive
(No. of
Co-solvent
(MTBE:co-sol-
vent)
Conversion[c] dr[d]
equiv.)
equiv.)
1[a]
2[a]
3[b]
4[c]
5
–
–
–
–
–
–
–
1[a]
2[b]
3
HMPA (5)
HMPA (5)
HMPA (5)
–
–
–
25%
50%
53%
52%
60:40
HMPA (3)
HMPA (5)
HMPA (5)
–
HMPA (5)
–
40%
65%
43%
60%
89%
93%
80:20
70:30
70:30
90:10
80:20
90:10
60:40
50:50
50:50
THF (2:3)
DME (1:2)
4
THF (1:2)
THF (2:3)
DME (1:2)
[a]
[b]
[c]
[d]
Reaction performed at 428C.
Reaction performed at 708C.
Conversions determined by GC-MS.
Determined by GC-MS.
6
7
[a]
[b]
[c]
[d]
[e]
Allyl bromide was used as electrophile.
Reaction performed at 428C.
Reaction performed at 708C.
Conversions determined by GC-MS.
Determined by GC-MS.
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-
philes was studied as well, under mostly identical con- fective but, on the other hand, it is toxic. DMPU [1,3-
ditions. dimethyltetrahydropyrimidine-2(1H)-one] can often
As in the benzylation, the allylation reaction with be used as a versatile alternative, and is mostly ap-
no additives showed no conversion (Table 4, entry 1). plied in somewhat larger amounts.[35] The addition of
Remarkably, however, addition of HMPA now only 10 equiv. of DMPU was therefore studied (Scheme 3).
showed moderate improvement whereas DME in- We were pleased to see that this procedure gave con-
creased the conversion to 93% (entry 7)! tert-Butyl sistently excellent conversions, good isolated yields
bromoacetate (Table 5), turned out to be rather un- and diastereomeric ratios for the various electro-
reactive in this reaction and also the diastereomeric philes.[36] Also tert-butyl bromoacetate performed well
ratio dropped. Reaction with propargyl bromide gave now, and also methyl iodide (not used earlier) gave
upon addition of 3 equiv. HMPA incomplete conver- close to complete conversion (Scheme 3). The diaste-
sion (75%) and a dr of 85:15.
reoselectivity is not strongly dependent on substitu-
The picture that arose from this study is that al- tion at the 3 position. The similar reaction sequence
though high conversion and diastereoselectivities with EtMgBr and benzyl bromide afforded a dr of
could be obtained for most electrophiles (tert-butyl 84:16, whereas the combination of isobutylmagnesium
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Scheme 3. Conjugate addition followed by a-alkylation in t-BuOMe/DMPU (3.5 equiv. of the electrophile and 10 equiv. of
DMPU were used).[37]
bromide and tert-butyl bromoacetate afforded a dr of conjugate addition–enolate alkylation leads in a one-
85:15.
pot reaction to the formation of two vicinal stereocen-
tres one of which is quaternary. The products made in
this way are highly useful building blocks for the syn-
thesis of natural products.
Conclusions
An efficient catalyst system has been identified for
the conjugate addition of Grignard reagents to 2-
methylcyplopentenone (1). The products are obtained
in good yields, and in high enantioselectivities em-
ploying CuBr·SMe2 and Rev-JosiPhos L1 in t-BuOMe
at À788C. The method is nicely complementary with
the one recently reported by Mauduit and Alexakis.
Linear Grignard reagents perform well, whereas with
their reported Cu-NHC catalyst system, the per-
formance of branched Grignard reagents is superior.
A thorough study on the subsequent alkylation of the
regioselectively formed enolate identified DMPU as
Experimental Section
General Experimental Details
All reactions were performed under a nitrogen atmosphere,
using flame-dried glassware and dry solvents. t-BuOMe and
THF were taken from an MBraun solvent purification
system (SPS-800). All other reagents were purchased from
Sigma–Aldrich or Acros Organics and were used without
further purification. Racemic products were synthesized by
reacting 1 with the corresponding Grignard reagent and
1 equiv. of CuBr·SMe2 in MTBE at À788C. 1H NMR and
an essential and superior additive. This sequential 13C NMR spectra were recorded on a Varian AMX400 (400
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Copper-Catalysed Conjugate Addition of Grignard Reagents
and 100.59 MHz, respectively) using CDCl3 as the solvent.
