Route Scouting towards a Methyl Jasmonate Precursor

Article abstract of DOI:10.1002/hlca.201500257

For the synthesis of methyl jasmonate (1), via the strategic intermediates 3, 4, and 6a, we constructed a synthetic network via the diverse intermediates 7-10, 13, 14, 17, and 18. This allowed us to compare the efficiency of more than 20 novel routes. The most productive pathway with a total yield of 38% is represented by the sequence→5a→5m→13b→13a→6a→4 and proceeds via sequential bromination, basic elimination, decarbomethoxylation, isomerization, and finally Lindlar hydrogenation. The shortest selective way, 2a→[(E,E)-12b]→3→4, is a two-pot sequence using a modification of Naef's method, based on an aldol condensation between inexpensive cyclopentanone (2a) and crotonaldehyde, with in situ Corey-Chaykovsky cyclopropanation under phase transfer conditions. The key intermediate 3 was then simply pyrolyzed to afford 4 in 27% total yield. The alternative isomerization method via the six-step deviation→5a→5c→8c→13a→6a→4 was longer, although more efficient, with a total yield of 32%. Alternatively, a yield of 34% was obtained via the five-step sequence→5a→5c→2h→2i→4. Another favored six-step pathway,→5a→5c→2h→17a→14a→4 afforded the target compound in 35% total yield.

Full text of DOI:10.1002/hlca.201500257

Helv. Chim. Acta 2016, 99, 95 – 109
95
FULL PAPER
1
Route Scouting towards a Methyl Jasmonate Precursor )
by Christian Chapuis*, Eric Walther, Fabrice Robvieux, Claude-Alain Richard, Laurent Goumaz, and
Jean-Yves de Saint Laumer
Firmenich SA, Corporate R&D Division, Synthesis Department, P. O. Box 239, CH-1211 Geneva 8
(phone: þ 41-22-7803610; fax: þ 41-22-7803334; e-mail: christian.chapuis@firmenich.com)
Dedicated to Dr. F. Naef on the occasion of his 75th birthday
For the synthesis of methyl jasmonate (1), via the strategic intermediates 3, 4, and 6a, we constructed a synthetic network via
the diverse intermediates 7 – 10, 13, 14, 17, and 18. This allowed us to compare the efficiency of more than 20 novel routes. The
most productive pathway with a total yield of 38% is represented by the sequence ! 5a ! 5m ! 13b ! 13a ! 6a ! 4 and
proceeds via sequential bromination, basic elimination, decarbomethoxylation, isomerization, and finally Lindlar hydrogenation.
The shortest selective way, 2a ! [(E,E)-12b] ! 3 ! 4, is a two-pot sequence using a modification of Naefꢀs method, based on an
aldol condensation between inexpensive cyclopentanone (2a) and crotonaldehyde, with in situ CoreyÀChaykovsky cyclo-
propanation under phase transfer conditions. The key intermediate 3 was then simply pyrolyzed to afford 4 in 27% total yield. The
alternative isomerization method via the six-step deviation ! 5a ! 5c ! 8c ! 13a ! 6a ! 4 was longer, although more efficient,
with a total yield of 32%. Alternatively, a yield of 34% was obtained via the five-step sequence ! 5a ! 5c ! 2h ! 2i ! 4.
Another favored six-step pathway, ! 5a ! 5c ! 2h ! 17a ! 14a ! 4 afforded the target compound in 35% total yield.
Introduction. – On the occasion of the 50th anniversary standing, industrially feasible approaches have been dis-
of the publication of methyl jasmonate (1; see the Scheme), cussed, such as those of Büchi and Egger [3], Naef and
we have recently presented a particularly short three-step Decorzant [4]3), Tsuji et al. [6j]4), Lem et al. [8]5), Pauson
synthesis [1] as well as a review of selected synthetic et al. [7i]6), and an optically active version by Fehr et al.
approaches towards this ubiquitous natural product, which [6s][6t][12]7). All these approaches make use of either
is particularly appreciated by perfumers for its radiant, enone 4 or 6a as key intermediate. With respect to our own
deep, and sweet floral jasmine scent [2]2). Several out- interest in this subject [13], we tried to apply the industrial
1
´
) Work presented by C. C. at the ꢂ6›me Journee Arômes et Parfums 2015ꢀ (June 19th, 2015, Nice, France).
2) For its bioactivities, as well as those of its epi-stereoisomer and enantiomers, see [2a][2b]. For former reviews, see [2c][2d].
3) This elegant approach is based on a double alkylation of cyclopentanone (2a) using piperylene dibromide to afford (E)-3 [5], as key intermediate for a
thermal homodienyl 1,5-H shift, leading stereoselectively to 4 [3 – 6], after in situ equilibration of the diastereomeric mixture to the more favored and
reactive trans cyclopropane.
4) Starting from either diallyl adipate or the commercially available keto ester 2c, alkylation was performed to generate either 2g or 5b as key intermediates
for catalytic Pd2þ-assisted intramolecular decarboxylative dehydrogenation, leading directly to either 4 or 6a [3][6f][6j][6t][7], resp. For semi-
hydrogenation of 6a to 4 (H2, Lindlar catalyst, BuOH, 95%), see [6j].
5) For a modified version, based on cascade BaylisÀHillman/Claisen rearrangement, see [9]. For a more recent application of our method, see [10].
6) For the first truly catalytic version of the PausonÀKhand reaction, applied to the analogous saturated Hedioneꢃ (methyl (3-oxo-2-pentylcyclopentyl)-
acetate), see [11].
7) For a more academic approach based on asymmetric Michael addition to 6a, see [7j]. When 4 was treated in analogy to [7l] (30 mol-equiv. dimethyl
malonate, 0.15 mol-equiv. K2CO3, 0.10 mol-equiv. 1-(anthracen-9-ylmethyl)-9-hydroxycinchonan-1-ium chloride, 08, 24 h, 88% (52% ee)), the
intermediate dimethyl {(1R,2S)-3-oxo-2-[(2Z)-pent-2-en-1-yl]cyclopentyl}propanedioate exhibited the following analytical data [6g][6j]. [a]2D0 ¼ 17.9
(c ¼ 1.0, CHCl3). 13C-NMR: 218.3 (s); 168.8 (s); 168.4 (s); 134.5 (d); 124.4 (d); 53.8 (d); 52.6 (q); 52.5 (q); 51.6 (d); 40.3 (d); 37.5 (t); 26.0 (t); 24.1 (t); 20.6
(t); 14.1 (q). MS: 282 (2, Mþ), 219 (8), 193 (7), 191 (8), 154 (10), 150 (83), 135 (20), 133 (100), 121 (32), 117 (11), 109 (18), 107 (15), 101 (22), 95 (20), 93
(20), 91 (20), 83 (31), 79 (30), 77 (17), 69 (14), 67 (18), 59 (20), 55 (22), 53 (14), 41 (26). Further demethoxycarbonylation (H2O, NMP, 1608)
quantitatively afforded (þ)-1 as (E)/(Z) 95:5 mixture. Dimethyl {(1S,2R)-3-oxo-2-[(2Z)-pent-2-en-1-yl]cyclopentyl}propanedioate ([a]2D0 ¼ À26.2 (c ¼
2.2, CHCl3)) was obtained in 97% yield and 75% ee using N-(anthracen-9-ylmethyl)quinidinium chloride. Similarly, under the latter conditions, 6a
afforded the intermediate dimethyl [(1S,2R)-3-oxo-2-(pent-2-yn-1-yl)cyclopentyl]propanedioate. Yield: 84% (48% ee). [a]2D0 ¼ À28.5 (c ¼ 1.5, CHCl3).
13C-NMR: 216.8 (s); 168.9 (s); 168.5 (s); 84.0 (s); 75.4 (s); 53.7 (d); 52.6 (q); 52.4 (q); 50.6 (d); 40.2 (d); 37.5 (t); 24.3 (t); 18.0 (t); 14.1 (q); 12.4 (t)
[3a][3c][7f][7h]. Demethoxycarbonylation towards methyl [(1R,2R)-3-oxo-2-(pent-2-yn-1-yl)cyclopentyl]acetate ([a]2D0 ¼ À67.0 (c ¼ 1.0, CHCl3)),
followed by monohydrogenation afforded (À)-1 as (E)/(Z) 93:7 mixture in 88% total yield. The ee values were determined either on 1 or after
perhydrogenation by chiral GC (Chirasil-DEX; 25 m  250 mm  0.25 mm) [9]. As earlier reported, K2CO3 may be replaced by KOH. Thus, for example,
2-(2,2-dimethoxyethyl)cyclopent-2-en-1-one (10 mol-equiv. dimethyl malonate, 0.14 mol-equiv. KOH, 0.10 mol-equiv. N-(anthracen-9-ylmethyl)quinidi-
nium chloride, toluene, 08, 20 h, 78% (58% ee). 13C-NMR: 209.6 (s); 160.1 (d); 141.2 (s); 102.4 (d); 53.0 (2q); 34.2 (t); 28.4 (t); 26.8 (t)) also gave the
opposite enantiomer dimethyl [(1R,2S)-2-(2,2-dimethoxyethyl)-3-oxocyclopentyl]propanedioate in 82% yield and 57% ee (MS: 302 (1, Mþ), 270 (5), 207
(8), 175 (7), 155 (19), 139 (80), 138 (100), 123 (11), 109 (18), 107 (10), 101 (24), 95 (27), 89 (25), 79 (14), 75 (59), 59 (19).), using N-(anthracen-9-
ylmethyl)quininium chloride [8]. We are indebted to Ms. J. Quintaine for chiral GC analyses.
DOI: 10.1002/hlca.201500257
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Helv. Chim. Acta 2016, 99, 95 – 109
method reported for dehydrohedione by Crawford et al. afford a 70 :30 mixture of 11a/6a. Herein, we describe our
[14] to generate the cyclopentenone functionality via attempts to circumvent this drawback.
cascade epoxidation/rearrangement of an enol derivative.
Indeed, since a CꢀC bond is relatively stable under mild
Results and Discussion. – Either the presence or
peracidic conditions, we envisaged, starting from the absence, in our reaction mixtures, of enone 13a reminded
commercially available methyl keto ester 2b8) and via the us that such monosubstituted cyclopentenones undergo
known intermediates 5a9) [20] and 5c10) [6j][6t] isomerization, under either acidic or basic conditions, to
[7c][12][19][21a][23] the generation of the known enol the thermodynamically more stable trisubstituted com-
acetate 7a [7c] (Ac2O, TsOH, 74% (81:19 mixture of 7a/ pounds [27]15). Thus, our aim was to regioselectively
8a))11). Unfortunately, under acidic conditions (H2SO4 generate an enol derivative at the alternative a’-position, as
(cat.), MeOH), the 81:19 mixture of unreported epoxides compared to 7. We studied three possible options. First of
9a/10 (AcOOH, NaHCO3, CH2Cl2, 358, 95%) did not all, we generated this regioisomer under kinetic rather than
undergo rearrangement to form the endocyclic enone 6a, thermodynamic conditions. Alternatively, we also decided
but instead eliminated AcOH by abstraction of a more to take advantage of the blocked a-position offered by
acidic H-atom, to afford the known conjugated ynenone intermediate 5a. Finally, we also considered the possible
11a [6j][7b][7c]12), contaminated by ca. 19% of enone activation of the a’-position by starting from 5d [22d],
13a13). An identical result was observed when the inter- readily available from 5a via a thermodynamically driven
mediate 81:19 mixture of enol acetates 7a/8a was used as retro-Claisen/Claisen cascade reaction (MeONa, xylene,
starting material for the intermolecular Tsuji dehydrogen- 1458, 94%), via the known dimethyl 2-(pent-2-yn-1-yl)hex-
ation (0.07 mol-equiv. (AcO)2Pd, MeOC(O)OCH2- anedioate intermediate16) [23a].
CH¼CH2, MeCN, 828, 65%). Finally, when a 7:3 mixture
With respect to the first option, the enolate of 5c
of trimethylsilyl enol ethers 7c/8c (Me3SiCl, Et3N, DMF, (lithium diisopropylamide (LDA), THF, À 788, then either
1308, 49% from 5c)14) was treated with N-bromosuccin- AcCl or Me3SiCl) afforded either 8a (13%)17) or 8c (71%),
imide (NBS) in THF/H2O at 68, the crude intermediate was respectively. Subsequent Tsuji dehydrogenation (0.07 mol-
dehydrohalogenated to afford a 73 :27 mixture of 11a/6a equiv. (AcO)2Pd, MeOC(O)OCH2CH¼CH2, MeCN, 828)
(Li2CO3, pyridine, 1008, 78% [17c]). Alternatively, 5c was afforded enone 13a in 65 and 56% yield, respectively. This
also directly treated successively in the same pot with either regioisomer was then treated with 0.2 mol-equiv. of 1,8-
CuCl2 · 2 H2O, LiCl, DMF, 808, then Li2CO3, LiBr, DMF, diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene under
808 (54% total yield) [17a] or either CuCl2 · 2 H2O or reflux to afford the desired enone 6a in 90% yield18). This
FeCl3 · 6 H2O, EtOH, H2O, 808 (35% total yield) [17d] to approach was preferred to the alternative treatment of 8c
8) The corresponding ethyl ester is also commercially available.
9) Instead of alkylating 2b using 1-chloropent-2-yne (K2CO3, acetone, 90%), we preferred a slightly modified version (K2CO3, acetone, 98%) using pent-2-yn-
1-yl methanesulfonate [15], readily obtained in quantitative yield from the corresponding commercially available pent-2-yn-1-ol (MeSO2Cl, Et3N, CH2Cl2).
Attempted alkylation of 2e [16a][16b], using either NaNH2, THF, EtBr, 208, or BuLi, THF, tetrahydro-1,3-dimethylpyrimidin-2(1H)-one (DMPU), EtBr,
À 408, or LDA, THF, DMPU, EtI, À 788, failed [16f]. Neither Sonogashira nor Fu method, nor an alternative coupling of EtBr with either the already
reported 2j [17b] or its corresponding analogous 2-(prop-2-yn-1-yl)cyclopent-2-en-1-one [6f][18c], or 2-(prop-2-yn-1-yl)cyclohexane-1,3-dione precursor
[18] were attempted. In our case, 2j was obtained via decarbomethoxylation of 2e (LiOH, THF, H2O, 96%). Hydrogenation of 5a with Lindlar catalyst in
cyclohexane afforded 2f in 95% yield. For the ethyl ester analog of 2e, see [16c–16e]. For ethyl and tert-butyl ester analogs of 5a, see [19].
10) Readily obtained by decarbomethoxylation of either 5a (LiOH, THF, H2O, 208, 95%) or 5d (either LiOH, THF, H2O, 208, 94% or H2O, 1508, 84%). The
previously reported hydrogenation of 5c with Lindlar catalyst in cyclohexane afforded the (Z)-substituted cyclopentanone 2h in 95% yield [6j][21].
Furthermore, 5c is an important synthetic intermediate, earlier used by Demole and Winter, for a regioselective BaeyerÀVilliger oxidation directed towards
(Z)-d-jasmolactone [21a][22]. This capricious reaction was later optimized and exploited by Nippon Zeon, Ltd. [22c] and Firmenich SA.
11) The formation of the corresponding propanoyl analog ((EtC(O))2O, TsOH, 59% (80 :20 mixture of regioisomers 7b/8b)) was less efficient.
12) Its hydrogenation with Lindlar catalyst in cyclohexane afforded stereoisomer (E,Z)-12a in 96% yield. For its stereoisomer (E,E)-12a, see [24a][24b]. The
pKa values of allylic and propargylic H-atoms are estimated to be ca. 43 and 36, respectively, on F. G. Bordwellꢀs scale in DMSO [24c][24d].
13) Lindlar hydrogenation of 13a in cyclohexane afforded 14a in 95% yield. For the corresponding (E) stereoisomer, see [25]. During the syntheses of 9a/10,
the isomerized a-acetoylketones 5j/5i were isolated for analytical purpose. Their thermal elimination was not attempted [26], but they were eventually
hydrolyzed to their corresponding hydroxy ketones 5h/5g, resp. (LiOH, THF, H2O, > 94%). Epoxide 9b was analogously obtained from 7b (aq. AcOOH,
NaHCO3, toluene, 48%).
14) The same ratio of regioisomers was obtained with Me3SiCl, NaI, pyridine, MeCN, 758, but the conversion was much slower and incomplete.
15) For the inspiring preliminary work of Snowden (Firmenich SA, unpublished results, 1992), see reference 39a in [2a]. For an even more favorable
isomerization of analogous a,b-disubstituted cyclopentenones to the tetrasubstituted compounds, see [28]. The enthalpies of our diverse isomers are as
follows: 13a (5.00 kcal molÀ1) is less stable than 6a (1.43 kcal molÀ1) and (Z)-11a (3.34 kcal molÀ1) is less stable than the most favorable (E)-11a (0.00 kcal
molÀ1). Similarly, 14a (8.32 kcal molÀ1) is less stable than 4 (4.55 kcal molÀ1) and (Z,Z)-12a (2.94 kcal molÀ1) is less stable than either (E,Z)-12a (1.57 kcal
molÀ1) or the most favorable (E,E)-12a (0.00 kcal molÀ1). These energies do not take into account the entropic factor, advantaging the less rigid structures.
16) This intermediate exhibited the following NMR data: 1H-NMR: 3.70 (s, 3 H); 3.67 (s, 3 H); 2.54 (m, 1 H); 2.49 – 2.42 (m, 1 H); 2.39 – 2.33 (m, 1 H); 2.32
(br. t, J ¼ 6.8, 2 H); 2.13 (tq, J ¼ 7.4, 2.4, 2 H); 1.73 – 1.60 (m, 4 H); 1.09 (t, J ¼ 7.4, 3 H). 13C-NMR: 175.0 (s); 173.6 (s); 83.6 (s); 76.0 (s); 51.7 (q); 51.5 (q);
44.8 (d); 33.8 (t); 30.6 (t); 22.5 (t); 21.6 (t); 14.2 (q); 12.4 (t).
