Synthesis of 1,4-Cyclohexadiene Carboxylates through a Formal [2+4]-Cycloaddition of Propiolates under Cobalt Catalysis

Article abstract of DOI:10.1002/hlca.202000175

A low-valent cobalt(I) complex, formed from the reduction of CoBr₂(dppe) with zinc, acts as catalyst for the efficient [2+4] cycloaddition of β-alkyl, cycloalkyl and aryl substituted propiolates to dienes. This transformation yields synthetical

Full text of DOI:10.1002/hlca.202000175

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chimica acta
Accepted Article
Title: Synthesis of 1,4-Cyclohexadiene Carboxylates via a Formal
[2+4]-Cycloaddition of Propiolates under Cobalt Catalysis
Authors: Andreas Goeke, Julie Charpentier, Francis Voirol, Felix
Flachsmann, Silvia Tanner, Natalie Aeberli, and Gerhard
Brunner
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10.1002/hlca.202000175
Helvetica Chimica Acta
Synthesis of 1,4-Cyclohexadiene Carboxylates via a Formal [2+4]-
Cycloaddition of Propiolates under Cobalt Catalysis
Julie Charpentier,a Francis Voirol,a Felix Flachsmann,a Silvia Tanner,a Natalie Aeberli,a Gerhard Brunner,a Andreas
Goeke*,a
a
Givaudan Schweiz AG, Fragrances S&T, Ingredients Research, Kemptpark 50, 8310 Kemptthal, Switzerland, andreas.goeke@givaudan.com
Dedicated to Prof. Antonio Togni on the occasion of his 65th birthday
A low-valent cobalt(I) complex, formed from the reduction of CoBr2(dppe) with zinc, acts as catalyst for the efficient [2+4] cycloaddition of - alkyl, cyclo-
alkyl and aryl substituted propiolates to dienes. This transformation yields synthetically relevant 1,4-cyclohexadiene carboxylates in good to excellent
yields. Furthermore, the target compounds are novel lead structures for the discovery of fragrance ingredients from the fruity, floral and spicy odor family.
Keywords: [2+4] • Cycloaddition • Cobalt Catalysis • Fragrance Chemistry • Cyclohexadiene • Alkynes
aromatic compounds and submit them to dissolved metal (Birch) reduc-
tion conditions (Scheme 1B).[14,15] Unfortunately, this strategy does not
Introduction
The development of innovative and safe odorants is an important objec-
tive in the fragrance industry. In the context of the fruity, floral odor fami-
ly, the positioning of double bonds and the degree of unsaturation of six-
membered ring esters has been recognized.[1] For instance, Esterly™ (1)[2]
and Tropicalia™ (2)[3] are potent recent representatives along with the
well-established Ethyl Safranate™ (3).
yield the desired selectivity as the carboxylate directs the reduction to the
ipso position. Recently, Hall and co-workers published a new method for
the [2+4] cycloaddition of propiolic acid with 1,3-dienes under boron
catalysis under very mild conditions. For substituted 2-butynoic acids the
substrate scope for linear dienes was limited to the very reactive 2,3-
dimethyl-1,3-butadiene. In addition, longer reaction times were required
and lower yields were observed (Scheme 1C).[16]
A catalytic system largely used by Hilt and coworkers for cycloadditions
and hydrovinylations consists of a Co(II) pre-catalyst, a chelating phos-
phine ligand and an external reductant.[17] This methodology has been
used for the formal cycloaddition reaction between alkynes with dienes to
form 6-membered rings either with electron-rich substituents or with
subsequent in situ derivatization of the final products.[18-26] Based on this
system, we decided to expand the scope of this method to substituted
propiolates as dienophiles.
Figure 1. Fruity odorants based on a ethyl cyclohexane motif.