Chemical shift values are reported in ppm with the solvent
resonance as the internal standard (CHCl3: d=7.26 for 1 H,
d=77.0 for 13C). Data are reported as follows: chemical
shifts, 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 GC
analysis [Agilent Technologies 7890, CP-Chiralsil-Dex-CB
column (25 mꢁ25 mmꢁ25 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 HP1
or HP5 column (Agilent Technologies, Palo Alto, CA).
Flash chromatography: Merck silica gel type 9385 230–400
mesh. TLC: Merck silica gel 60, 0.25 mm. Compounds were
visualised by UV, Seebachꢂs reagent (phosphomolybdic acid,
25 g; cerium sulfate, 7.5 g; H2O, 500 mL; H2SO4, 25 mL) and
potassium permanganate staining. Synthesised Grignard re-
agents were titrated according to literature procedures.[38]
(major trans diastereomer), 9.9 min and 10.1 min (minor cis
diastereomer); H NMR (400 MHz, CDCl3) (mixture of dia-
1
stereomers): d=2.23–2.11 (m, 1H), 2.08–1.84 (m, 2H), 1.67–
1.47 (m, 2H), 1.47–1.31 (m, 1H), 1.29–1.08 (m, 2H), 0.90 (d,
J=6.9 Hz, 3H), 0.83 (t, J=7.5 Hz, 3H); 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]2D0: +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. The
product was obtained as a colourless oil, the volatility of the
product did not allow completele removal of the solvents
after column chromatography on SiO2, n-pentane:Et2O
(90:10) hampering the determination of an accurate isolated
yield. Retention times on chiral GC for the major trans dia-
1
stereomer 5.5 min and 5.7 min. H NMR (400 MHz, CDCl3;
mixture of diastereomers): d=5.84–5.68 (m, 1H), 4.98 (d,
J=17.1 Hz, 1H), 4.91 (d, J=10.2 Hz, 1H), 2.34–2.24 (m,
1H), 2.24–1.98 (m, 4H), 1.81–1.69 (m, 1H), 1.69–1.52 (m,
2H), 1.40–1.25 (m, 2H), 1.01 (d, J=6.6 Hz, 3H); 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]2D0: +72.1 (c=2.7, CHCl3); HR-
MS (ESI+): m/z=175.1093, calcd. for C10H16ONa [M+Na]+:
175.1093.
Typical Procedure for the Enantioselective Conjugate
Addition: (+)-(2S,3R)-3-Pentyl-2-methylcyclo-
pentanone (7)
(+)-(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 as
a 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 min
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 to
stir for 30 min at À788C. Pentylmagnesium bromide (2M in
Et2O,1.7 equiv., 0.25 mL) was then added dropwise over
15 min and the reaction was left to stir for 3 to 4 h at
À788C. The reaction was quenched with MeOH (2 mL), al-
lowed to warm up to room temperature and diluted with
Et2O. 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, and
concentrated at reduced pressure to afford 7 as a yellowish
oil 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 cis
1
and 31.0 min (minor cis diastereomer). H NMR (400 MHz,
CDCl3) (mixture of diastereomers) d=5.12 (t, J=7.1, 1H),
2.42–2.29 (m, 1H), 2.27–1.92 (m, 5H), 1.79–1.59 (m, 2H),
1.70 (s, 3H), 1.62 (s, 3H), 1.49–1.16 (m, 2H), 1.07 (d, J=6.7,
3H); 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]2D0: +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 Conjugate
Addition 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 to
stir for 30 min at À788C. Pentylmagnesium bromide (2M in
Et2O, 0.51 mmol, 0.25 mL) was added dropwise over 15 min
and the reaction mixture was left to stir for 3 h at À788C.
Dry DMPU (3 mmol, 0.36 mL) was added to the reaction
mixture which was left to stir for 10 min at À788C. tert-
Butyl 2-bromoacetate (1.05 mmol, 0.15 mL) was added, the
reaction mixture was allowed to warm up to room tempera-
ture and left to stir for 16 h. The mixture was diluted with
Et2O, NH4Claq was added and the layers were separated.