17) Even under these kinetic conditions an 80 :20 mixture of 7a/8a was isolated in 66% yield. Alternatively, a 45 :55 mixture of 7a/8a was obtained when 5a
was treated under the following conditions: prop-1-en-2-yl acetate, TsOH (cat.), 1008, > 97%.
18) Alternatively, isomerization of 13a was also performed with 30% isolated yield, by treatment with 0.056 mol-equiv. of RhCl3 · 3 H2O and 1.0 mol-equiv. of
K2CO3 in EtOH/H2O 9 :1 under reflux for 24 h, while this isomerization failed in KOH/MeOH at 658. Carbomethoxylation of 6a (NaH, THF,
dimethylcarbonate) also failed.
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Scheme
ꢁ 2016 Verlag Helvetica Chimica Acta AG, Zürich
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Helv. Chim. Acta 2016, 99, 95 – 109
Scheme (cont). a) 2b to 5a: K2CO3, acetone, pent-2-yn-1-yl methanesulfonate, 95%. b) H2O, 1508, 84%. c) LiOH, THF, H2O, 208, 93 – 95%. d1) 5a
to 8d (72%); 5c to a 45 :55 mixture of 8a/7a (98%): prop-1-en-2-yl acetate, 0.01 mol-equiv. TsOH, 1008. d2) 5c to 8c (71%); 2h to 17a (78%): LDA,
THF, Me3SiCl, – 78 À 208. d3) 5a to 8e (82%); 5c to 7c (49%); 2h to 18 (19%): Me3SiCl, NaI, Et3N, MeCN, 758. e1) 5c to a 19 :81 mixture of 8a/7a:
Ac2O, TsOH, 1708, 74%. e2) 5c to a 20 :80 mixture of 8b/7b: (EtC(O))2O, 0.01 mol-equiv. TsOH, 1708, 50%. f) 8a to 13a (65%); 8c to 13a (56%);
8e to 13b (23%); 7a to 11a (65%); 17a to 14a (56%): 0.07 mol-equiv. (AcO)2Pd, MeOC(O)OCH2CH¼CH2, MeCN, 828. g) H2, cyclohexane,
quinoline, Lindlar catalyst. h) 13a to 6a (90%); 14a to 4 (91%): 0.2 mol-equiv. DBU, toluene, 1108. i) MeONa, MeOH, xylene, 110 – 1458, 81 – 94%.
j) 5d to 5e: 0.03 mol-equiv. (Oct)2SnO, prop-2-en-1-ol, cyclohexane, 818, 72%. k1) 5d to 15a: AcCl, Et3N, DMAP, CH2Cl2, 208, 54%. k2) 5d to 15b:
TMSOTf, EtN(iPr)2, CH2Cl2, 208, 59%. l) 8a to 10 (45%); 7a to 9a (95%): AcOOH/H2O, NaHCO3, toluene, 358. m) 10 to 5i: AcOOH/AcOH,
NaHCO3, toluene, 358, > 95%. n) 2b to 2d (97%); 5d to 5f (94%): SO2Cl2, CH2Cl2, 208. o) 5f to 16: LiCl, DMF, 1008, 9%. p) 2a to 12b: 4% aq.
NaOH, crotonaldehyde, 60%. q) 12b to 3: 50% aq. NaOH, Me3S(O)I, 0.167 mol-equiv. Bu4NBr, CH2Cl2, 408, 51%. r) 240 – 3508, 89%. s) 1) CuCl2 ·
2 H2O, LiCl, DMF, 808; 2) LiBr, DMF, 808, 34%. t) 9a/10 to 11a/13a: H2SO4, MeOH, 80%. u) 1) NBS, THF, H2O; 2) Li2CO3, pyridine, 1008. v) LiBr,
DMF, 808.
with NBS in THF/H2O at 68, followed by dehydrohaloge- 5a, we thus readily obtained enol acetate 8d (prop-1-en-2-
nation (Li2CO3, pyridine, 1008, 77% total yield), which yl acetate, 0.01 mol-equiv. TsOH, 72%), as well as the
afforded a 27:37:36 mixture of 6a/11a/13a. These basic trimethylsilyl enol ether 8e (Me3SiCl, NaI, Et3N, MeCN,
conditions are obviously too drastic and lead to excessive 758 (82%) or Me3SiOSO2CF3 (TMSOTf), EtN(iPr)2,
isomerization. Although our strategy was successful, the CH2Cl2, 208 (46%)). Tsuji Dehydrogenation of the latter
regioselective formation of this kinetic enolate at low compound (0.07 mol-equiv. (AcO)2Pd, MeOC(O)OCH2-
temperature is not acceptable from an economical and CH¼CH2, MeCN, 828, 23%) was sluggish, probably due to
industrial point of view. We thus repeated this sequence by significant steric crowding. Similarly, when 8d was used as
generating the appropriate trimethylsilyl enol ether 8c at a starting material, Tsuji conditions also afforded 13b in 39%
more practicable temperature of either À 20 or 08 without yield. Alternatively, 8d was sequentially treated with NBS
any erosion of either regioselectivity or efficiency. Only (THF/H2O, 68, 97%) and then 5m was dehydrohalogenated
then did we turn our attention to the second option.
with either LiBr/Li2CO3 in DMF at 808 or DBU in toluene
The advantage of this option is the absence of under reflux, to afford 13b in 23 – 53% yield, respective-
regioisomers, which simplifies both halogenation and ly19). The total yield was 31% when 8e was treated under
formation of the enol derivative. Starting from keto ester the same conditions. The carefully monitored monohydro-
19) Alternatively, 5n was obtained in 98% yield from 8d using N-chlorosuccinimide (NCS) under the same conditions. Further elimination was conducted in
toluene under reflux with 1.1 mol-equiv. of DBU to afford 13b in 32% yield. Attempted epoxidation of 8d (AcOOH, NaHCO3, CH2Cl2) afforded, after
purification by column chromatography (CC; SiO2), methyl 3-(acetyloxy)-2-oxo-1-(pent-2-yn-1-yl)cyclopentanecarboxylate in 27% yield as 5 :1 mixture
of diastereoisomers. Major diastereoisomer: IR: 2976, 2955, 2919, 1766, 1734, 1434, 1372, 1322, 1225, 1207, 1162, 1120, 1063, 1009, 962, 945, 886, 832, 800.
1H-NMR: 5.43 (dd, J ¼ 11, 8.7, 1 H); 3.72 (s, 3 H); 2.79 (dt, J ¼ 16.6, 2.3, 1 H); 2.69 (dt, J ¼ 16.6, 2.3, 1 H); 2.52 – 2.37 (m, 4 H); 2.15 (s, 3 H); 2.13 (tq, J ¼ 7.4,
2.3, 2 H); 1.09 (t, J ¼ 7.4, 3 H). 13C-NMR: 206.7 (s); 170.3 (s); 170.0 (s); 84.3 (s); 75.3 (d); 74.1 (s); 56.1 (s); 53.2 (q); 27.6 (t); 25.4 (t); 23.9 (t); 20.7 (q); 13.9
(q); 12.3 (t). MS: 266 (Mþ), 224 (12), 207 (22), 178 (28), 165 (13), 152 (30), 147 (9), 139 (13), 137 (12), 135 (13), 121 (13), 109 (16), 93 (30), 91 (27), 79
(17), 77 (20), 65 (10), 59 (10), 55 (11), 43 (100), 41 (12). Minor diastereoisomer: 1H-NMR: 5.20 (dd, J ¼ 11.8, 8.6, 1 H); 3.74 (s, 3 H); 2.83 (dt, J ¼ 16.7, 2.3,
1 H); 2.60 (dt, J ¼ 16.7, 2.3, 1 H); 2.52 – 2.37 (m, 4 H); 2.15 (s, 3 H); 2.00 (tq, J ¼ 7.4, 2.3, 2 H); 1.10 (t, J ¼ 7.3, 3 H). 13C-NMR: 207.6 (s); 170.4 (s), 170.1 (s);
85.5 (s); 75.9 (d); 74.0 (s); 56.9 (s); 53.0 (q); 26.9 (t); 26.3 (t); 24.6 (t); 20.7 (q); 14.1 (q); 12.3 (t). Further thermal elimination was not attempted [26].
Under identical epoxidation conditions, 8e afforded, after purification by CC (SiO2), methyl 3-oxo-1-(pent-2-yn-1-yl)-2-[(trimethylsilyl)oxy]cyclopen-
tanecarboxylate in 10% yield. 1H-NMR: 4.34 (s, 1 H); 3.76 (s, 3 H); 2.75 (dt, J ¼ 16.6, 2.4, 1 H); 2.39 – 2.36 (m, 4 H); 2.22 (dt, J ¼ 16.6, 2.4, 1 H); 2.11 (tq,
J ¼ 7.4, 2.4, 2 H); 1.08 (t, J ¼ 7.4, 3 H); 0.13 (s, 9 H). 13C-NMR: 212.9 (s); 174.7 (s); 84.4 (s); 80.2 (d); 75.3 (s); 53.6 (s); 52.4 (q); 31.8 (t); 25.1 (t); 19.9 (t);
14.0 (q); 12.4 (t); 0.0 (3q). MS: 296 (0, Mþ), 281 (100), 240 (12), 237 (11), 229 (17), 225 (78), 221 (83), 213 (42), 209 (10), 197 (20), 195 (10), 187 (10), 181
(15), 147 (12), 136 (25), 129 (14), 121 (12), 108 (10), 101 (11), 91 (13), 89 (15), 75 (28), 73 (94), 59 (18), 45 (14).
20) The intermediate methyl 3-bromo-2-oxo-1-[(2Z)-pent-2-en-1-yl]cyclopentanecarboxylate (55 :45 mixture of diastereoisomers) exhibited the following
data. IR: 2956, 2875, 1759, 1728, 1434, 1315, 1282, 1237, 1206, 1159, 1132, 1071, 977, 837. 1H-NMR (major diastereoisomer): 5.59 – 5.53 (m, 1 H); 5.28 – 5.24
(m, 1 H); 4.43 (dd, J ¼ 5.9, 3.5, 1 H); 3.71 (s, 3 H); 2.85 – 2.45 (m, 4 H); 2.33 – 1.95 (m, 4 H); 0.98 (t, J ¼ 7.5, 3 H). 1H-NMR (minor diastereoisomer): 5.59 –
5.53 (m, 1 H); 5.18 – 5.14 (m, 1 H); 4.26 (t, J ¼ 7.4, 1 H); 3.76 (s, 3 H); 2.85 – 2.45 (m, 4 H); 2.33 – 1.95 (m, 4 H); 0.95 (t, J ¼ 7.4, 3 H). 13C-NMR (major
diastereoisomer): 206.9 (s); 170.6 (s); 136.1 (d); 122.3 (d); 59.3 (s); 52.9 (q); 47.4 (d); 33.0 (t); 31.3 (t); 30.0 (t); 20.7 (t); 14.1 (q). 13C-NMR (minor
diastereoisomer): 206.7 (s); 170.4 (s); 136.7 (d); 121.8 (d); 58.3 (s); 53.0 (q); 47.1 (d); 32.0 (t); 30.8 (t); 29.4 (t); 20.7 (t); 14.0 (q). MS (major
diastereoisomer): 289 (0, Mþ), 231 (17), 229 (24), 222 (23), 220 (25), 209 (23), 207 (56), 191 (16), 189 (10), 179 (20), 177 (35), 175 (28), 152 (31), 149
(100), 147 (42), 142 (42), 133 (23), 121 (77), 119 (32), 109 (89), 107 (27), 105 (34), 95 (24), 93 (46), 91 (82), 81 (30), 79 (62), 77 (54), 67 (40), 65 (29), 59
(28), 55 (71), 53 (31), 41 (49), 39 (32), 28 (81). MS (minor diastereoisomer): 289 (0, Mþ), 231 (17), 229 (17), 222 (24), 220 (23), 209 (23), 191 (16), 189
(7), 179 (10), 177 (40), 153 (9), 151 (23), 149 (87), 142 (60), 133 (10), 125 (23), 121 (88), 119 (14), 109 (100), 107 (26), 105 (16), 95 (25), 93 (38), 91 (30),
81 (27), 79 (53), 77 (30), 68 (58), 67 (44), 65 (16), 59 (22), 55 (67), 53 (28), 41 (52), 39 (32), 28 (79). When 2f was treated with AcOH, H2SO4, KBrO3,
and KBr, we isolated a 1:1 mixture of 3-(1-bromopropyl)-2-oxaspiro[4.4]nonane-1,6-dione diastereoisomers in 41% yield, which was separated in
analytical amounts by CC (SiO2; cyclohexane/AcOEt 8 :2). Less polar diastereoisomer: IR: 2970, 2879, 1770, 1731, 1446, 1403, 1338, 1318, 1186, 1166,
1128, 1095, 1020, 929, 913, 845, 802, 731. 1H-NMR: 4.82 (ddd, J ¼ 8.7, 7.3, 3.1, 1 H); 3.96 (ddd, J ¼ 8.7, 4.7, 3.1, 1 H); 2.65 (quint., J ¼ 6.2, 1 H); 2.57 (dd, J ¼
13.1, 7.0, 1 H); 2.53 – 2.48 (m, 1 H); 2.40 – 2.33 (m, 2 H); 2.15 (dd, J ¼ 12.9, 8.7, 1 H); 2.04 – 1.93 (m, 4 H); 1.11 (t, J ¼ 7.3, 3 H). 13C-NMR: 214.1 (s); 174.0
(s); 78.6 (d); 58.9 (d); 58.0 (s); 37.4 (t); 36.5 (t); 34.0 (t); 28.4 (t); 19.7 (t); 12.5 (q). MS: 276 (8, Mþ), 274 (9), 221 (21), 219 (20), 195 (74), 177 (100), 166
(9), 153 (26), 149 (23), 139 (63), 127 (15), 125 (28), 121 (18), 111 (23), 109 (16), 97 (24), 95 (27), 93 (81), 81 (11), 79 (22), 77 (14), 67 (29), 55 (29), 53
(14), 41 (37), 39 (23). More polar diastereoisomer: IR: 2970, 2941, 2880, 2831, 1769, 1734, 1447, 1402, 1336, 1317, 1193, 1163, 1123, 1086, 1022, 960, 937, 869,
841, 802, 732. 1H-NMR: 4.67 (dt, J ¼ 9.1, 6.2, 1 H); 4.07 (ddd, J ¼ 9.4, 5.6, 3.3, 1 H); 2.68 (dd, J ¼ 13.3, 9.4, 1 H); 2.63 – 2.52 (m, 2 H); 2.37 – 2.30 (m, 2 H);
2.13 (dd, J ¼ 13.3, 6.6, 1 H); 2.06 – 1.95 (m, 3 H); 1.88 – 1.80 (m, 1 H); 1.12 (t, J ¼ 7.2, 3 H). 13C-NMR: 213.0 (s); 174.4 (s); 79.7 (d); 57.3 (s); 56.6 (d); 37.4 (t);
35.2 (t); 35.1 (t); 26.3 (t); 19.3 (t); 12.0 (q). MS: 276 (6, Mþ), 274 (7), 221 (18), 219 (19), 195 (72), 177 (100), 166 (8), 153 (45), 149 (27), 139 (57), 127 (16),
125 (36), 121 (20), 111 (23), 109 (16), 97 (24), 95 (27), 93 (78), 81 (12), 79 (24), 77 (16), 67 (27), 55 (29), 53 (14), 41 (38), 39 (26).
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99
genation of 13b (H2, Lindlar catalyst, cyclohexane, 87%) (Oct)2SnO, cyclohexane, 818, 72%), but the latter gave the
afforded 14b. Finally, decarbomethoxylation of either 13b desired enone 13a in poor 19% yield (0.07 mol-equiv.
or 14b (LiOH, THF, H2O, 208, 93 – 95%) gave either 13a or (AcO)2Pd, MeCN, 758). We then regioselectively prepared
14a, respectively. A promising abridgement, consisting in both enol acetate 15a (AcCl, Et3N, 4-(dimethylamino)pyr-
treating either 5a or 2f under conditions described by Ohta idine (DMAP), CH2Cl2, 208, 54%)22), and trimethylsilyl
et al. (either trichloroisocyanuric acid, AcOH, BF3 · Et2O, enol ether 15b (TMSOTf, EtN(iPr)2, CH2Cl2, 208, 59%),
208, then 6m aq. HCl/AcOH, 1008 [27a] or NBS, but their epoxidation also proved to be more sluggish, due
ClCH2CH2Cl, 838, then 6m aq. HCl/AcOH, 1008 [28j]) to an electronic deactivation (either AcOOH, NaHCO3,
to directly afford either 6a or 4 was not attempted, in view toluene or m-chloroperoxybenzoic acid, CH2Cl2)23). De-
of the alternative eliminative mechanism, concomitant to hydrogenation of 15b (0.07 mol-equiv. (AcO)2Pd, MeO-
the decarbomethoxylation, suggested by these authors. C(O)OCH2CH¼CH2, MeCN, 758) also failed, possibly due
We rather proceeded stepwise by direct bromination to the low temperature. We then treated 5d with SO2Cl2 in
À
(Me3PhNþBr3 , THF, 08 (59%) or AcOH, H2SO4, KBrO3, CH2Cl2 at 208, anticipating chlorination at the a’-position,
KBr, 208 (63%) [29a], or CuBr2, MeOH, 658 (90%) [29c]), in between the ketone and ester functionalities. Here again,
leading to either 5m or its semi-hydrogenated analog we were surprised by the result, since a 3 :2 mixture of
(CuBr2, MeOH, 658, 60%)20), followed by basic elimina- diastereoisomers 5f 24) was isolated in 94% yield, even-
tion (LiBr, Li2CO3, DMF, 808) to give 13b (31%) or 14b tually as a result of a double enolization of both ester and
(42%), with a subsequent independent decarbomethoxy- ketone moieties, which furnished 16 under eliminating
lation (vide supra). In complement to these encouraging conditions (LiCl, DMF, 1008) in a fully conjugated enolic
results, we also quickly explored the third strategy.
form, albeit in poor 9% yield of isolated product25). An
In analogy with the Tsuji intramolecular reaction, we alternative method to activate either 2h or 5c, consisted in
initially trans-esterified methyl ester 5d21) to the unre- treatment with diethyl ethanedioate (EtONa, EtOH, >
ported allyl ester 5e (HOCH2CH¼CH2, 0.03 mol-equiv. 94% [27c][32])26
)
27). Unfortunately, further chlorination
21) Direct oxidation of 5d (HIO3, DMSO, 658 [9] (and references cited therein)) failed, as did treatment of 5a with H2C¼CHCH2ONa in xylene under reflux.