The strategic positioning of a second double bond was not yet systemati-
cally addressed. 1,4-Cyclohexadiene carboxylates are moreover flexible
intermediates in chemical synthesis. They can be isomerized into conju-
gation[4] or regioselectively converted, as exemplified in the expedient
synthesis of Oseltamivir (Tamiflu),[5] and other natural products.[6] Unfor-
tunately, the synthesis of 1,4-cyclohexadiene carboxylates is less straight-
forward, which is in part due to their inherent instability with respect to
oxidation and aromatization. One of the most atom economic and well
established ways to assemble 1,4-cycloxadiene derivatives is the thermal[7-
10]
or catalyzed [2+4]-cycloaddition[11,12,13] of a diene with the correspond-
ing alkyne. The access to 2-substituted cyclohexadiene carboxylates is,
however, limited to unsubstituted or double activated propiolates such as
acetylene dicarboxylates, phosphonates or dialdehydes. (see Scheme 1A).
Alkyl, alkenyl and aryl-substituted propiolates usually fail to undergo
intermolecular [4+2] cycloaddition reactions. Another synthetic strategy
to target this skipped diene-motif inside a ring, is to use the corresponding
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ZnI2 to be the root cause: A solution of pure cyclohexadiene carboxylate
6a in DCM and traces of ZnI2 would rapidly oxidize 6a, as exemplified in
Scheme 2. After extensive experimentation this undesired aromatization
of 6a could be completely prevented through the replacement of ZnI2 by
TMSCl as activating agent of the reductant Zn (entry 17) and we used this
protocol if the separation of compounds 6 by chromatography required
purer crude reaction products.
Table 1. Optimization of the reaction conditions.[a]
Entry
Reductant
Additive
Solvent
Yield
(%)[b]
1
Zn
Zn
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
LiBr
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
-
DCM
DCM
91
59
38
51
46
53
61
NR
1
2[c]
3[d]
4[e]
5
6[f]
7[f]
8
Scheme 1. Synthetic strategies for the assembly of cyclohexadiene carboxylates.
Zn
DCM
Zn
DCM
Results and Discussion
Zn
dioxane
dioxane
toluene
Et2O
Zn
We started our investigation using pentadiene (4a) and ethyl 2-
Zn
pentynoate (5a) in the presence of
a catalytic system composed of
Li
CoBr2(dppe) (5 mol %), which is reduced in situ with zinc in the presence of
ZnI2 in dichloromethane (DCM).[17] After 90 minutes at 40 °C, we were
pleased to observe that the reaction had gone to full conversion with 91 %
of the desired product 6a being regioselectively formed (Table 1, Entry 1),
as determined by GC chromatography using an internal standard. Higher
catalyst loadings resulted in reduced amounts of product (Entry 2 and 3).
This is not an uncommon observation, and can be attributed to a slow
turnover rate due to accumulation of an unproductive metal complex at
high concentrations of precatalyst. Lowering the reaction temperature to
25 °C afforded only 51 % of desired product, even after an extended reac-
tion time of 24 h (Entry 4). Entries 5-8 show that DCM was identified as the
best solvent, which was already observed by Hilt and coworkers.[17] In-
creasing reaction temperatures in higher boiling and more sustainable
solvents did not provide improved events. Hydride reductants (entries 9
and 10), elemental metals (entries 11 and 12), as well as organometallic
reductants (entries 13 and 14) did not yield the desired product in satisfac-
tory yields. Moreover, no reaction was observed in the absence of ZnI2
(entry 15) or Zn (entry 16), showing the necessity of both the reductant
and the activation agent. In various control experiments, neither thermal
nor Lewis acid-catalyzed Diels-Alder conditions were productive, leading
predominantly to the decomposition of the substrates or, in some cases,
to the dimerization of the diene. Importantly, during attempts to upscale
the reaction to gram scale, we observed that product 6a would partially
oxidize during work-up, affording the corresponding benzoic acid ester as
a side product in up to double digit yields. As pure compound 6a is stable,
even if exposed to air over several weeks, we concluded that the catalytic
system must be involved in the oxidation process. Indeed, we finally found
9
NaBH4
NBu4BH4
Mg
DCM
10
11
12
13
14
15
16
17
DCM
11
8
DCM
Mn
DCM
17
iPrMgCl
ZnEt2
Zn
DCM
NR
43
3.6
NR
85
DCM
DCM
-
ZnI2
TMSCl
DCM
Zn
DCM
[a]
Reaction conditions: Unless otherwise stated, propiolate
5 (1.0 mmol, 1.0 equiv.) and diene 4 (1.0 mmol , 2.0 equiv.)