The aqueous layer was extracted with Et2O and the com-
1
diastereomer). H NMR (400 MHz, CDCl3) (mixture of dia-
stereomers): d=2.41–2.28 (m, 1H), 2.20–2.02 (m, 2H), 1.77–
1.55 (m, 3H), 1.40–1.23 (m, 8H), 1.05 (d, J=5.8 Hz, 3H),
0.90 (t, J=6.8 Hz, 3H); 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]D20: [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 volatility
of 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 isolated
yield. Retention times on chiral GC: 8.8 min and 8.9 min
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Beatriz C. Calvo et al.
bined organic layers were dried over MgSO4, filtered, and
the solvent was removed under reduced pressure. Com-
pound 13 was obtained as a colorless oil after flash column
chromatography 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 (major
trans diastereomer), 14.4 min and 14.6 min (minor cis diaste-
n-pentane:Et2O (95:5). Retention times on chiral GC:
8.8 min and 8.9 min (major trans diastereomer), 9.9 min and
10.1 min (minor cis diastereomer); 1H NMR (400 MHz,
CDCl3, mixture of diastereomers): d=7.27–7.14 (m, 4H),
7.06 (d, J=6.7 Hz, 1H), 3.10 (d, J=13.5 Hz, 1H), 2.53 (d,
J=13.5, 3.2 Hz, 1H), 2.30 (dd, J=18.7, 7.8 Hz, 1H), 2.05–
1.95 (m, 1H), 1.85–1.68 (m, 2H), 1.58–1.46 (m, 1H), 1.40–
1.23 (m, 2H), 0.92 (s, 3H), 0.92 (t, 3H); 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]2D0:
+60.7 (c=0.14, CHCl3); HR-MS (ESI+): m/z=217.1587,
calcd. for C15H21O [M+H]+: 217.1592.
1
reomer). H NMR (400 MHz, CDCl3, mixture of diastereo-
mers): d=2.68 (d, J=16.5 Hz, 1H), 2.39–2.27 (m, 3H), 2.30
(d, J=16.5 Hz, 1H), 2.26–2.08 (m, 2H), 1.51–1.36 (m, 8H),
1.40 (s, 9H), 0.89 (t, J=6.6 Hz, 3H), 0.79 (s, 3H); 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]2D0: +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 after
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 cis
(+)-(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 isolated
as a colourless oil after 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
1
and 14.6 min (minor cis diastereomer); H NMR (400 MHz,
CDCl3; mixture of diastereomers): d=2.47 (dd, J=16.9,
2.5 Hz, 1H), 2.43–2.34 (m, 2H), 2.22 (dd, J=17.1, 2.5 Hz,
1H), 2.33–2.04 (m, 5H), 1.95 (t, J=2.5 Hz, 1H), 1.61–1.37
(m, 6H), 0.90 (t, J=6.1 Hz, 3H), 0.85 (s, 3H); 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]2D0:
+39.0 (c=0.10, CHCl3); HR-MS (ESI+): m/z=229.1562,
calcd. for C14H22ONa [M+Na]+: 229.1568.
1
diastereomer); H NMR (400 MHz, CDCl3; mixture of dia-
stereomers): d=7.31–7.13 (m, 4H), 7.05 (d, J=7.6 Hz, 1H),
3.10 (d, J=13.6 Hz, 1H), 2.52 (d, J=13.6 Hz, 1H), 2.30 (dd,
J=18.8, 7.9 Hz, 1H), 2.02–1.93 (m, 1H), 1.86–1.72 (m, 2H),
1.49–1.10 (m, 9H), 0.92 (s, 3H), 0.90 (t, J=7.2 Hz, 3H);
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]2D0: +30.8 (c=0.17, CHCl3); HR-MS (ESI+): m/z=
281.1876, calcd. for C18H26ONa [M+Na]+: 281.1881.
Acknowledgements
(+)-(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 oil
after 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 cis
Financial support from The Netherlands Organization for
Scientific Research (NWO-CW) is acknowledged. T. D. Tie-
mersma-Wegman (Stratingh Institute for Chemistry) is ac-
knowledged for high resolution mass spectrometry support.
1
diastereomer); H NMR (400 MHz, CDCl3; mixture of dia-
stereomers): d=5.56 (m, 1H), 4.99–4.90 (m, 2H), 2.36–2.23
(m, 2H), 2.07–1.87 (m, 4H), 1.45–1.29 (m, 3H), 1.30–1.16
(m, 6H), 0.83 (t, J=6.9, 3H), 0.77 (s, 3H); 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]2D0:
+61.4 (c=0.10, CHCl3); HR-MS (ESI+): m/z=209.1899,
calcd. for C14H25O [M+H]+: 209.1905.
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ÞÞ
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FULL PAPERS
10 Copper-Catalysed Conjugate Addition of Grignard
Reagents to 2-Methylcyclopentenone and Sequential
Enolate Alkylation
Adv. Synth. Catal. 2014, 356, 1 – 10
Beatriz C. Calvo, Ashoka V. R. Madduri,
Syuzanna R. Harutyunyan, Adriaan J. Minnaard*
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