Treatment of dimethyl (3-oxo-2-pentylcyclopentyl)propanedioate with HIO3 in DMSO at 658 afforded dimethyl (3-oxo-2-pentylcyclopent-1-en-1-
yl)propanedioate in 7% yield. 1H-NMR: 4.78 (s, 1 H); 3.80 (s, 6 H); 2.73 (t, J ¼ 4.5, 2 H); 2.43 (dt, J ¼ 4.7, 2.6, 2 H); 2.19 (t, J ¼ 7.5, 2 H); 1.40 – 1.20 (m,
6 H); 0.87 (t, J ¼ 7.0, 3 H). 13C-NMR: 208.8 (s); 166.7 (2s); 160.6 (s); 145.1 (s); 53.1 (2q); 53.0 (d); 34.3 (t); 31.7 (t); 27.9 (t); 27.2 (t); 23.4 (t); 22.4 (t); 14.0
(q). MS: 282 (1, Mþ), 223 (8), 218 (5), 194 (20), 175 (10), 167 (20), 165 (17), 162 (28), 151 (100), 137 (15), 135 (20), 133 (29), 121 (12), 107 (12), 105 (10),
91 (13), 79 (15), 77 (18), 59 (18), 55 (10), 41 (14), 29 (14). This intermediate is readily prone to quantitative demethoxycarbonylation (AcOH, H2O, 208)
according to [14b].
22) The conditions isopropenyl acetate and TsOH at 1008 afforded a 1:1 inseparable mixture of regioisomers in 98% yield.
23) Treatment of 15b with Pd(OH)2, tBuOOH, and Na2HPO4 failed, and we did not prepare the corresponding triisopropylsilyl enol ether [29b].
24) MS Analysis of 5f is reminiscent to that of 11a.
25) No traces of 6b were detected. For the ethyl ester analog of 6c, see [7g]. Decarboxylative saponification of 16 with LiOH, THF, and H2O afforded mainly
11a, whose isomerization was not attempted in view of its thermodynamic stability. Alkylation of the known chloro keto ester 2d [30] with 1-chloropent-2-
yne (either LDA, THF, À 788 or tBuOK, tBuOH, or KH, THF) was unsuccessful. Furthermore, either direct oxidation of 2b (HIO3, DMSO, 658 [9] (and
references cited therein)) or elimination of 2d (either DBU, toluene 1108 or DMF, 1008, or NMP, 1408) failed to give the reported unstable methyl 5-
oxocyclopent-1-ene-1-carboxylate [31] as a suitable substrate for Michael addition and cascade in situ alkylation. Hydrogenation of neat 5d with 1 wt-% of
Lindlar catalyst furnished methyl 2-oxo-3-[(2Z)-pent-2-en-1-yl]cyclopentanecarboxylate in 92% yield as 55 :45 mixture of diastereoisomers. Major
diastereoisomer tentatively deduced from the mixture: IR: 2957, 2930, 2872, 1753, 1725, 1662, 1621, 1435, 1341, 1297, 1245, 1199, 1177, 1130, 1037, 970, 881,
798, 726. 1H-NMR: 5.51 – 5.43 (m, 1 H); 5.31 – 5.24 (m, 1 H); 3.75 (s, 3 H); 3.13 (dd, J ¼ 11.0, 8.2, 1 H); 2.53 – 2.10 (m, 6 H); 2.05 (quint., J ¼ 7.3, 2 H); 1.9 –
1.5 (m, 1 H); 0.96 (t, J ¼ 7.3, 3 H). 13C-NMR: 212.7 (s); 169.9 (s); 134.0 (d); 125.2 (d); 55.2 (d); 52.7 (q); 49.6 (d); 26.9 (t); 26.7 (t); 25.1 (t); 20.6 (t); 14.3 (q).
MS: 210 (16, Mþ), 192 (15), 179 (16), 150 (18), 142 (100), 133 (36), 123 (15), 121 (19), 110 (88), 107 (17), 95 (30), 93 (14), 87 (27), 81 (38), 69 (20), 67
(33), 55 (73), 54 (20), 41 (40), 39 (19), 28 (25). The latter was either readily decarboxymethylated (LiOH, THF/H2O, 93%) to afford 2h, or trans-
esterified (HOCH2CH¼CH2, 0.03 mol-equiv. (Oct)2SnO, cyclohexane, 818, 51%) to afford the corresponding allyl ester with the following data,
tentatively deduced from a 66:34 mixture of diastereoisomers. IR: 3009, 2963, 2934, 2874, 1752, 1724, 1453, 1366, 1328, 1298, 1239, 1182, 1128, 1027, 980,
1
930, 797, 724. H-NMR: 5.95 – 5.88 (m, 1 H); 5.49 – 5.44 (m, 1 H); 5.37 – 5.33 (m, 1 H); 5.29 – 5.24 (m, 2 H); 4.69 – 4.60 (m, 2 H); 3.31 (dd, J ¼ 8.7, 5.5,
0.34 H); 3.15 (dd, J ¼ 10.2, 7.9, 0.66 H); 2.52 – 2.41 (m, 1 H); 2.37 – 2.10 (m, 5 H); 2.04 (quint., J ¼ 7.1, 2 H); 1.90 – 1.83 (m, 0.34 H); 1.56 – 1.49 (m, 0.66 H);
0.96 (t, J ¼ 7.1, 3 H). 13C-NMR (major diastereoisomer): 212.4 (s); 169.2 (s); 134.0 (d); 131.8 (d); 125.1 (d); 118.5 (t); 65.9 (t); 55.1 (d); 49.4 (d); 26.9 (t);
26.7 (t); 25.1 (t); 20.6 (t); 14.2 (q). 13C-NMR (minor diastereoisomer): 213.0 (s); 169.0 (s); 133.9 (d); 131.7 (d); 125.3 (d); 118.5 (t); 65.9 (t); 54.2 (d); 48.9
(d); 27.3 (t); 27.0 (t); 25.1 (t); 20.6 (t); 14.2 (q). MS: 236 (0, Mþ), 152 (26), 123 (26), 95 (22), 84 (100), 83 (40), 81 (20), 79 (17), 69 (10), 67 (28), 55 (22), 41
(27), 39 (17), 32 (24), 28 (87). Further dehydrogenation (0.07 mol-equiv. (AcO)2Pd, MeCN, 828, 53%) furnished 14a.
26) Ethyl (2Z)-hydroxy{2-oxo-3-[(2Z)-pent-2-en-1-yl]cyclopentylidene}acetate. IR: 2964, 2934, 2873, 1727, 1667, 1605, 1462, 1443, 1394, 1370, 1352, 1328,
1302, 1280, 1228, 1167, 1112, 1093, 1019, 966, 902, 863, 791, 728, 702, 679. 1H-NMR: 12.9 (br. s, OH); 5.52 – 5.41 (m, 1 H); 5.35 – 5.26 (m, 1 H); 4.35 (q, J ¼
7.0, 2 H); 3.11 – 2.97 (m, 1 H); 2.82 – 2.72 (m, 1 H); 2.61 – 2.46 (m, 2 H); 2.44 – 2.25 (m, 2 H); 2.25 – 1.98 (m, 2 H); 1.88 – 1.54 (m, 1 H); 1.38 (t, J ¼ 7.2, 3 H);
0.96 (t, J ¼ 7.2, 3 H). 13C-NMR: 214.9 (s); 162.8 (s); 152.7 (s); 134.0 (d); 125.1 (d); 116.9 (s); 62.0 (t); 49.0 (d); 27.4 (t); 26.8 (t); 25.6 (t); 20.6 (t); 14.2 (q);
14.1 (q). MS: 252 (11, Mþ), 184 (54), 179 (100), 177 (47), 151 (10), 149 (10), 133 (11), 123 (29), 110 (74), 109 (49), 107 (12), 105 (10), 95 (21), 93 (14), 91
(13), 81 (39), 79 (18), 77 (13), 69 (38), 67 (28), 55 (58), 53 (18), 41 (38), 39 (15), 29 (20).
27) Ethyl (2Z)-hydroxy[2-oxo-3-(pent-2-yn-1-yl)cyclopentylidene]acetate. IR: 2977, 2937, 2915, 2878, 1726, 1661, 1600, 1473, 1459, 1437, 1396, 1377, 1359,
1338, 1280, 1259, 1224, 1182, 1164, 1136, 1088, 1036, 1016, 976, 952, 894, 867, 828, 805, 787. 1H-NMR: 12.82 (br. s, OH); 4.36 (q, J ¼ 7.1, 2 H); 3.07 (ddd, J ¼
17.7, 8.4, 2.6, 1 H); 2.77 (ddd, J ¼ 17.7, 9.2, 8.4, 1 H); 2.68 – 2.62 (m, 1 H); 2.62 – 2.54 (m, 1 H); 2.44 – 2.37 (m, 1 H); 2.33 – 2.25 (m, 1 H); 2.13 (tq, J ¼ 7.4, 2.4,
1 H); 1.91 – 1.80 (m, 2 H); 1.38 (t, J ¼ 7.1, 3 H); 1.09 (t, J ¼ 7.4, 3 H). 13C-NMR: 213.4 (s); 162.8 (s); 152.8 (s); 116.9 (s); 83.5 (s); 75.8 (s); 62.1 (t); 48.0 (d);
26.6 (t); 25.6 (t); 19.3 (t); 14.2 (q); 14.1 (q); 12.4 (t). MS: 250 (2, Mþ), 222 (13), 217 (11), 177 (100), 149 (10), 123 (12), 121 (18), 109 (24), 107 (15), 105
(10), 93 (21), 91 (20), 81 (15), 79 (27), 77 (14), 69 (11), 67 (22), 55 (41), 53 (11), 41 (15), 39 (11), 29 (12).
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100
Helv. Chim. Acta 2016, 99, 95 – 109
(either SO2Cl2, toluene or CuCl2 · 2 H2O, DMF, 808) failed, 808 for 5 h, a 70 :30 mixture of 6a/11a was obtained in 82%
and only minor side products corresponding to heterobi- yield31). Purification by CC (SiO2) furnished pure 6a in
)
cyclic materials28 29) could be isolated in mediocre 12 and 36% yield. Alternatively, a 15 :85 mixture of regioisomers
8% yield, respectively. Alternatively, the reported product 17a/18 (Me3SiCl, NaI, Et3N, MeCN, 758, 57%) was purified
of condensation between cyclopentanone (2a) and diethyl by CC (SiO2) to afford pure 18 in 19% yield. This latter
ethanedioate (EtONa, 80%)30) [33] could be alkylated compound was treated with NBS in THF/H2O at 68 to
with pentynyl chloride (K2CO3, acetone) to directly afford afford, after dehydrohalogenation (LiBr, DMF, 808, 61%
5c, albeit in very poor 8% yield.
total yield), a 79 :21 mixture of 4/(E,E)-12a33).
At this stage, in view of the detour inherent in this
Finally, reconsidering the approach designed by Naef
strategy, we decided to take a short-cut. We discovered that and Decorzant, via pyrolysis of (E)-3 (240 – 3508, 89% [4]),
treatment of the kinetic trimethylsilyl enol ether 17a we envisaged, in order to avoid the bromination of
(LDA, Me3SiCl, THF, À 788, 78% from 2h) under Tsujiꢀs piperylene34), to perform an aldol condensation between
dehydrogenative conditions (0.07 mol-equiv. (AcO)2Pd, cyclopentanone (2a) and crotonaldehyde (4% aq. NaOH,
MeOC(O)OCH2CH¼CH2, MeCN, 828, 56%) afforded 60% [24b]), thus affording the conjugated dienone
enone 14a, which was then isomerized to 4 (0.2 mol-equiv. (E,E)-12b [36]. Further cyclopropanation under phase
DBU, toluene, 1108, 91%). Moreover, the direct treatment transfer CoreyÀChaykovsky conditions (50% aq. NaOH,
of 2h with CuCl2 · 2 H2O/LiCl in DMF at 808, furnished Me3S(O)I, 0.17 mol-equiv. Bu4NBr, CH2Cl2, 408, 51%
quantitatively a 80 :20 mixture of 4/(E,E)-12a, allowing us [37]) afforded regioselectively (E)-3. Since the base is
to isolate pure 4 in 34% yield after chromatography31). the same in both steps, we performed the sequential aldol
With the end of the story in view, we revisited the beginning condensation and cyclopropanation in a single-pot version
of our synthesis by treating either 2h or 5c with either with a total yield of 31%. The observed regioselectivity
SO2Cl2, toluene, 208 (6 – 43%) [35a – 35c] or trichloroiso- may eventually be rationalized by the higher reactivity of
cyanuric acid, AcOH, BF3 · Et2O, 208 (32 – 27%) [35f], or the trisubstituted C¼C bond. Indeed, in this case, and by
NCS, Amberlyst 15, AcOEt, 208 (24 – 16%) [35g] to afford definition, two of the substituents are in the sterically
either 2i or 5l, respectively. The latter compound was strained (Z) disposition, as compared to the (E) config-
sluggishly monohydrogenated to give the key intermediate uration of the disubstituted C¼C bond. For the sake of
2i (H2, Lindlar catalyst, cyclohexane, 83%), which was completeness, we also envisaged to take advantage of the
heated at 808 in DMF in the presence of LiCl to afford a conjugative exocyclic elimination under basic conditions.
72 :9 :19 mixture of 4/(E,Z)-12a/(E,E)-12a in 74% yield. Thus, the reported norketone 2l [38] was considered as
When 5l32) was dehydrohalogenated with LiBr in DMF at potential starting material, but finally, the halogenation/
28) Ethyl (2Z)-(3-chloro-2-ethyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-ylidene)(hydroxy)acetate. IR: 3027, 2955, 2927, 2858, 1706, 1603, 1495, 1453,
1376, 1203, 1071, 1029, 746, 699. 1H-NMR: 5.50 (dt, J ¼ 9.8, 4.3, 1 H); 5.31 (s, OH); 4.33 (dq, J ¼ 9.8, 6.6, 2 H); 3.96 (dt, J ¼ 4.3, 1 H); 3.19 – 3.12 (m, 1 H);
2.94 (dd, J ¼ 14.8, 7.2, 1 H); 2.60 (dd, J ¼ 13.9, 4.9, 1 H); 2.45 – 2.35 (m, 2 H); 2.19 – 2.11 (m, 1 H); 2.07 – 1.78 (m, 2 H); 1.37 (t, J ¼ 7.2, 3 H); 1.12 (t, J ¼ 7.1,
3 H). 13C-NMR: 181.9 (s); 174.4 (s); 164.5 (s); 104.6 (s); 95.3 (d); 82.1 (s); 63.6 (d); 62.1 (t); 42.5 (t); 37.6 (t); 31.5 (t); 27.8 (t); 14.1 (q); 11.2 (q). MS: 286 (3,
Mþ), 284 (3), 249 (27), 247 (43), 213 (33), 211 (74), 175 (100), 147 (21), 123 (10), 121 (10), 119 (14), 107 (27), 105 (13), 91 (28), 79 (17), 77 (22), 67 (14),
65 (13), 55 (18), 53 (15), 41 (13), 29 (18).
29) Ethyl 2-ethyl-4-hydroxy-6,7-dihydro-1-benzofuran-7a(5H)-carboxylate. IR: 3450, 2976, 2938, 2876, 1726, 1445, 1369, 1240, 1171, 1139, 1094, 1017, 964, 940,
899, 858, 810, 757. 1H-NMR: 5.82 (s, 1 H); 4.26 (dq, J ¼ 11.2, 6.9, 2 H); 3.5 (br. s, OH); 2.67 – 2.54 (m, 2 H); 2.58 (q, J ¼ 7.4, 2 H); 2.14 – 1.87 (m, 4 H); 1.27
(t, J ¼ 7.4, 3 H); 1.19 (t, J ¼ 7.4, 3 H). 13C-NMR: 176.0 (s); 156.6 (s); 151.6 (s); 118.6 (s); 101.8 (d); 71.9 (s); 62.1 (t); 35.0 (t); 22.7 (t); 21.4 (t); 19.5 (t); 14.2
(q); 12.1 (q). MS: 238 (5, Mþ), 220 (90), 218 (21), 205 (55), 203 (10), 177 (20), 175 (28), 173 (27), 165 (100), 147 (72), 145 (18), 131 (31), 119 (13), 115
(11), 91 (96), 79 (10), 77 (19), 57 (16), 55 (15), 29 (13).
30) Ethyl (2Z)-hydroxy(2-oxocyclopentylidene)acetate. IR: 2979, 2906, 1727, 1668, 1605, 1465, 1444, 1395, 1369, 1346, 1307, 1281, 1231, 1189, 1094, 1017, 911,
861, 824, 791. MS: 184 (10, Mþ), 111 (100), 55 (13).
31) In contrast to the procedure reported by Tolstikov et al. for an (E) homolog, it was neither necessary nor appropriate to perform the dehydrohalogenation
with Li2CO3/LiBr in DMF under reflux [34]. This difference of behavior as compared to 5l (see footnote 11 for estimated pKa values and the Introduction
section for comparison) may eventually find its origin in the absence of Li2CO3 and the more acidic propargylic position, as compared to the corresponding
allylic position in the case of 2i. Alternatively, steric considerations for either accessibility to 2i/5l, or stability of 11a/12a may also be invoked, since the
elimination is conducted under neutral conditions.
32) The corresponding bromides, such as 5k, could not be obtained using either KBrO3, KBr, AcOH, H2SO4 or NBS, AcONH4, Et2O, 208 in analogy to [29a]
and [35e].