were added to the CoBr2(dppe) (0.05 mmol, 5 mol%),
reducing agent (0.2 mmol, 0.2 equiv.), and additive (0.25
mmol, 0.25 equiv.) in the described solvent (1 mL, 1M). The
[b]
reaction was allowed to stir for 1h at 40 °C. Yields de-
termined by GC-analysis with ethyl valerate as internal
standard . [c] 10 mol% of CoBr2(dppe) were used. [d] 20 mol%
of CoBr2(dppe) were used. [e] The reaction was run at room
temperature. [f] The reaction was run at 60 °C.
Scheme 2. Slow oxidation of the desired product in the presence of ZnI2 under air.
2
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10.1002/hlca.202000175
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equiv.), CoBr2(dppe) (0.125 mmol, 5 mol%), Zn (0.5 mmol, 0.2 equiv.), TMSCl (0.625
mmol, 0.25 equiv.), DCM (2.5 mL, 1M), 2h, 40 °C. Conditions B: Propiolate 5 (2.5
mmol, 1.0 equiv.), diene 4 (5.0 mmol , 2.0 equiv.), CoBr2(dppe) (0.125 mmol, 5 mol%),
Zn (0.5 mmol, 0.2 equiv.), ZnI2 (0.625 mmol, 0.25 equiv.), DCM (2.5 mL, 1M), 2h,
40 °C. The yields reported are isolated yields after column chromatography or
Kugelrohr distillation. [a] Using 1.05 equiv. of the diene.
Next, we explored the scope of this reaction as summarized in Scheme 3.
The reactions were in general carried out with both activating agents,
TMSCl (method A) and ZnI2 (method B). In many cases, the latter gave
higher yields and oxidized byproducts could be removed during purifica-
tion. Starting with pentadiene we subjected different propiolates to the
reaction conditions. Ethyl pent-2-ynoate gave the desired product 6a in
60 % isolated yield in the presence of TMSCl, and 85% yield with ZnI2 as
additive as a single regioisomer. Similarly, 6b and 6d were achieved in
moderate yields using ethyl but-2-ynoate or ethyl oct-2-ynoate as starting
material respectively. Isopropyl substitution was supported, yielding 6c in
39% as a single regioisomer. In contrast, when using 1-phenylbutadiene
we observed the formation of 2 regioisomers with but-2-ynoate, yielding
preferentially the 2,3-substituted cyclohexadiene 6e versus the 1,1’-
substitution pattern in 6e’, in a 2:1 ratio and mediocre 25% yield. Similar
regioselectivities were observed when using longer chain propiolates, with
slightly better yields (6f/6f’ and 6g/6g’). With isoprene as diene, a 1:1
mixture of regioisomers 6h and 6h’ was obtained in a combined yield of
70%. Myrcene is another naturally occurring and renewable[27] diene well
known in the perfume industry as feedstock for a number of fragrance
materials.[28] It also underwent readily the cycloaddition with ethyl 2-
pentynoate as dienophile in 72% (respectively 95%) yield with a regio-
isomeric ratio close to 1:1 for both reaction conditions. Unfortunately, the
electron-rich trimethylsilyloxy-substituted diene was not a suitable sub-
strate in the reaction, and no conversion was observed to yield 6q.
When using 2,3-dimethylbutadiene, we were pleased to observe that the
reaction proceeded exceptionally well. The corresponding products 6k-6q
were all formed in good yields, even though a higher substitution degree
at the β-position of the propiolate moiety heavily decreased its reactivity
and required longer reaction times (24 h), as shown in examples 6l-6p .