33) When a 85 :15 mixture of trimethylsilyl enol ethers 18/17a was treated under Tsujiꢀs conditions (MeOC(O)OCH2CH¼CH2, 0.07 mol-equiv. (AcO)2Pd,
MeCN, 828, 75%), a 32 :56 :12 mixture of 14a/4/(E,E)-12a was isolated. This unexpected ratio may eventually result from isomerization of either the
initial or the final mixture with Pd2þ, although no (Z)/(E) isomerization was observed in the side chain of either 4 or 14a. Further isomerization (DBU,
toluene, 1108, 90%) furnished a 87:13 mixture of 4/(E,E)-12a. When 2h was treated with TMSOTf and Et3N in CH2Cl2 at 08, a 50 :50 mixture of kinetic/
thermodynamic trimethylsilyl enol ethers 17a/18 was quantitatively obtained. Alternatively, when the kinetic trimethylsilyl enol ether 17a (LDA, THF, À
788, then Et3N, Me3SiCl, 78%) was treated with NBS in THF/H2O at 68, the resulting intermediate bromoketone afforded quantitatively a 62 :10 :28
mixture of 4/(E,Z)-12a/(E,E)-12a after elimination under basic conditions (Li2CO3, pyridine, 1008). Monohydrogenation of either 5, 7 – 9, or 10 was not
systematically attempted. Indeed, only 8d was hydrogenated to 17b (H2, Lindlar catalyst, cyclohexane, 18%). The analogous trimethylsilyl enol ether 17c
was more efficiently obtained from 2f (TMSOTf, Et3N, CH2Cl2, 61%). As for 8d, we did not immediately recognize that during the hydrogenation of 8e,
the starting material, as well as both 17c and its perhydrogenated side chain analog (MS: 284 (12, Mþ), 269 (63), 225 (48), 214 (11), 199 (42), 142 (12), 115
(80), 73 (100), 55 (11)), exhibit the same tR values on an apolar column during GC analysis.
34) See footnote 27 in [2a] for our reluctance in using Br2.
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101
179 (9), 153 (13), 151 (30), 142 (58), 127 (10), 121 (100), 110 (46), 108
(12), 95 (20), 93 (19), 91 (11), 81 (15), 79 (25), 77 (13), 67 (25), 59 (10),
55 (28), 53 (14), 41 (31), 39 (13).
dehydrohalogenation, followed by either CoreyÀChaykov-
sky reaction and Lindlar hydrogenation or vice versa,
towards (Z)-3 was not attempted35).
2-[(2Z)-Pent-2-en-1-yl]cyclopentanone (2h)38). Obtained by hy-
drogenation of 5c with Lindlar catalyst according to [21a]. Yield: >
95%. Also obtained by saponification of methyl 2-oxo-3-[(2Z)-pent-
2-en-1-yl]cyclopentanecarboxylate according to the LiOH procedure
used for 5c. Yield: 93%. Fruity, veloutone, peach, melon, ylang, green,
violet leaf, nice39). B.p. 908/12 mbar. IR: 3007, 2962, 2934, 2874, 1735,
1453, 1406, 1335, 1300, 1270, 1153, 1069, 1025, 1003, 923, 814, 750.
1H-NMR: 5.49 – 5.41 (m, 1 H); 5.32 – 5.26 (m, 1 H); 2.51 – 2.43 (m,
1 H); 2.35 – 2.27 (m, 1 H); 2.22 – 2.16 (m, 1 H); 2.15 – 1.96 (m, 6 H);
1.84 – 1.72 (m, 1 H); 1.61 – 1.52 (m, 1 H); 0.96 (t, J ¼ 7.0, 3 H).
13C-NMR: 220.9 (s); 133.5 (d); 125.8 (d); 49.2 (d); 38.2 (t); 29.0 (t);
27.0 (t); 20.7 (t); 20.6 (t); 14.2 (q). MS: 152 (30, Mþ), 123 (27), 97 (12),
95 (21), 84 (100), 83 (37), 81 (18), 79 (12), 69 (10), 67 (22), 56 (18), 41
(24), 39 (12).
Conclusions. – We have constructed a synthetic net-
work comprising several new intermediates, 7 – 10, 13, 14,
17, and 18, allowing access to the desired enone 4, precursor
of methyl jasmonate (1), via more than 20 different routes.
Using the isomerization strategy, most of these routes
necessitated six steps. The sequences ! 5a ! either 8d or
8e ! 13b ! 13a ! 6a ! 4 are the longest and amongst the
less efficient ones, with a total yield of ca. 22%. The
alternative sequences ! 5a ! 5c ! either 8a or 8c ! 13a !
6a ! 4 allow to increase the total yield (ca. 32%), whilst the
most efficient sequences are either! 5a ! 5c or 2f ! 2h !
17a ! 14a ! 4, or! 5a ! 5m ! 13b ! 13a ! 6a ! 4 with
35 – 38% total yields, respectively. Furthermore, this meth-
od does not need to be regioselective, since mixtures of
regioisomers can be used, and intermediate purifications
can be avoided until the ultimate isomerization. It is
noteworthy that this method may also be performed on
14a, by reversing the isomerization/monohydrogenation
sequence36). Formation of the conjugated enones 11a and
12a is minimized under neutral a-dehydrohalogenation
conditions. A four- to five-step version via ! 5a ! either 2f
or 5c ! 2h ! either 4, or 14a ! 4, or 2i ! 4 is compara-
tively less productive with 31 – 34% total yield, while the
approach via inexpensive 2a ! [(E,E)-12b] ! 3 ! 4, with a
total yield of 27% is the shortest one. Indeed, it neces-
sitates only a three-step/two-pot procedure, including a
linear continuous thermal reactor.
2-Chloro-2-[(2Z)-pent-2-en-1-yl]cyclopentanone (2i). A soln. of 5l
(350 mg, 1.78 mmol) in cyclohexane (10 ml) was hydrogenated with
Lindlar catalyst (35 mg). After 1 h and 50% of conversion according to
MS analyses, the mixture was filtered and conversion completed under
the same conditions with fresh Lindlar catalyst to afford 2i. Yield: 83%.
IR: 3016, 2960, 2924, 2853, 1750, 1462, 1404, 1196, 1161, 1023, 975, 925,
893, 861, 796, 720. 1H-NMR: 5.62 – 5.57 (m, 1 H); 5.37 – 5.31 (m, 1 H);
2.78 (dd, J ¼ 14.5, 7.6, 1 H); 2.62 – 2.56 (m, 2 H); 2.52 (dd, J ¼ 14.8, 7.3,
1 H); 2.31 – 2.27 (m, 2 H); 2.16 – 1.94 (m, 4 H); 0.98 (t, J ¼ 7.6, 3 H).
13C-NMR: 211.0 (s); 136.2 (d); 121.7 (d); 71.7 (s); 37.4 (t); 35.3 (t); 34.1
(t); 20.8 (t); 18.3 (t); 14.0 (q). MS: 186 (1, Mþ), 151 (34), 121 (25), 120
(32), 118 (100), 95 (11), 91 (10), 83 (13), 81 (10), 79 (17), 77 (12), 69
(16), 67 (16), 55 (20), 41 (17), 39 (11).
Methyl 1-(But-2-yn-1-yl)-2-oxocyclopentanecarboxylate (2k). Ob-
tained from 2b and the corresponding mesylate [38], as described for
5a. Yield: 74%. IR: 2956, 2921, 1751, 1725, 1434, 1404, 1324, 1227, 1188,
1152, 1137, 1106, 1042, 1008, 928, 873, 849, 835, 809, 786, 768, 654, 619.
1H-NMR: 3.71 (s, 3 H); 2.66 (q, J ¼ 2.5, 2 H); 2.50 – 2.44 (m, 2 H);
2.32 – 2.25 (m, 2 H); 2.10 – 2.00 (m, 2 H); 1.75 (t, J ¼ 2.5, 3 H).
13C-NMR: 214.2 (s); 171.1 (s); 78.2 (s); 74.3 (s); 59.1 (s); 52.7 (q);
38.4 (t); 32.6 (t); 23.6 (t); 19.8 (t); 3.5 (q). MS: 194 (6, Mþ), 166 (12),
163 (14), 138 (38), 135 (100), 109 (12), 107 (25), 105 (13), 93 (16), 92
(23), 91 (48), 79 (42), 77 (32), 74 (15), 59 (10), 55 (12), 53 (15), 39 (10).
2-(But-2-yn-1-yl)cyclopentanone (2l). Obtained from 2k using
LiOH in THF/H2O, as described for 5c. Yield: 12%. Alternatively,
obtained from 1-(cyclopent-1-en-1-yl)pyrrolidine, in analogy to the
procedure reported in [21a]. Yield: 27%. IR: 2960, 2920, 2875, 1739,
1452, 1433, 1405, 1343, 1271, 1157, 1117, 1071, 1032, 1008, 922, 808.
1H-NMR: 2.51 – 2.46 (m, 1 H); 2.35 – 2.26 (m, 3 H); 2.23 – 2.19 (m,
1 H); 2.14 – 2.03 (m, 2 H); 1.88 – 1.77 (m, 2 H); 1.76 (t, J ¼ 2.5, 3 H).
13C-NMR: 219.5 (s); 76.8 (s); 76.3 (s); 48.1 (d); 38.2 (t); 28.8 (t); 20.5
(t); 18.9 (t); 3.5 (q). MS: 136 (2, Mþ), 121 (6), 108 (75), 93 (8), 91 (94),
79 (37), 77 (18), 55 (8), 53 (8), 51 (7), 41 (6), 39 (13), 32 (24), 28 (100).
Experimental Part
General. See [42a]. Calculations were performed at the B3LYP/6-
31G** level of theory [42b].
Methyl 2-Oxo-1-[(2Z)-pent-2-en-1-yl]cyclopentanecarboxylate
(2f). Obtained by hydrogenation of 5a with Lindlar catalyst, as
described for 12a. Yield: > 95%. Jasmine, Hedioneꢃ, minty37). IR:
2962, 2877, 1748, 1722, 1451, 1434, 1405, 1316, 1224, 1208, 1149, 1093,
1006, 972, 920, 838, 797, 723. 1H-NMR: 5.56 – 5.48 (m, 1 H); 5.24 – 5.16
(m, 1 H); 3.71 (s, 3 H); 2.67 (dd, J ¼ 15, 7.5, 1 H); 2.51 – 2.37 (m, 3 H);
2.33 – 2.20 (m, 1 H); 2.09 – 1.90 (m, 5 H); 0.96 (t, J ¼ 7.5, 3 H).
13C-NMR: 214.7 (s); 171.6 (s); 135.9 (d); 122.8 (d); 60.3 (s); 52.7 (q);
38.2 (t); 32.3 (t); 31.3 (t); 20.8 (t); 19.6 (t); 14.1 (q). MS: 210 (5, Mþ),
35) Mesylation of but-2-yn-1-ol (MeSO2Cl, Et3N, CH2Cl2, 72% [39]: 13C-NMR: 86.6 (s); 71.5 (s); 58.5 (t); 39.0 (q); 3.7 (q). MS: 148 (0, Mþ), 133 (14), 80 (17),
79 (21), 69 (57), 65 (14), 63 (12), 53 (100), 52 (26), 51 (18), 50 (12), 43 (44), 41 (16), 39 (23), 27 (16) allowed, after alkylation of 2b [35d] (K2CO3,
acetone, 74%), isolation of 2k. For the corresponding ethyl ester, see [40a – 40c]. Further decarbomethoxylation afforded 2l (LiOH, THF, H2O, 12%).
Alternatively, the latter compound was preferably obtained in 27% yield from the same mesylate by alkylation of 1-(cyclopent-1-en-1-yl)pyrrolidine, in
analogy to the procedure reported in [21a]. An attempted transesterification of 2k with HOCH2CH¼CH2 and (Oct)2SnO at 908 failed. We were asked to
interrupt our project at this point, as a result, chemical yields or failed experiments were neither optimized nor repeated. Related transformations were not
studied and, as in a former case [40d], basic ideas and new intermediates were rendered public rather than patented (see footnote 1).
36) For the syntheses of such enones based on a retro-DielsÀAlder method, see [41].
37) First delivered to our perfumers by Dr. C. Fehr (Firmenich SA, unpublished work, 2000).
38) Its commercially available (E)-stereoisomer (celery, milky odor) exhibits the following analytical data: IR: 2961, 2934, 2874, 1736, 1453, 1438, 1406, 1270,
1
1152, 967, 923, 822. H-NMR: 5.50 (dtt, J ¼ 15.2, 6.8, 1.1, 1 H); 5.34 (dtt, J ¼ 15.2, 6.8, 1.1, 1 H); 2.45 – 2.39 (m, 1 H); 2.34 – 2.25 (m, 2 H); 2.20 – 2.15 (m,
2 H); 2.14 – 2.07 (m, 1 H); 2.04 – 1.95 (m, 3 H); 1.83 – 1.72 (m, 1 H); 1.62 – 1.53 (m, 1 H); 0.96 (t, J ¼ 6.8, 3 H). 13C-NMR: 220.9 (s); 134.3 (d); 126.0 (d);
49.1 (d); 38.3 (t); 32.7 (t); 28.9 (t); 25.6 (t); 20.7 (t); 13.9 (q). MS: 152 (28, Mþ), 123 (27), 97 (12), 95 (22), 84 (100), 83 (36), 81 (22), 79 (14), 69 (13), 67
(28), 55 (23), 41 (30), 39 (15)
39) First delivered to our perfumers by Dr. F. Naef (Firmenich SA, unpublished work, 1978).
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102
Helv. Chim. Acta 2016, 99, 95 – 109
1-[(1E)-Prop-1-en-1-yl]spiro[2.4]heptan-4-one ((E)-3). A mixture
Alternatively, 5d afforded 5c when submitted to the latter conditions.
Yield: 94%. Chemical odor37). B.p. 52 – 588/1 hPa. For IR and 1H-NMR
analyses, see [6j][19a]. 13C-NMR: 216.4 (s); 82.9 (s); 77.4 (s); 48.0 (d);
37.8 (t); 28.8 (t); 20.5 (t); 19.3 (t); 14.5 (q); 12.7 (t). MS: 150 (4, Mþ),
135 (19), 122 (100), 107 (44), 93 (12), 91 (22), 79 (49), 77 (22), 67 (9),
65 (10), 55 (12), 41 (11), 39 (12).
of 12b (0.5 g, 3.55 mmol), Me3S(O)I (0.781 g, 3.55 mmol), and Bu4NBr
(0.191 g, 0.592 mmol) in CH2Cl2 (30 ml) was heated under reflux for
72 h in the presence of aq. NaOH (50%, 0.284 g, 3.55 mmol) under
vigorous stirring. The cold org. phase was concentrated, and the residue
was diluted in AcOEt (20 ml). The suspension was filtered over Celiteꢃ,
concentrated, and then purified by CC (SiO2; cyclohexane/AcOEt
95 :5) to afford (E)-3. Yield: 51%. Alternatively, a soln. of aq. NaOH
(1.0m, 2 ml, 2 mmol) was added dropwise to cyclopentanone (2a; 5.0 g,
59.4 mmol) at < 208, then crotonaldehyde (4.17 g, 59.4 mmol) was
added dropwise at < 108. After 1 h, CH2Cl2 (100 ml) was added, then
Me3S(O)I (13.08 g, 59.4 mmol) and Bu4NBr (3.19 g, 9.91 mmol),
followed by solid NaOH (2.3 g, 57.5 mmol). The well-stirred mixture
was heated under reflux for 18 h, than aq. NaOH (50%, 2 ml, 25 mmol)
was added, and after further 18 h under reflux, the cold org. phase was
concentrated. The residue was diluted in AcOEt (20 ml), filtered,
concentrated, and then purified by CC (SiO2; CH2Cl2) to afford pure
(E)-3. Yield: 31%. Fruity, lactonic, fatty, not interesting39). IR: 2963,
2933, 2875, 1698, 1629, 1442, 1404, 1375, 1351, 1241, 1171, 1109, 1050,
1001, 937, 789, 738, 675. 1H-NMR: 5.62 (dq, J ¼ 15, 6.5, 1 H); 5.07 (ddq,
J ¼ 15, 8.5, 1.6, 1 H); 2.32 (t, J ¼ 7, 2 H); 2.06 – 1.90 (m, 5 H); 1.70 (dd,
J ¼ 6.5, 1.6, 3 H); 1.48 (dd, J ¼ 8.5, 3.6, 1 H); 0.86 (dd, J ¼ 6.5, 3.6, 1 H).
13C-NMR: 218.6 (s); 128.4 (d); 128.1 (d); 38.7 (t); 35.9 (s); 31.8 (d); 27.7
(t); 23.0 (t); 21.0 (t); 18.1 (q). MS: 150 (52, Mþ), 135 (25), 121 (98), 107
(20), 94 (42), 91 (31), 79 (100), 77 (30), 67 (17), 55 (11), 39 (11).
2-[(2Z)-Pent-2-en-1-yl]cyclopent-2-en-1-one (4). A 85 :15 mixture
of thermodynamic/kinetic trimethylsilyl enol ethers 18/17a (80 mg,
0.356 mmol) was treated as described for 13b to afford a 32 :56 :12
mixture of 14a/4/(E,E)-12a in 75% yield, further isomerized with DBU
as described for 6a to afford a 87:13 mixture of 4/(E,E)-12a in 90%
yield. This mixture was also obtained from pure 14a with 0.2 mol-equiv.
of DBU as described for 6a. Yield: 91%. Alternatively, a soln. of 2h
(120 mg, 0.788 mmol) in DMF (2 ml) was added dropwise to a
suspension of CuCl2 · 2 H2O (660 mg, 3.87 mmol) and LiCl (66 mg,
1.56 mmol) in DMF (8 ml) at 808. After 6 h, the cold mixture was
poured into H2O (40 ml) and extracted with hexane. The org. phase was
washed with brine and dried (Na2SO4) to afford quantitatively a 80 :20
mixture of 4/(E,E)-12a. Purification by CC (SiO2; cyclohexane/AcOEt
96 :4) afforded pure 4. Yield: 34%. For analyses, see [3][6r].
Methyl 2-Oxo-3-(pent-2-yn-1-yl)cyclopentanecarboxylate (5d). In
a 2-l Schmizo reactor, MeONa (30% in MeOH, 225 g, 1249 mmol) in
xylene (800 ml) was heated from 110 to 1458 to distill the MeOH off.
The temp. was adjusted to 708 and N-methylpyrrolidone (66 g) was
added, followed by addition of dimethyl adipate (200 g, 1149 mmol)
within 0.5 h, the mixture was heated for 3 h from 100 to 1458 to distill
the formed MeOH off, then 1-chloropent-2-yne (113 g, 1102 mmol) was
added at 1008 within 0.5 h, and the mixture was further stirred at 1008
for 17 h. MeONa (30% in MeOH, 214 g, 1188 mmol) was added within
0.5 h at 708, and the mixture was heated at 1108 to distill off MeOH.
After 2 h, the dark brown soln. was cooled down to 258 and AcOH
(162 g) was added, followed by H2O (380 g). The aq. phase was
removed, and the org. phase was washed with H2O (2 Â 150 g). The org.
phase was concentrated and then distilled to afford 5d as 2 :1 mixture of
diastereoisomers. Yield: 94%. Alternatively, in a 2-l Schmizo reactor,
MeONa (30% in MeOH, 225 g, 1249 mmol) and 5a (239 g, 1150 mmol)
in xylene (800 ml) were heated from 110 to 1458 to distill the MeOH
off. After 2 h the dark brown soln. was cooled down to 258 and AcOH
(162 g) was added, followed by H2O (380 g). The aq. phase was
removed and the org. phase was washed with H2O (2 Â 150 g). The org.
phase was concentrated and then distilled to afford 5d as 2 :1 mixture of
diastereoisomers. Yield: 81%. IR: 2974, 2952, 2925, 2878, 2850, 1754,
1726, 1448, 1435, 1346, 1335, 1321, 1298, 1254, 1199, 1177, 1136, 1111,
1044, 980, 964, 880, 786. 1H-NMR (major diastereoisomer): 3.74 (s,
3 H); 3.14 (dd, J ¼ 11.2, 8.3, 1 H); 2.49 – 2.46 (m, 1 H); 2.44 – 2.30 (m,
4 H); 2.22 – 2.16 (m, 1 H); 2.12 (tq, J ¼ 7.4, 2.5, 2 H); 1.85 – 1.75 (m,
1
1 H); 1.09 (t, J ¼ 7.4, 3 H). H-NMR (minor diastereoisomer): 3.72 (s,
3 H); 3.32 (dd, J ¼ 8.3, 5.4, 1 H); 2.53 – 2.50 (m, 1 H); 2.44 – 2.30 (m,
4 H); 2.25 – 2.16 (m, 3 H); 1.85 – 1.75 (m, 1 H); 1.09 (t, J ¼ 7.4, 3 H).
13C-NMR: 211.8 (s); 169.2 (s); 83.2 (s); 76.1 (s); 54.0 (d); 52.4 (q); 48.0
(d); 27.0 (t); 24.8 (t); 19.3 (t); 14.2 (q); 12.4 (t). MS (major
diastereoisomer): 208 (0, Mþ), 135 (19), 122 (100), 107 (50), 93 (14),
91 (29), 79 (53), 77 (28), 65 (10), 55 (13), 41 (11), 39 (15). MS (minor
diastereoisomer): 208 (0, Mþ), 135 (19), 122 (100), 107 (46), 93 (14), 91
(29), 79 (53), 77 (29), 67 10), 65 (10), 55 (12), 41 (12), 39 (16).
Prop-2-en-1-yl 2-Oxo-3-(pent-2-yn-1-yl)cyclopentanecarboxylate
(5e). A mixture of 5d (558 mg, 2.68 mmol), prop-2-en-1-ol (156 mg,
2.68 mmol) and (Oct)2SnO (29 mg, 0.081 mmol) in cyclohexane (5 ml)
was heated under reflux for 1 h, and MeOH was distilled off. The cold
mixture was concentrated and then purified by CC (SiO2; cyclohexane/
AcOEt 9 :1) to afford 5e. Yield: 72%. IR: 2974, 2938, 2878, 1753, 1725,
1663, 1452, 1366, 1321, 1296, 1238, 1182, 1134, 1111, 978, 931, 785.
1H-NMR (major diastereoisomer): 5.97 – 5.86 (m, 1 H); 5.35 (dq, J ¼ 17,
1.5, 1 H); 5.24 (dq, J ¼ 10.2, 1.3, 1 H); 4.70 – 4.58 (m, 1 H); 3.16 (dd, J ¼
11.2, 8.4, 1 H); 2.56 – 2.47 (m, 1 H); 2.45 – 2.07 (m, 8 H); 1.86 – 1.75 (m,
Methyl 2-Oxo-1-(pent-2-yn-1-yl)cyclopentanecarboxylate (5a). In
a 2-l Schmizo reactor, a suspension of K2CO3 (280 g, 2.03 mol), 2b
(200 g, 1.35 mol), and pent-2-yn-1-yl methanesulfonate [15]40) (219 g,
1.35 mol) in acetone (1000 g) was heated at 608 for 20 h. Acetone was
then distilled off under 400 mbar and the mixture was finally cooled to
258. Toluene (250 g) and H2O (800 g) were added. The org. phase was
washed with H2O (2 Â 300 g), concentrated, and then purified by
distillation to afford pure 5a. Yield: 95%. Jasmine, Hedioneꢃ, green,
1
paper37). For H- and 13C-NMR analyses, see [20]. B.p. 1208/0.06 hPa.
IR: 2974, 2955, 2919, 1753, 1727, 1434, 1404, 1321, 1244, 1227, 1189,
1151, 1137, 1106, 1008, 925, 835, 783, 688, 620. MS: 208 (3, Mþ), 193
(12), 180 (10), 177 (12), 165 (8), 152 (47), 149 (100), 147 (32), 137 (14),
121 (14), 109 (15), 105 (21), 93 (27), 91 (51), 79 (22), 77 (28), 65 (10),
55 (13), 41 (12), 39 (11).
1
1 H); 1.09 (t, J ¼ 7.4, 3 H). H-NMR (minor diastereoisomer): 5.97 –
5.86 (m, 1 H); 5.33 (dq, J ¼ 17.1, 1.5, 1 H); 5.24 (dq, J ¼ 10.2, 1.3,
1 H); 4.70 – 4.58 (m, 1 H); 3.33 (dd, J ¼ 8.2, 5.3, 1 H); 2.56 – 2.47 (m,
1 H); 2.45 – 2.07 (m, 8 H); 1.86 – 1.75 (m, 1 H); 1.10 (t, J ¼ 7.4, 3 H).
13C-NMR (major diastereoisomer): 211.2 (s); 169.0 (s); 131.8 (d); 118.5
(t); 83.5 (s); 75.8 (s); 65.9 (t); 55.2 (d); 48.2 (d); 26.2 (t); 25.0 (t) 18.9 (t);
14.2 (q); 12.3 (t). 13C-NMR (minor diastereoisomer): 211.6 (s); 168.5
(s); 131.7 (d); 118.4 (t); 83.2 (s); 76.1 (s); 65.9 (t); 54.1 (d); 48.1 (d); 27.0
(t); 24.8 (t); 19.3 (t); 14.2 (q); 12.4 (t). MS: 234 (0, Mþ), 135 (18), 122
(100), 107 (47), 93 (13), 91 (23), 79 (52), 77 (22), 55 (11), 41 (10), 39
(12).
2-(Pent-2-yn-1-yl)cyclopentanone (5c). To a 2-l Schmizo reactor
containing Marlotherm SH (125 g) and 5d (25 g, 120.2 mmol) at 1508,
5d (225 g, 1082 mmol) and H2O (24 g, 1333 mmol) were simultaneously
added within 3 h, with the aid of an immersed long needle. After further
0.5 h, the mixture was cooled to 258, and the crude material was
distilled to furnish pure 5c. Yield: 84%. Alternatively, a mixture of 5a
(120 mg, 0.576 mmol) and LiOH (179 mg, 7.49 mmol) in THF (5 ml)
and H2O (1 ml) was stirred at 208 for 2 h. The mixture was acidified
with 1n aq. HCl and extracted with Et2O. The org. phase was dried
(Na2SO4) and then concentrated to afford pure 5c. Yield: 95%.
40) This reagent exhibits the following analytical data: 13C-NMR: 92.3 (s); 71.7 (s); 58.6 (t); 39.0 (q); 13.3 (q); 12.4 (t). MS: 162 (0, Mþ), 147 (20), 97 (17), 83
(49), 79 (41), 67 (94), 66 (74), 65 (84), 63 (15), 57 (100), 55 (45), 53 (22), 51 (20), 41 (58), 39 (50).
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Helv. Chim. Acta 2016, 99, 95 – 109
103
Methyl 3-Chloro-2-oxo-3-(pent-2-yn-1-yl)cyclopentanecarboxylate
(5f). A soln. of SO2Cl2 (0.561 g, 4.16 mmol) in CH2Cl2 (5 ml) was
added to a soln. of 5d (0.866 g, 4.16 mmol) in CH2Cl2 (20 ml) at 208.
After 2 h, the mixture was poured into H2O, washed with sat. aq.
NaHCO3 and brine, dried (Na2SO4), and concentrated to afford crude
5f as 3 :2 mixture of major diastereoisomers. Yield: 94%. The main
diastereoisomer deduced from the mixture showed the following
analytical data. IR: 2976, 2953, 2938, 2877, 1734, 1671, 1630, 1446, 1321,
1233, 1211, 1197, 1148, 1031, 979, 880, 853, 780, 735, 700, 668. 1H-NMR:
3.80 (s, 3 H); 2.91 (t, J ¼ 2.2, 1 H); 2.62 – 2.29 (m, 6 H); 2.17 – 2.11 (m,
2 H); 1.09 (t, J ¼ 7.2, 3 H). 13C-NMR: 202.7 (s); 170.4 (s); 85.0 (s); 75.0
(s); 73.7 (s); 52.8 (d); 51.6 (q); 36.0 (t); 30.5 (t); 24.4 (t); 14.0 (q); 12.4
(t). MS: 242 (0, Mþ), 148 (92), 147 (83), 105 (31), 91 (100), 79 (12), 77
(16), 65 (12), 51 (12).
229 (2, Mþ), 227 (2), 167 (11), 140 (29), 137 (12), 125 (11), 109 (14), 97
(12), 84 (34), 81 (12), 79 (10), 57 (79), 55 (22), 41 (11), 39 (10), 32
(33), 28 (100).
2-Chloro-2-(pent-2-yn-1-yl)cyclopentanone (5l). A soln. of SO2Cl2
(4.94 g, 2.97 ml, 36.6 mmol) in toluene (5 ml) was added dropwise to a
soln. of 5c (5.0 g, 33.3 mmol) in toluene (15 ml) at < 308. After 2.5 h at
208, H2O was added at 08. The mixture was washed with sat. aq.
NaHCO3 and brine, dried (Na2SO4), and concentrated to afford 5l after
bulb-to-bulb distillation. Yield: 43%. B.p. 1008/0.05 mbar. IR: 2976,
2938, 2917, 1751, 1614, 1461, 1438, 1422, 1402, 1374, 1323, 1259, 1242,
1198, 1160, 1147, 1112, 1005, 937, 924, 894, 799, 776, 716, 661. 1H-NMR:
2.81 (t, J ¼ 2.5, 2 H); 2.62 – 2.11 (m, 8 H); 1.10 (t, J ¼ 7.4, 3 H).
13C-NMR: 210.0 (s); 85.2 (s); 73.7 (s); 69.4 (s); 37.2 (t); 35.6 (t); 27.5
(t); 18.3 (t); 14.0 (q); 12.3 (t). MS: 184 (2, Mþ), 149 (100), 105 (17), 93
(16), 91 (38), 79 (16), 77 (25).
2-Hydroxy-5-(pent-2-yn-1-yl)cyclopentanone (5g). A 55:(23 :22)
mixture of 5j/5i (1.2 g, 5.759 mmol) and LiOH (0.538 g, 22.47 mmol) in
THF (10 ml) and H2O (2 ml) was stirred for 4 h at 208. The mixture was
diluted with H2O (10 ml) and extracted with Et2O. The org. phase was
washed with brine, dried (Na2SO4), and then concentrated to afford
quantitatively a 55:(23 :22) mixture of 5h/5g. Purification by CC (SiO2;
cyclohexane/AcOEt 8 :2) afforded pure 5g. Yield: 1.6% (9 :1 mixture
of diastereoisomers). 1H-NMR: 3.94 (dd, J ¼ 11.2, 1.7, 1 H); 2.77 (br. s,
OH); 2.55 – 2.42 (m, 3 H); 2.37 – 2.29 (m, 1 H); 2.25 – 1.98 (m, 4 H);
1.81 – 1.75 (m, 1 H); 1.13 (t, J ¼ 7.5, 3 H). 13C-NMR: 217.2 (s); 84.7 (s);
79.0 (d); 75.3 (s); 42.3 (d); 33.7 (t); 21.5 (t); 21.4 (t); 14.3 (q); 12.4 (t).
MS (major diastereoisomer): 166 (2, Mþ), 137 (24), 123 (14), 110 (64),
107 (14), 105 (15), 99 (80), 95 (100), 93 (10), 91 (29), 81 (62), 79 (63),
77 (29), 67 (48), 65 (14), 57 (27), 55 (22), 53 (20), 51 (11), 43 (14), 41
(30), 39 (27), 29 (12), 27 (11). MS (minor diastereoisomer): 166 (2,
Mþ), 137 (19), 123 (12), 110 (32), 107 (13), 105 (16), 99 (83), 95 (52),
93 (17), 91 (33), 81 (34), 79 (100), 77 (50), 67 (41), 65 (14), 57 (13), 55
(25), 53 (14), 51 (10), 43 (13), 41 (27), 39 (22), 29 (9), 27 (13).
2-Hydroxy-2-(pent-2-yn-1-yl)cyclopentanone (5h). See above,
pure 5h was isolated during the chromatographic purification of 5g.
Yield: 5%. 1H-NMR: 2.80 (br. s, OH); 2.45 (dt, J ¼ 2.4, 1.6, 2 H); 2.38 –
2.34 (m, 2 H); 2.28 – 2.23 (m, 1 H); 2.17 (tq, J ¼ 7.5, 2.3, 2 H); 2.04 – 1.96
(m, 2 H); 1.93 – 1.85 (m, 1 H); 1.12 (t, J ¼ 7.5, 3 H). 13C-NMR: 218.1 (s);
85.1 (s); 77.6 (s); 73.2 (s); 35.4 (t); 34.8 (t); 27.1 (t); 17.4 (t); 14.1 (q);
12.4 (t). MS: 166 (41, Mþ), 138 (32), 122 (12), 110 (26), 98 (14), 95
(25), 91 (14), 81 (100), 71 (32), 67 (42), 57 (21), 55 (14), 53 (28), 43
(22), 42 (20), 41 (18), 39 (17).
Methyl 3-Bromo-2-oxo-1-(pent-2-yn-1-yl)cyclopentanecarboxylate
(5m). NBS (1.47 g, 8.28 mmol) was added in five portions to a soln. of
8d (1172 mg, 6.84 mmol) in THF (10 ml) and H2O (0.9 ml) at 68 in the
dark. After 1 h the mixture was poured into brine and extracted with
CH2Cl2. The org. phase was washed with H2O, dried (Na2SO4), and
then concentrated to afford crude 5m. Yield: 97% (4 :1 mixture of
diastereoisomers). Alternatively, H2SO4 (210 mg, 2.16 mmol) was
added dropwise to a soln. of 5a (150 mg, 0.72 mmol) in AcOH (3 ml)
at 208. A mixture of KBr (214 mg, 1.8 mmol) and KBrO3 (60 mg,
0.36 mmol) was then added portionwise. After 18 h at 208, the mixture
was filtered and diluted with CH2Cl2. Extraction with H2O, 15% aq.
NaHCO3, and then addition of H2O until neutrality, afforded pure 5m.
Yield: 63% (3 :1 mixture of diastereoisomers). IR (major diaster-
eoisomer): 2976, 2954, 2879, 1759, 1722, 1434, 1367, 1320, 1241, 1206,
1176, 1159, 1138, 1112, 1062, 1004, 977, 933, 917, 871, 833, 795, 768, 747,
661, 631. 1H-NMR: 4.50 (dd, J ¼ 7.1, 5.3, 1 H); 3.72 (s, 3 H); 2.78 (tq, J ¼
16.9, 2.4, 2 H); 2.70 – 2.60 (m, 1 H); 2.56 – 2.45 (m, 2 H); 2.36 – 2.28 (m,
1 H); 2.16 – 2.10 (m, 2 H); 1.10 (t, J ¼ 7.4, 3 H). 13C-NMR (major
diastereoisomer): 206.1 (s); 170.1 (s); 85.0 (s); 74.0 (s); 58.7 (s); 53.1
(q); 47.2 (d); 31.3 (t); 30.5 (t); 24.9 (t); 13.9 (q); 12.4 (t). 13C-NMR
(minor diastereoisomer deduced from the mixture): 206.2 (s); 170.0 (s);
85.3 (s); 68.0 (s); 57.2 (s); 53.1 (q); 47.5 (d); 31.1 (t); 29.6 (t); 24.5 (t);
14.1 (q); 12.3 (t). MS: 287 (0, Mþ), 229 (17), 227 (16), 207 (100), 179
(18), 175 (40), 152 (35), 148 (32), 147 (43), 137 (16), 133 (14), 119
(26), 109 (21), 105 (24), 93 (13), 91 (53), 79 (14), 77 (27), 65 (14), 59
(10), 55 (20), 41 (13), 39 (12).
2-Oxo-3-(pent-2-yn-1-yl)cyclopentyl Acetate (5i). AcOOH (39%
in AcOH, 2.62 g, 13.42 mmol) was added dropwise within 3 h to a
45 :55 mixture of 8a/7a (2.0 g, 10.4 mmol) and NaHCO3 (1.31 g,
15.6 mmol) in toluene (15 ml) at 358. The cold mixture was washed with
H2O and then sat. aq. NaHCO3, dried (Na2SO4), and concentrated to
afford quantitatively a 55:(23 :22) mixture of 5j/5i as a ca. 1:1 mixture
for the latter. MS (1st diastereoisomer): 208 (1, Mþ), 165 (14), 148 (89),
137 (10), 133 (13), 130 (17), 109 (22), 105 (11), 95 (13), 93 (14), 91
(28), 86 (10), 79 (29), 77 (20), 67 (17), 55 (13), 43 (100), 41 (13), 39
(11). MS (2nd diastereoisomer): 208 (1, Mþ), 165 (23), 148 (54), 137
(9), 133 (11), 130 (35), 109 (22), 105 (11), 95 (12), 93 (13), 91 (28), 86
(10), 79 (28), 77 (19), 67 (17), 55 (13), 43 (100), 41 (13), 39 (10).
2-Oxo-1-(pent-2-yn-1-yl)cyclopentyl Acetate (5j). See 5i. Obtained
pure after CC (SiO2; cyclohexane/AcOEt 99 :1 to 9 :1). Yield: 9%.
1H-NMR: 2.76 (dt, J ¼ 7.2, 3, 1 H); 2.67 (quint., J ¼ 9.3, 2 H); 2.52 (dt,
J ¼ 8.2, 2.5, 2 H); 2.46 – 2.23 (m, 2 H); 2.16 (tq, J ¼ 7.5, 2.3, 2 H), 2.04 (s,
3 H); 1.98 – 1.88 (m, 1 H); 1.12 (t, J ¼ 7.5, 3 H). 13C-NMR: 214.4 (s);
169.8 (s); 84.8 (s); 82.7 (s); 72.8 (s); 36.3 (t); 32.2 (t); 26.3 (t); 20.7 (q);
18.2 (t); 14.0 (q); 12.4 (t). MS: 208 (0.5, Mþ), 148 (100), 147 (54), 137
(10), 105 (18), 95 (18), 91 (47), 81 (16), 77 (10), 67 (11), 43 (45).
2-Bromo-2-(pent-2-yn-1-yl)cyclopentanone (5k). Compound 5 was
obtained and used crude when a 7:3 mixture of 7c/8c was treated with
NBS in THF/H2O at 68. The following analytical data were tentatively
deduced from the crude mixture. 1H-NMR: 3.05 – 3.02 (m, 2 H); 2.94 –
1.70 (m, 8 H); 1.09 (t, J ¼ 7.1, 3 H). 13C-NMR: 209.9 (s); 85.8 (s); 74.4
(s); 64.9 (s); 36.9 (t); 35.0 (t); 29.0 (t); 15.7 (t); 14.3 (q); 12.9 (t). MS:
Methyl 3-Chloro-2-oxo-1-(pent-2-yn-1-yl)cyclopentanecarboxylate
(5n). NCS (913 mg, 6.84 mmol) was added portionwise to a soln. of 8d
(2000 mg, 6.84 mmol) in THF (10 ml) and H2O (0.86 ml) at 68 in
absence of light. After 1 h at 68, the mixture was poured onto ice and
then extracted with CH2Cl2. The org. phase was dried (Na2SO4) and
then concentrated to afford quantitatively crude 5n, used as such for the
next step. For anal. purpose, CC (SiO2; cyclohexane/AcOEt 93 :7)
afforded pure 5n. Yield: 50%. IR: 2976, 2954, 2920, 2879, 2848, 1766,
1732, 1434, 1319, 1217, 1162, 1136, 1113, 1073, 1007, 980, 919, 872, 841,
799, 787. 1H-NMR: 4.42 (t, J ¼ 8.1, 1 H); 3.72 (s, 3 H); 2.77 (tq, J ¼ 14.5,
2.3, 2 H); 2.59 (dq, J ¼ 13.8, 6.6, 1 H); 2.48 (t, J ¼ 6.6, 2 H); 2.22 (dq, J ¼
15.3, 7.9, 1 H); 2.13 (tq, J ¼ 7.6, 2.6, 2 H); 1.09 (t, J ¼ 7.6, 3 H).
13C-NMR: 205.7 (s); 170.3 (s); 84.8 (s); 73.9 (s); 58.4 (d); 57.8 (s); 53.1
(q); 30.6 (t); 29.7 (t); 24.4 (t); 13.9 (q); 12.3 (t). MS: 242 (1, Mþ), 211
(7), 207 (6), 185 (23), 183 (58), 179 (42), 152 (100), 149 (13), 147 (47),
137 (28), 119 (21), 109 (26), 105 (16), 93 (18), 91 (58), 79 (18), 77 (34),
65 (19), 59 (13), 55 (13), 53 (11), 51 (12), 41 (17), 39 (16), 28 (14).
2-(Pent-2-yn-1-yl)cyclopent-2-en-1-one (6a). A mixture of 13a
(150 mg, 0.977 mmol) and DBU (30 mg, 0.195 mmol) in toluene was
heated under reflux for 2 h. The cold mixture was concentrated and
then purified by CC (SiO2; cyclohexane/AcOEt 97:3) to afford pure
6a. Yield: 90%. Compound 6a was also obtained after CC (SiO2)
purification of a 70 :30 mixture of 6a/11a obtained by dehydrohaloge-
nating 5l with LiBr in DMF at 808. Yield: 36%. For analyses, see
[3][6j][7a][7d][7e][7i]. Jasmine absolute, osmanthus, violet leaf37).
ꢁ 2016 Verlag Helvetica Chimica Acta AG, Zürich
www.helv.wiley.com

104
Helv. Chim. Acta 2016, 99, 95 – 109
2-(Pent-2-yn-1-yl)cyclopent-1-en-1-yl Acetate (7a). Ac2O (50 g,
soln. of 5c (2.7 g, 17.97 mmol) in THF (20 ml) followed, after 45 min,
by Me3SiCl (5.62 g, 51.8 mmol) were added. The temp. was adjusted to
208 and after 0.5 h, the mixture was washed with sat. aq. NaHCO3. The
aq. phase was washed with Et2O (2 Â 25 ml), and the org. phase was
dried (Na2SO4), concentrated, and then purified by CC (SiO2; cyclo-
hexane/AcOEt 9 :1) to afford pure 8c after bulb-to-bulb distillation.
Yield: 71%. B.p. 1008/1.1 mbar. IR: 2957, 2849, 1644, 1450, 1341, 1264,
1251, 1207, 1134, 1045, 1033, 885, 867, 839, 751, 691, 626. 1H-NMR: 4.62
(q, J ¼ 1.9, 1 H); 2.64 – 2.56 (m, 1 H); 2.39 (dquint., J ¼ 16.3, 2.3, 1 H);
2.29 – 2.04 (m, 6 H); 1.76 – 1.67 (m, 1 H); 1.11 (t, J ¼ 7.3, 3 H); 0.21 (s,
9 H). 13C-NMR: 155.9 (s); 102.0 (d); 82.0 (s); 78.0 (s); 44.5 (d); 27.2 (t);
27.0 (t); 22.5 (t); 14.4 (q); 12.5 (t); 0.0 (3q). MS: 222 (9, Mþ), 207 (13),
194 (52), 165 (17), 155 (32), 75 (14), 73 (100), 45 (7).
0.5 mol) was added dropwise to a mixture of 5c (35 g, 0.2 mol) and
TsOH (0.35 g, 0.002 mol) at 1508, and AcOH was distilled off using a
Vigreux column. After 20 h, another portion of Ac2O (45 g, 0.44 mol)
was added dropwise and distillation was carried out under 800 mbar.
After a total of 26 h, the residue was distilled under reduced pressure to
afford a 81:19 mixture of 7a/8a. Yield: 74%. B.p. 508/0.2 mbar. IR:
2973, 2937, 2853, 1750, 1433, 1369, 1201, 1183, 1029, 886. 1H-NMR: 2.88
(br. s, 2 H); 2.53 – 2.47 (m, 2 H); 2.45 – 2.39 (m, 2 H); 2.18 – 2.11 (m,
2 H); 2.15 (s, 3 H); 1.93 (quint., J ¼ 7.5, 2 H); 1.11 (t, J ¼ 7.2, 3 H).
13C-NMR: 168.7 (s); 144.4 (s); 122.1 (s); 82.0 (s); 75.4 (s); 31.2 (t); 31.1
(t); 20.8 (q); 19.5 (t); 16.7 (t); 14.2 (q); 12.4 (t). MS: 192 (3, Mþ), 150
(25), 135 (18), 122 (30), 107 (10), 95 (9), 83 (100), 55 (19), 43 (30).
2-(Pent-2-yn-1-yl)cyclopent-1-en-1-yl Propanoate (7b)41). Propa-
noic anhydride (65 g, 0.5 mol) was added dropwise to a mixture of 5c
(25 g, 0.2 mol) and TsOH (0.3 g, 0.001 mol) at 1608, and propanoic acid
was distilled off using a Vigreux column. After a total of 8 h, the residue
was distilled under reduced pressure to afford a 4 :1 mixture of 7b/8b in
33% yield, as well as pure 7b in 26% yield. B.p. 90 – 978/0.2 mbar. IR:
2974, 2938, 2878, 2854, 1757, 1701, 1461, 1421, 1352, 1334, 1321, 1300,
Methyl 2-(Acetyloxy)-1-(pent-2-yn-1-yl)cyclopent-2-ene-1-carbox-
ylate (8d). A mixture of 5a (0.7 g, 3.06 mmol), prop-1-en-2-yl acetate
(1.53 g, 15.3 mmol), and TsOH (15 mg, 0.087 mmol) was heated at 908
and acetone was slowly distilled off within 18 h. The reaction volume
was maintained by adding prop-1-en-2-yl acetate (1.53 g, 15.3 mmol).
The cold mixture was washed with sat. aq. NaHCO3. The aq. phase was
extracted with Et2O (3 Â 10 ml). The org. phase was then washed with
brine, dried (Na2SO4), concentrated, and purified by CC (SiO2;
cyclohexane/AcOEt 96 :4 to 9 :1) to afford pure 8d in 52% yield,
besides recovered 5a (21%). When this reaction was repeated with a
reaction time of 7 d, complete conversion was obtained and 8d was
isolated in 72% yield after distillation. B.p. 1158/0.08 mbar. IR: 2975,
2938, 2857, 1763, 1731, 1434, 1369, 1320, 1250, 1196, 1179, 1066, 1050,
1
1268, 1182, 1145, 1077, 1063, 1026, 973, 869, 805. H-NMR: 2.88 (br. s,
2 H); 2.53 – 2.46 (m, 2 H); 2.45 – 2.39 (m, 2 H); 2.37 – 2.27 (m, 2 H);
2.18 – 2.10 (m, 2 H); 1.93 (quint., J ¼ 7.2, 2 H); 1.18 (t, J ¼ 7.6, 3 H); 1.10
(t, J ¼ 7.3, 3 H). 13C-NMR: 172.0 (s); 144.5 (s); 121.8 (s); 82.0 (s); 75.5
(s); 31.3 (t); 31.1 (t); 27.5 (t); 19.6 (t); 16.7 (t); 14.2 (q); 12.4 (t); 9.1 (q).
MS: 206 (5, Mþ), 150 (100), 149 (45), 135 (31), 132 (22), 122 (80), 121
(64), 107 (30), 91 (21), 79 (19), 57 (53), 25 (17).
1
1007, 878, 802, 715. H-NMR: 5.78 (t, J ¼ 2.5, 1 H); 3.70 (s, 3 H); 2.68
Trimethyl{[2-(pent-2-yn-1-yl)cyclopent-1-en-1-yl]oxy}silane (7c).
Me3SiCl (3.98 g, 36.6 mmol) was added dropwise to a soln. of 5c
(5.0 g, 33.3 mmol) and Et3N (6.74 g, 66.6 mmol) in DMF (30 ml) at 208.
After 18 h at 1308, the cold mixture was diluted with Et2O (50 ml),
extracted with 10% aq. HCl (2 Â 20 ml), washed with sat. aq. NaHCO3
and brine, dried (Na2SO4), and concentrated to afford a 7:3 mixture of
7c/8c in 74% yield, still contaminated by 10% of 5c. Purification by CC
(SiO2; cyclohexane/AcOEt 98 :2) afforded a 7:3 mixture of 7c/8c.
Yield: 49%. The following anal. data were deduced from this mixture.
IR: 2957, 2937, 1686, 1448, 1341, 1312, 1251, 1207, 1045, 1033, 885, 867,
839, 751. 1H-NMR: 2.89 (br. s, 2 H); 2.34 – 2.27 (m, 4 H); 2.14 (tq, J ¼
7.5, 2.5, 2 H); 1.82 (quint., J ¼ 7.5, 2 H); 1.10 (t, J ¼ 7.4, 3 H); 0.18 (s,
9 H). 13C-NMR: 147.0 (s); 112.5 (s); 81.1 (s); 77.1 (s); 33.8 (t); 30.7 (t);
19.5 (t); 16.3 (t); 14.4 (q); 12.5 (t); 0.63 (3q). MS: 222 (68, Mþ), 207
(25), 193 (20), 179 (27), 155 (14), 111 (11), 91 (10), 75 (30), 73 (100),
45 (13).
5-(Pent-2-yn-1-yl)cyclopent-1-en-1-yl Acetate (8a). A mixture of
5c (10 g, 66.6 mmol), prop-1-en-2-yl acetate (13.2 g, 132 mmol), and
TsOH (0.115 g, 0.666 mmol) was heated to 1008, while acetone was
slowly distilled off using a Vigreux column within 20 h. The cold
mixture was washed with sat. aq. NaHCO3. The aq. phase was extracted
with Et2O, and the org. phase was washed with H2O, dried (Na2SO4),
and concentrated to afford quantitatively a 45 :55 chromatographically
inseparable mixture of 8a/7a. For analytical purposes, pure 8a was
obtained by Fischer distillation. Yield: 6%. B.p. 100 – 1358/0.1 mbar. IR:
2973, 2937, 2855, 1753, 1432, 1368, 1194, 1166, 1030, 1012, 905, 883, 819.
1H-NMR: 5.51 (q, J ¼ 2, 1 H); 2.98 – 2.91 (m, 1 H); 2.50 – 2.31 (m, 4 H);
2.21 – 2.12 (m, 3 H); 2.10 (s, 3 H); 1.80 – 1.73 (m, 1 H); 1.11 (t, J ¼ 7.3,
3 H). 13C-NMR: 168.7 (s); 151.6 (s); 114.0 (d); 82.4 (s); 77.2 (s); 42.7
(d); 27.2 (2t); 22.6 (t); 21.1 (q); 14.3 (q); 12.5 (t). MS: 192 (4, Mþ), 150
(100), 149 (40), 135 (27), 122 (70), 121 (66), 107 (38), 93 (11), 91 (28),
79 (30), 77 (20), 55 (10), 43 (30).
(dt, J ¼ 16.6, 2.5, 1 H); 2.55 (dt, J ¼ 16.6, 2.5, 1 H); 2.52 – 2.37 (m, 2 H);
2.16 – 2.09 (m, 4 H); 2.14 (s, 3 H); 1.08 (t, J ¼ 7.4, 3 H). 13C-NMR: 174.0
(s); 168.2 (s); 147.6 (s); 116.9 (d); 83.7 (s); 75.0 (s); 57.7 (s); 52.4 (q);
31.4 (t); 27.2 (t); 25.2 (t); 21.1 (q); 14.2 (q); 12.4 (t). MS: 250 (4, Mþ),
208 (20), 191 (33), 180 (64), 153 (16), 149 (58), 148 (54), 147 (23), 141
(20), 133 (13), 131 (10), 121 (18), 109 (100), 105 (13), 93 (12), 91 (29),
79 (11), 77 (16), 55 (22), 43 (43).
Methyl 1-(Pent-2-yn-1-yl)-2-[(trimethylsilyl)oxy]cyclopent-2-ene-
1-carboxylate (8e). Me3SiCl (2.035 g, 18.73 mmol) was added to a
suspension of NaI (4.32 g, 28.8 mmol) in MeCN (6 ml) at 08. After
0.15 h, Et3N (2.92 g, 28.8 mmol) followed by a soln. of 5a (3.0 g,
14.41 mmol) in MeCN (4 ml) were added dropwise. After 0.5 h at 758,
the mixture was poured into sat. aq. NaHCO3 and then extracted with
Et2O (3 Â 20 ml). The org. phase was dried (Na2SO4), concentrated,
and purified by bulb-to-bulb distillation to afford pure 8e. Yield: 82%.
B.p. 1208/0.4 mbar. IR: 2951, 2912, 2859, 1732, 1650, 1434, 1320, 1251,
1239, 1218, 1167, 1071, 1057, 842, 780, 753. 1H-NMR: 4.75 (t, J ¼ 2.1,
1 H); 3.69 (s, 3 H); 2.68 (dt, J ¼ 16.6, 2.4, 1 H); 2.48 (dt, J ¼ 16.6, 2.4,
1 H); 2.40 – 2.26 (m, 3 H); 2.15 – 2.06 (m, 3 H); 1.09 (t, J ¼ 7.5, 3 H);
0.19 (s, 9 H). 13C-NMR: 175.0 (s); 153.1 (s); 103.9 (d); 82.9 (s); 76.1 (s);
58.3 (s); 52.0 (q); 31.6 (t); 26.7 (t); 24.6 (t); 14.3 (q); 12.5 (t); À 0.1
(3q). MS: 280 (25, Mþ), 265 (22), 252 (28), 237 (92), 221 (34), 213
(13), 197 (31), 181 (21), 109 (100), 107 (11), 89 (10), 75 (10), 73 (77),
45 (9).
5-(Pent-2-yn-1-yl)-6-oxabicyclo[3.1.0]hex-1-yl Acetate (9a).
AcOOH (31.5% in H2O, 20 g, 0.0825 mol) was added dropwise to a
9 :1 mixture of 7a/8a (10 g, 0.05 mol) and NaHCO3 (6.5 g, 0.08 mol) in
toluene (5 ml) at 358. After 3 h, the cold mixture was diluted with H2O
(5 ml). The org. phase was washed with sat. aq. NaHCO3, 10% aq.
Na2SO3, and sat. aq. NaHCO3, dried (Na2SO4), concentrated, and then
the ca. 90 :5 :5 mixture of diastereoisomers (95%) was used as such in
the next step. For analytical purposes, an aliquot was purified by CC
(SiO2; cyclohexane/AcOEt 99 :1 to 8 :2) to afford pure 9a. Yield: 81%.
IR: 2975, 2940, 2855, 1758, 1462, 1335, 1321, 1185, 1148, 1080. 1H-NMR:
2.57 (q, J ¼ 2.2, 1 H); 2.41 (dd, J ¼ 13.2, 8.5, 1 H); 2.17 (tq, J ¼ 7.7, 2.5,
Trimethyl{[5-(pent-2-yn-1-yl)cyclopent-1-en-1-yl]oxy}silane (8c).
A soln. of BuLi (1.6m, 35.7 ml, 57.2 mmol) was added to a soln. of
HN(iPr)2 (5.78 g, 57.2 mmol) in THF (80 ml) at À 788. After 30 min, a
41) Its regioisomer, 8b, exhibits an olefinic signal at d(H) 5.52 (q, J ¼ 2.2, 1 H) in the 1H-NMR spectrum. The following spectral analytical data were deduced
from the mixture: 13C-NMR: 172.1 (s); 151.7 (s); 113.6 (d); 82.4 (s); 77.2 (s); 42.9 (d); 28.7 (t); 27.4 (t); 27.2 (t); 22.6 (t); 14.3 (q); 12.5 (t); 9.1 (q). MS: 206
(4, Mþ), 177 (39), 150 (28), 149 (28), 135 (28), 122 (36), 121 (26), 107 (15), 95 (10), 91 (10), 83 (70), 79 (11), 77 (10), 57 (100), 29 (21).
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Helv. Chim. Acta 2016, 99, 95 – 109
105
2 H); 2.10 (s, 3 H); 2.08 – 1.87 (m, 4 H); 1.69 – 1.61 (m, 1 H); 1.50 – 1.37
(m, 1 H); 1.12 (t, J ¼ 7.7, 3 H). 13C-NMR: 169.3 (s); 91.8 (s); 84.0 (s);
73.6 (s); 69.1 (s); 28.6 (t); 28.1 (t); 20.9 (q); 20.4 (t); 19.0 (t); 14.1 (q);
12.4 (t). MS: 208 (1, Mþ), 165 (13), 148 (83), 133 (13), 130 (17), 109
(20), 105 (10), 95 (13), 93 (13), 91 (28), 86 (10), 79 (28), 77 (19), 67
(17), 55 (13), 43 (100), 41 (13), 39 (10).
12a. Yield: 95%. IR: 2955, 2935, 2865, 1708, 1460, 1375, 1360, 1305,
1275, 1255, 1227, 1175, 1117, 1057, 968, 950, 940, 865. 1H-NMR: 7.25 (dt,
J ¼ 12, 2.5, 1 H); 6.09 (dd, J ¼ 12, 11, 1 H); 5.98 (dt, J ¼ 11, 7.6, 1 H);
2.70 (dt, J ¼ 7.6, 2.5, 2 H); 2.37 (t, J ¼ 7.6, 2 H); 2.34 (quint., J ¼ 7.6, 2 H);
1.97 (quint., J ¼ 7.6, 2 H); 1.03 (t, J ¼ 7.6, 3 H). 13C-NMR: 208.0 (s);
144.4 (d); 136.6 (s); 126.2 (d); 124.2 (d); 38.7 (t); 27.0 (t); 21.6 (t); 19.8
(t); 14.0 (q). MS: 150 (21, Mþ), 121 (100), 93 (7), 91 (10), 79 (23), 77
(12)42).
5-(Pent-2-yn-1-yl)-6-oxabicyclo[3.1.0]hex-1-yl Propanoate (9b).
Compound 9b was obtained from 7b according to the procedure used
for 9a. Yield: 48%. IR: 2976, 2937, 2851, 1761, 1461, 1431, 1357, 1310,
(2E)-2-[(2E)-But-2-en-1-ylidene]cyclopentanone (12b). A soln. of
aq. NaOH (1.0m, 2 ml, 2 mmol) was added dropwise to cyclopentanone
(2a; 5.0 g, 59.4 mmol) at < 208 and then, crotonaldehyde (2.08 g,
29.7 mmol) was added dropwise at < 108. After 1 h, the mixture was
extracted with Et2O (3 Â 30 ml). The org. phase was washed with 1n aq.
HCl, then with sat. aq. NaHCO3 to neutrality, and with brine, dried
(Na2SO4), and concentrated. The residual oil (80% yield) was purified
by bulb-to-bulb distillation to afford pure 12b. Yield: 60%. Delphoneꢃ,
1
1271, 1177, 1143, 1090, 1076, 1062, 1014, 941, 805, 687, 651. H-NMR:
2.56 (tq, J ¼ 13.0, 2.5, 1 H); 2.43 – 2.41 (m, 1 H); 2.39 (q, J ¼ 7.5, 2 H);
2.18 (tq, J ¼ 7.4, 2.5, 1 H); 2.06 – 1.97 (m, 2 H); 1.94 – 1.89 (m, 1 H);
1.69 – 1.63 (m, 1 H); 1.47 – 1.41 (m, 3 H); 1.15 (t, J ¼ 7.5, 3 H); 1.12 (t,
J ¼ 7.4, 3 H). 13C-NMR: 172.8 (s); 91.8 (s); 83.9 (s); 73.7 (s); 69.1 (s);
28.7 (t); 28.1 (t); 27.5 (t); 20.5 (t); 19.0 (t); 14.1 (q); 12.5 (t); 8.8 (q). MS:
222 (0, Mþ), 165 (23), 148 (68), 147 (43), 137 (20), 109 (10), 105 (17),
99 (13), 95 (26), 91 (56), 81 (9), 79 (15), 77 (15), 67 (23), 57 (100), 55
(23), 41 (17), 28 (36).
2-(Pent-2-yn-1-yl)-6-oxabicyclo[3.1.0]hex-1-yl Acetate (10). See
above for 9a, 10 was also obtained as 55 :45 mixture of diastereoisom-
ers. Yield: 45%. Analytical data deduced from the mixture: 1H-NMR:
3.76 (br. s, 1 H); 2.41 (dd, J ¼ 13.2, 8.5, 1 H); 2.17 (tq, J ¼ 7.7, 2.5, 2 H);
2.10 (s, 3 H); 2.08 – 1.87 (m, 4 H); 1.69 – 1.61 (m, 1 H); 1.50 – 1.37 (m,
1 H); 1.11 (t, J ¼ 7.7, 3 H). 13C-NMR: 168.7 (s); 89.8 (s); 82.0 (s); 77.3
(s); 63.9 (d); 39.6 (d); 26.6 (t); 25.4 (t); 21.6 (q); 18.1 (t); 14.3 (q); 12.4
(t). MS: 208 (1, Mþ), 165 (23), 148 (54), 133 (12), 130 (34), 109 (22),
105 (12), 95 (13), 93 (14), 91 (28), 86 (10), 79 (28), 77 (19), 67 (17), 55
(13), 43 (100), 41 (13), 39 (10).
celery, spearmint, slightly phenolic43 44). IR: 2954, 2935, 2863, 1708,
)
1460, 1376, 1359, 1306, 1275, 1254, 1227, 1175, 1117, 1057, 968, 950, 940,
864, 605. 1H-NMR: 6.89 (dq, J ¼ 7.7, 2.6, 1 H); 6.22 – 6.18 (m, 2 H); 2.68
(tq, J ¼ 7.4, 1.6, 2 H); 2.34 (t, J ¼ 7.7, 2 H); 1.96 (quint., J ¼ 7.4, 2 H); 1.89
(d, J ¼ 5.0, 3 H). 13C-NMR: 207.8 (s); 140.6 (d); 134.6 (s); 131.6 (d);
128.3 (d); 38.6 (t); 27.0 (t); 19.9 (t); 19.1 (q). MS: 136 (29, Mþ), 121
(100), 93 (10), 91 (11), 80 (17), 79 (56), 77 (21), 39 (16).
5-(Pent-2-yn-1-yl)cyclopent-2-en-1-one (13a). (AcO)2Pd (25 mg,
0.112 mmol) was added to a soln. of 8c (0.4 g, 1.60 mmol) and
MeOC(O)OCH2CH¼CH2 (0.558 g, 4.8 mmol) in MeCN (5 ml). After
1.5 h under reflux, the cold mixture was concentrated, diluted with
Et2O (10 ml), filtered over Celiteꢃ, concentrated, and then purified by
CC (SiO2; cyclohexane/AcOEt 95 :5) to afford pure 13a. Yield: 56%.
Alternatively, (AcO)2Pd (8.2 mg, 0.364 mmol) was added to a soln. of a
45 :55 mixture of 8a/7a (2.0 g, 10.4 mmol) and MeO-
C(O)OCH2CH¼CH2 (1.81 g, 15.60 mmol) in MeCN (15 ml). After
1.5 h under reflux, the cold mixture was concentrated to afford
quantitatively a 45 :55 mixture of 13a/11a. Purification by CC (SiO2;
cyclohexane/AcOEt 95 :5) afforded pure 13a in 26% yield, as well as
pure 11a in 29% yield. When pure 8a was used as starting material, pure
13a was obtained after bulb-to-bulb distillation. Yield: 65%. Alter-
natively, a mixture of 13b (53 mg, 0.257 mmol) and LiOH (80 mg,
3.34 mmol) in THF (2 ml) and H2O (0.5 ml) was stirred at 208 for 2 h.
The mixture was acidified with 1n aq. HCl and extracted with Et2O. The
org. phase was dried (Na2SO4) and then concentrated to afford pure
13a. Yield: > 95%. Alternatively, an 8 :2 mixture of 9a/10 (208 mg,
1.0 mmol) in MeOH (0.7 ml) was added dropwise to a soln. of H2SO4
(15 mg) in MeOH (1 ml) at 658 to afford a 19 :9 :72 mixture of 13a/6a/
(2E)-2-(Pent-2-yn-1-ylidene)cyclopentanone (11a). Pure 9a (8.7 g,
41.82 mmol) was added dropwise during 1 h to H2SO4 (0.6 g) in MeOH
(15 ml) at 658. After 1.5 h, MeONa (30% in MeOH, 1.6 g) was added to
the cold mixture, followed by toluene (25 ml). The org. phase was
washed with H2O (3 Â 35 ml), dried (Na2SO4), concentrated, and
purified by distillation to afford 11a in 43% yield, as well as 4 in 7%
yield. Alternatively, a soln. of 5c (1.2 g, 7.99 mmol) in DMF (10 ml) was
added dropwise to a suspension of CuCl2 · 2 H2O (2.24 g, 13.14 mmol)
and LiCl (0.224 g, 5.28 mmol) in DMF at 808. After 3 h, LiBr (0.406 g,
4.68 mmol), as well as Li2CO3 (0.59 g, 8.0 mmol) were added. After 5 h
at 808, the cold mixture was diluted with H2O (40 ml) and then
extracted with hexane. The org. phase was washed with brine, dried
(Na2SO4), and concentrated to afford a 70 :30 mixture of 11a/6a in 54%
yield. Further purification by CC (SiO2; cyclohexane/AcOEt 99 :1 to
8 :2) afforded pure 11a in 35% yield, as well as an anal. quantity of the
1
intermediate 5l. For IR and H-NMR analyses, see [6j][7b][7c]. B.p.
1208/0.02 mbar. 13C-NMR: 206.0 (s); 146.5 (s); 113.4 (d); 105.0 (s); 78.0
(s); 38.6 (t); 28.9 (t); 19.4 (t); 13.8 (t); 13.8 (q). MS: 148 (100, Mþ), 147
(90), 105 (30), 92 (30), 91 (95), 79 (13), 77 (13), 65 (11), 51 (11), 39
(10).
1
11a. Yield: 80%. H-NMR: 7.73 (dt, J ¼ 5.7, 2.4, 1 H); 6.20 (dt, J ¼ 5.7,
2.1, 1 H); 2.89 (ddt, J ¼ 19.3, 6.3, 2.4, 1 H); 2.64 (dq, J ¼ 19.3, 2.3, 1 H);
2.57 (ddt, J ¼ 15.7, 3.8, 2.4, 1 H); 2.49 – 2.42 (m, 1 H); 2.39 (tt, J ¼ 7.4, 2.4,
1 H); 2.10 (tq, J ¼ 7.4, 2.1, 2 H); 1.08 (t, J ¼ 7.4, 3 H). 13C-NMR: 210.5
(s); 164.0 (d); 133.8 (d); 83.0 (s); 75.6 (s); 43.6 (d); 34.8 (t); 20.2 (t); 14.2
(q); 12.3 (t). MS: 148 (39, Mþ), 133 (100), 119 (22), 105 (53), 103 (10),
91 (61), 82 (23), 81 (26), 79 (25), 77 (25), 68 (12), 65 (15), 53 (29), 51
(11), 41 (10), 39 (20).
(2E)-2-[(2Z)-Pent-2-en-1-ylidene]cyclopentanone (12a). A soln. of
11a (148 mg, 1.0 mmol) in cyclohexane (7 ml) was hydrogenated with
Lindlar catalyst (14 mg) at atmospheric pressure in the presence of a
drop of quinoline. After absorption of 1 equiv. of H2, the mixture was
filtered, concentrated, and bulb-to-bulb distilled to afford > 95% pure
42) Anal. traces (<2%) of both the (E,E)-stereoisomer (Veloutoneꢃ, lactonic, peach, celery. IR: 2964, 2933, 2875, 1707, 1629, 1609, 1461, 1436, 1410, 1271,
1185, 968, 826, 760, 641. 1H-NMR: 6.91 (dt, J ¼ 10.6, 2.2, 1 H); 6.28 – 6.13 (m, 2 H); 2.69 (dt, J ¼ 7.2, 2.2, 2 H); 2.34 (t, J ¼ 7.6, 2 H); 2.23 (quint., J ¼ 7.2, 2 H);
1.96 (quint., J ¼ 7.6, 2 H); 1.06 (t, J ¼ 7.6, 3 H). 13C-NMR: 207.9 (s); 147.4 (d); 134.9 (s); 131.9 (d); 125.9 (d); 38.7 (t); 27.1 (t); 26.5 (t); 19.9 (t); 13.0 (q). MS:
150 (13, Mþ), 121 (100), 93 (6), 91 (11), 79 (26), 77 (15), 39 (9), 28 (6)), as well as the (Z,E)-stereoisomer (1H-NMR: 7.51 (dd, J ¼ 13.4, 11.2, 1 H); 6.33 (br.
d, J ¼ 11.2, 1 H); 6.01 (dt, J ¼ 15.2, 6.9, 1 H); 2.65 (dt, J ¼ 15.2, 7.4, 2 H); 2.34 (t, J ¼ 7.6, 2 H); 2.21 (quint., J ¼ 7.6, 2 H); 1.91 (quint., J ¼ 7.4, 2 H); 1.04 (t, J ¼
7.4, 3 H). 13C-NMR: 207.7 (s); 145.9 (d); 136.5 (d); 132.7 (s); 125.8 (d); 40.6 (t); 31.8 (t); 20.5 (t); 16.1 (t); 13.3 (q)) could also be either isolated or deduced
from the mixture, after purification by CC (SiO2; cyclohexane/AcOEt 95 :5).
43) First delivered to our perfumers by Dr. H. Strickler, (Firmenich SA, unpublished work, 1976).
44) When purification was performed by CC (SiO2; cyclohexane/AcOEt 99 :1 to 9 :1), analytical traces of (E,Z)-12b could be isolated in < 2% yield.
1H-NMR: 7.27 (dt, J ¼ 11.3, 2.8, 1 H); 6.21 – 6.01 (m, 2 H); 2.70 (br. t, J ¼ 5.7, 2 H); 2.37 (t, J ¼ 7.5, 2 H); 1.97 (quint., J ¼ 7.5, 2 H); 1.91 (d, J ¼ 7.0, 3 H).
13C-NMR: 208.0 (s); 137.1 (d); 136.5 (s); 126.0 (d); 125.8 (d); 38.7 (t); 26.9 (t); 19.8 (t); 14.1 (q). MS: 136 (31, Mþ), 121 (100), 93 (11), 91 (12), 80 (13), 79
(44), 77 (15).
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106
Helv. Chim. Acta 2016, 99, 95 – 109
Methyl 2-Oxo-1-(pent-2-yn-1-yl)cyclopent-3-ene-1-carboxylate
brine, dried (Na2SO4), concentrated, and purified by CC (SiO2;
cyclohexane/AcOEt 95 :5) to afford pure 15a. Yield: 54%. IR: 2974,
2939, 2876, 1776, 1714, 1658, 1435, 1363, 1272, 1223, 1170, 1143, 1130,
1039, 1002, 877, 769. 1H-NMR: 3.71 (s, 3 H); 3.09 – 3.04 (m, 1 H); 2.67 –
2.54 (m, 2 H); 2.37 (ddt, J ¼ 16.6, 5.5, 2.3, 1 H); 2.28 – 2.11 (m, 4 H);
2.24 (s, 3 H); 1.84 – 1.75 (m, 1 H); 1.10 (t, J ¼ 7.5, 3 H). 13C-NMR: 167.7
(s); 164.0 (s); 160.3 (s); 118.9 (s); 83.0 (s); 76.3 (s); 51.4 (q); 44.9 (d);
27.9 (t); 25.6 (t); 22.0 (t); 20.8 (q); 14.2 (q); 12.4 (t). MS: 250 (1, Mþ),
180 (68), 177 (13), 148 (24), 140 (10), 131 (13), 109 (100), 91 (14), 79
(11), 77 (10), 55 (12), 43 (42), 41 (11).
(13b). (AcO)2Pd (81 mg, 0.359 mmol) was added to a soln. of 8d
(1.5 g, 5.13 mmol) and MeOC(O)OCH2CH ¼ CH2 (1.78 g, 15.4 mmol)
in MeCN (20 ml). After 1.5 h under reflux, the cold mixture was
concentrated, diluted with Et2O (20 ml), filtered over Celiteꢃ, concen-
trated, and then purified by CC (SiO2; cyclohexane/AcOEt 97:3) to
afford pure 13b. Yield: 39%. Alternatively, (AcO)2Pd (112 mg,
0.499 mmol) was added to a soln. of 8e (2.0 g, 7.13 mmol), and
MeOC(O)OCH2CH¼CH2 (2.484 g, 21.4 mmol) in MeCN (25 ml).
After 1.5 h under reflux, the cold mixture was concentrated, diluted
with Et2O (20 ml), filtered over Celiteꢃ, concentrated, and then purified
by CC (SiO2; cyclohexane/AcOEt 95 :5) to afford pure 13b. Yield:
23%. Alternatively, 5m afforded 13b either in 23 – 31% yield after
treatment with either LiBr or Li2CO3 in DMF at 808 for 5 h, or in 53%
yield after treatment with 1.1 mol-equiv. of DBU in toluene under
reflux for 4 h. IR: 2976, 2954, 2939, 2919, 2879, 2847, 1740, 1705, 1591,
1435, 1343, 1323, 1299, 1257, 1240, 1178, 1144, 1119, 1098, 1066, 1018,
956, 900, 867, 819, 759, 729. 1H-NMR: 7.83 (dt, J ¼ 5.7, 2.7, 1 H); 6.21 (dt,
J ¼ 5.7, 2.2, 1 H); 3.71 (s, 3 H); 3.22 (dt, J ¼ 19.2, 2.4, 1 H); 2.92 (dt, J ¼
19.2, 2.5, 1 H); 2.77 (tq, J ¼ 16.5, 2.2, 2 H); 2.06 (tq, J ¼ 7.5, 2.4, 2 H);
1.04 (t, J ¼ 7.5, 3 H). 13C-NMR: 204.6 (s); 170.4 (s); 164.5 (d); 132.2 (d);
84.0 (s); 73.8 (s); 56.8 (s); 52.9 (q); 39.4 (t); 24.0 (t); 14.1 (q); 12.3 (t).
MS: 206 (6, Mþ), 147 (100), 145 (13), 117 (18), 107 (10), 91 (29), 77
(10), 39 (8).
Methyl 3-(Pent-2-yn-1-yl)-2-[(trimethylsilyl)oxy]cyclopent-1-ene-
1-carboxylate (15b). TMSOTf (6.93 g, 31.16 mmol) was added dropwise
to a soln. of 5d (5 g, 24.01 mmol) and EtN(iPr)2 (4.65 g, 36 mmol) in
CH2Cl2 (25 ml) at 208. After 2 h, the mixture was concentrated, diluted
with pentane, filtered over Celiteꢃ, concentrated, and then purified by
CC (SiO2; cyclohexane/AcOEt 96 :4) to afford pure 15b. Yield: 59%.
IR: 2952, 2867, 1709, 1621, 1436, 1376, 1249, 1225, 1192, 1151, 1134,
1
1055, 844, 771, 751, 690. H-NMR: 3.70 (s, 3 H); 2.74 – 2.66 (m, 1 H);
2.61 – 2.54 (m, 1 H); 2.48 (ddd, J ¼ 8.8, 6.2, 1.6, 1 H); 2.41 (ddt, J ¼ 16.6,
4.2, 2.5, 1 H); 2.23 (ddt, J ¼ 16.6, 7.7, 2.4, 1 H); 2.14 (tq, J ¼ 7.4, 2.4, 2 H);
2.03 (ddq, J ¼ 13.1, 8.8, 4.7, 1 H); 1.81 – 1.72 (m, 1 H); 1.10 (t, J ¼ 7.4,
3 H); 0.27 (s, 9 H). 13C-NMR: 166.0 (s); 165.6 (s); 109.2 (s); 83.1 (s);
76.8 (s); 50.6 (q); 46.9 (d); 27.6 (t); 24.8 (t); 21.7 (t); 14.2 (q); 12.5 (t);
0.7 (3q). MS: 280 (4, Mþ), 265 (60), 249 (10), 197 (21), 109 (100), 107
(11), 89 (10), 73 (50).
Methyl (3E)-2-Hydroxy-3-(pent-2-yn-1-ylidene)cyclopent-1-ene-1-
carboxylate (16). A mixture of 5f (946 mg, 3.89 mmol) and LiCl
(247 mg, 5.83 mmol) in DMF (10 ml) was heated at 1008 for 0.5 h. To
the cold mixture was added aq. H2SO4 (2.5%, 5 ml) and Et2O (5 ml).
After 1 h at 208, the mixture was partitioned between brine and Et2O.
The org. phase was washed with H2O, dried (Na2SO4), concentrated,
and then purified by CC (SiO2; cyclohexane/AcOEt 95 :5) and bulb-to-
bulb distillation to afford pure 16. Yield: 9%. B.p. 908/0.09 mbar. IR:
3271, 2968, 2934, 2875, 2206, 1661, 1596, 1445, 1373, 1321, 1278, 1249,
1218, 1196, 1139, 1096, 998, 964, 887, 840, 817, 762, 727, 663, 627.
1H-NMR: 9.89 (s, OH); 5.90 (quint., J ¼ 2.4, 1 H); 3.79 (s, 3 H); 2.67 –
2.63 (m, 2 H); 2.55 – 2.53 (m, 2 H); 2.41 (dq, J ¼ 7.5, 2.4, 2 H); 1.19 (t,
J ¼ 7.5, 3 H). 13C-NMR: 170.0 (s), 167.6 (s); 148.9 (s); 107.8 (s); 104.4
(d); 101.5 (s); 77.8 (s); 51.4 (q); 25.6 (t); 24.4 (t); 14.1 (q); 13.6 (t). MS:
206 (0, Mþ), 148 (80), 147 (72), 105 (23), 92 (24), 91 (100), 79 (10), 77
(12), 65 (10), 51 (10), 39 (8).
Trimethyl({5-[(2Z)-pent-2-en-1-yl]cyclopent-1-en-1-yl}oxy)silane
(17a). BuLi (1.6m, 3.92 ml, 6.27 mmol) was added dropwise to a soln. of
HN(iPr)2 (634 mg, 6.27 mmol) in THF (1 ml) at À 788. After 0.5 h, a
soln. of 2h (300 mg, 1.97 mmol) in THF (1 ml) was added. After 0.75 h
at À 788, Me3SiCl (617 mg, 5.68 mmol) was added. The temp. was
equilibrated to 208, and the mixture was poured into aq. sat. NaHCO3.
The aq. phase was washed with Et2O. The org. phase was dried
(Na2SO4), concentrated, and purified by CC (SiO2; cyclohexane/
AcOEt 99 :1) to afford 17a. Yield: 78%. IR: 3006, 2959, 2926, 2852,
1641, 1446, 1348, 1251, 1188, 1047, 957, 873, 840, 776, 755, 693. 1H-NMR:
5.44 – 5.38 (m, 1 H); 5.35 – 5.30 (m, 1 H); 4.59 (q, J ¼ 2.0, 1 H); 2.51 –
2.47 (m, 1 H); 2.35 – 2.29 (m, 1 H); 2.21 – 2.16 (m, 2 H); 2.05 (quint.,
J ¼ 7.5, 2 H); 2.01 – 1.94 (m, 2 H); 1.51 – 1.45 (m, 1 H); 0.96 (t, J ¼ 7.5,
3 H); 0.20 (s, 9 H). 13C-NMR: 157.1 (s); 132.5 (d); 127.3 (d); 101.4 (d);
44.8 (d); 30.3 (t); 27.3 (t); 27.0 (t); 20.7 (t); 14.4 (q); 0.0 (3q). MS: 224
(8, Mþ), 167 (22), 156 (39), 155 (76), 154 (10), 75 (13), 73 (100), 45 (8),
41 (6).
Methyl 2-(Acetyloxy)-1-[(2Z)-pent-2-en-1-yl]cyclopent-2-ene-1-
carboxylate (17b). Compound 17b was obtained from 8d, as described
for 2i. Yield: 18%. IR: 3012, 2959, 2934, 2858, 1763, 1731, 1654, 1434,
1369, 1245, 1197, 1179, 1065, 1046, 1006, 868, 799, 725. 1H-NMR: 5.72 (t,
J ¼ 2.2, 1 H); 5.53 – 5.48 (m, 1 H); 5.27 – 5.23 (m, 1 H); 3.69 (s, 3 H);
2.62 (dd, J ¼ 14.4, 8.3, 1 H); 2.50 – 2.44 (m, 1 H); 2.40 (dd, J ¼ 14.4, 6.6,
1 H); 2.37 – 2.30 (m, 2 H); 2.15 (s, 3 H); 2.06 (quint., J ¼ 7.2, 2 H);
1.90 – 1.86 (m, 1 H); 0.96 (t, J ¼ 7.2, 3 H). 13C-NMR: 174.9 (s); 168.3 (s);
148.3 (s); 134.8 (d); 123.3 (d); 116.4 (d); 57.6 (s); 52.2 (q); 32.0 (t); 31.0
5-[(2Z)-Pent-2-en-1-yl]cyclopent-2-en-1-one (14a). Compound 14a
was obtained by hydrogenation of 13a with Lindlar catalyst, as
described for 12a. Yield: 95%. Alternatively, (AcO)2Pd (10.5 mg,
0.047 mmol) was added to a mixture of 17a (150 mg, 0.668 mmol) and
MeOC(O)OCH2CH¼CH2 (233 mg, 2.0 mmol) in MeCN (5 ml). After
1.5 h at 808, the cold mixture was concentrated, diluted with Et2O,
filtered, and concentrated again to afford quantitatively an 80 :20
mixture of 14a/2h. Purification by CC (SiO2; cyclohexane/AcOEt
97:3) afforded pure 14a. Yield: 56%. Alternatively, prop-2-en-1-yl 2-
oxo-3-[(2Z)-pent-2-en-1-yl]cyclopentanecarboxylate
(180 mg,
0.762 mmol) was treated with (AcO)2Pd (12 mg, 0.057 mmol) in MeCN
under reflux for 1.5 h to afford 14a after purification by CC (SiO2).
Yield: 53%. Alternatively, 14a was obtained by saponification of 14b
with LiOH, according to the procedure used for 13a. Yield: 93%. IR:
3008, 2962, 2930, 2874, 1701, 1588, 1462, 1431, 1344, 1205, 1171, 1092,
1069, 1026, 948, 840, 773, 742, 718, 670. 1H-NMR: 7.69 (dt, J ¼ 5.8, 2.6,
1 H); 6.19 (dt, J ¼ 5.8, 2.2, 1 H); 5.47 (dtt, J ¼ 11.0, 7.3, 2.0, 1 H); 5.27
(dtt, J ¼ 11.0, 7.3, 2.0, 1 H); 2.85 – 2.80 (m, 1 H); 2.55 – 2.50 (m, 1 H);
2.41 – 2.35 (m, 2 H); 2.22 – 2.16 (m, 1 H); 2.06 (br. quint., J ¼ 7.4, 2 H);
0.96 (t, J ¼ 7.4, 3 H). 13C-NMR: 212.0 (s); 163.8 (d); 134.1 (d); 133.9 (d);
125.0 (d); 44.6 (d); 35.0 (t); 28.4 (t); 20.6 (t); 14.2 (q). MS: 150 (12, Mþ),
121 (20), 95 (10), 82 (100), 81 (10), 79 (12), 77 (10), 53 (10), 41 (12), 39
(10).
Methyl 2-Oxo-1-[(2Z)-pent-2-en-1-yl]cyclopent-3-ene-1-carboxy-
late (14b). Compound 14b was obtained by hydrogenation of 13b with
3 wt-% of Lindlar catalyst in cyclohexane as described for 12a. Yield:
87%. Alternatively, 17c was treated with (AcO)2Pd and MeO-
C(O)OCH2CH¼CH2 in MeCN as described for 13b to afford 14b.
Yield: 52%. IR: 3011, 2960, 2933, 2874, 1741, 1705, 1592, 1434, 1373,
1343, 1291, 1246, 1176, 1095, 1065, 1046, 1027, 979, 956, 891, 860, 820,
753, 734, 676, 638. 1H-NMR: 7.76 (dt, J ¼ 5.7, 2.6, 1 H); 6.17 (dt, J ¼ 5.7,
1.8, 1 H); 5.52 – 5.47 (m, 1 H); 5.15 – 5.10 (m, 1 H); 3.71 (s, 3 H); 3.22
(dt, J ¼ 19.4, 2.6, 1 H); 2.78 (dd, J ¼ 14.1, 7.5, 1 H); 2.62 (dt, J ¼ 19.4, 2.2,
1 H); 2.54 (dd, J ¼ 14.1, 7.0, 1 H); 2.06 (quint., J ¼ 7.0, 2 H); 0.95 (t, J ¼
7.0, 3 H). 13C-NMR: 205.6 (s); 171.0 (s); 164.1 (d); 135.9 (d); 132.2 (d);
122.1 (d); 57.5 (s); 52.8 (q); 38.8 (t); 31.8 (t); 20.6 (t); 14.1 (q). MS: 208
(2, Mþ), 176 (8), 149 (64), 147 (13), 140 (100), 133 (8), 119 (50), 108
(66), 107 (19), 105 (10), 93 (10), 91 (18), 80 (16), 79 (18), 77 (13), 55
(18), 41 (12), 39 (10).
Methyl 2-(Acetyloxy)-3-(pent-2-yn-1-yl)cyclopent-1-ene-1-carbox-
ylate (15a). DMAP (0.146 g, 1.2 mmol) was added to a soln. of 5d (6 g,
21.9 mmol), Et3N (3.32 g, 32.8 mmol), and AcCl (2.15 g, 27.4 mmol) in
CH2Cl2 (100 ml) at 08. After 2 h at 208, the mixture was washed with
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Helv. Chim. Acta 2016, 99, 95 – 109
107
(t); 27.1 (t); 21.2 (q); 20.7 (t); 14.2 (q); 0.0 (3q). MS: 252 (1, Mþ), 210
(7), 178 (7), 153 (153), 151 (18), 142 (83), 141 (33), 140 (27), 121 (9),
109 (100), 95 (11), 81 (10), 79 (12), 69 (15), 67 (12), 55 (31), 53 (13), 43
(67), 41 (28), 39 (10), 28 (27).
Kapoor, Tetrahedron 1995, 51, 8573; q) H. Toshima, S. Nara, H.
Aramaki, A. Ichihara, Y. Koda, Y. Kikuta, Biosci., Biotechnol.,
Biochem. 1997, 61, 1724; r) T.-L. Ho, K.-F. Shyu, J. Chin. Chem.
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6262288, 2001; u) K. Itami, K. Mitsudo, J.-I. Yoshida, Angew.
Chem., Int. Ed. 2002, 41, 3481.
Methyl 1-[(2Z)-Pent-2-en-1-yl]-2-[(trimethylsilyl)oxy]cyclopent-2-
ene-1-carboxylate (17c). Compound 17c was obtained from 2f accord-
ing to the procedure used for 15b. Yield: 61%. IR: 3012, 2960, 2906,
2858, 1731, 1647, 1433, 1264, 1251, 1238, 1216, 1164, 1067, 867, 842, 785,
753. 1H-NMR: 5.50 – 5.45 (m, 1 H); 5.30 – 5.25 (m, 1 H); 4.70 (t, J ¼ 2.4,
1 H); 3.67 (s, 3 H); 2.60 (dd, J ¼ 14.5, 8.0, 1 H); 2.36 (dd, J ¼ 14.5, 6.3,
1 H); 2.34 – 2.30 (m, 1 H); 2.27 – 2.22 (m, 1 H); 2.20 – 2.15 (m, 1 H);
2.07 (quint., J ¼ 7.5, 2 H); 1.83 – 1.78 (m, 1 H); 0.96 (t, J ¼ 7.5, 3 H); 0.19
(s, 9 H). 13C-NMR: 175.8 (s); 153.9 (s); 134.1 (d); 124.4 (d); 103.3 (d);
58.1 (s); 51.8 (q); 31.5 (t); 31.3 (t); 26.5 (t); 20.7 (t); 14.3 (q); 0.0 (3q).
MS: 282 (7, Mþ), 267 (8), 225 (12), 223 (21), 213 (25), 199 (21), 197
(23), 181 (11), 109 (100), 73 (49).
Trimethyl({2-[(2Z)-pent-2-en-1-yl]cyclopent-1-en-1-yl}oxy)silane
(18). Compound 18 was obtained in 57% yield from 2h, as a 15 :85
mixture of 17a/18, as described for 8e. Alternatively, 18 was obtained
quantitatively from 2h, as a 50 :50 mixture of 17a/18, as described for
15b. Analytically pure 18 (cyclohexane/AcOEt 99 :1, 19% yield from
the 15 :85 mixture) exhibited the following analytical data: IR: 3009,
2958, 2927, 2872, 2848, 1683, 1462, 1340, 1304, 1251, 1204, 1045, 902, 872,
839, 751, 687, 625. 1H-NMR: 5.40 – 5.35 (m, 1 H); 5.30 – 5.25 (m, 1 H);
2.75 (br. d, J ¼ 7.2, 2 H); 2.28 (br. t, J ¼ 7.5, 2 H); 2.18 (br. t, J ¼ 7.2,
2 H); 2.08 (quint., J ¼ 7.7, 2 H); 1.78 (quint., J ¼ 7.5, 2 H); 0.96 (t, J ¼ 7.5,
3 H); 0.19 (s, 9 H). 13C-NMR: 146.2 (s); 131.9 (d); 126.6 (d); 115.8 (s);
33.7 (t); 30.9 (t); 24.5 (t); 20.4 (t); 19.7 (t); 14.3 (q); 0.6 (3q). MS: 224
(10, Mþ), 209 (7), 195 (38), 167 (10), 156 (100), 155 (42), 75 (21), 73
(73), 45 (9), 32 (10), 28 (30).
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Received October 6, 2015
Accepted October 29, 2015
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