Moreover it is noteworthy that the 4,5-dimethylcyclohexa-1,4-diene
carboxylates are stable, even in the presence of ZnI2, and thus the reaction
can proceed in the presence of either ZnI2 or TMSCl as activation agent,
with higher productivity in most cases when using ZnI2 as an activating
agent.
Scheme 4. Reaction scope for the synthesis of 1,4-cyclohexadiene carboxylates from
2,3-dimethylbutadiene. Conditions A: Propiolate 5 (2.5 mmol, 1.0 equiv.), diene 4b
(5.0 mmol , 2.0 equiv.), CoBr2(dppe) (0.125 mmol, 5 mol%), Zn (0.5 mmol, 0.2 equiv.),
TMSCl (0.625 mmol, 0.25 equiv.), DCM (2.5 mL, 1M), 2h, 40 °C. Conditions B: Propio-
late 5 (2.5 mmol, 1.0 equiv.), diene 4b (5.0 mmol , 2.0 equiv.), CoBr2(dppe) (0.125
mmol, 5 mol%), Zn (0.5 mmol, 0.2 equiv.), ZnI2 (0.625 mmol, 0.25 equiv.), DCM (2.5
mL, 1M), 2h, 40 °C. The yields reported are isolated yields after column chromatog-
raphy or Kugelrohr distillation. [a] The reaction was run for 24 h.
Successful [2+4]-cycloaddition was also observed between hex-3-yn-2-one
(9) and myrcene 4c yielding 10 and 10’ in good yield as a 1.25:1 regioiso-
meric ratio, similarly to what has been observed for the cycloaddition
reaction of ethyl 2-pentynoate as dienophile with the same diene 4c,
yielding a 1.3:1 ratio of 6i and 6i’.
Scheme 5. Synthesis of 1-acetylcyclohexadiene 10.
When the cycloaddition of ethyl 2-pentynoate (5a) with butadienyl ben-
zene (4d) was run at a 25 mmol scale, it was possible to reduce the amount
Scheme 3. Synthesis of 1,4-cyclohexadiene carboxylates from 1- or 2-substituted
dienes. Conditions A: Propiolate 5 (2.5 mmol, 1.0 equiv.), diene 4 (5.0 mmol , 2.0
3
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10.1002/hlca.202000175
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of diene 4b to 1.05 equivalents while reaching 61% yield; which amounts
to 3.97 g of the regioisomeric mixture 6e and 6e’ as the final product.
Nevertheless, the origin of the strong regioselectivity with pentadiene or
when using an alkynyl ketone as dienophile cannot be explained through
this simplified reaction mechanism.
Scheme 6. 25 mmol scale synthesis of 6e+6e’.
The olfactive assessment of a series of final products 6a, b, e, h, k, l, m
and q indicate that these unsaturated cyclohexyl esters turn into the
expected green fruity, safranate-like direction. While 6a, 6h and 6k main-
tain the saffron-like spicy note of ethyl safranate, the C5 chain of 6q trig-
gers transitions towards heavier plumy, damascone-like notes.[1] Still, the
classical green apple and fruity tonality is present for all the structures
assessed.
Scheme 7. Postulated reaction mechanism of the cobalt-catalytic cycle for the
synthesis of 1,4-cyclohexadiene carboxylates. (P◠P corresponds to the bidentate
1,2-bis(diphenylphosphino)ethane (dppe) ligand).
Conclusions
Figure 2. Qualitative olfactive assessment of selected cyclohexadiene carboxylates 7.
Herein we present the successful synthesis and olfactive evaluation of a
series ofcyclohexa-1,4-diene carboxylates through formal [2+4] cycloaddi-
tion reactions of 1,3-dienes with substituted propiolates. The described
reaction allows to obtain cyclohexa-1,4-diene carboxylates which can bear
substituents in any of the remaining 4 positions of the 6-membered ring
by appropriate choice of the reacting diene. The reaction takes place
under mild reaction conditions with a readily available cobalt(II) complex
which is reduced in situ with metallic zinc, and is scalable to gram-scale
quantities, demonstrating the preparative usefulness of this transfor-
mation .
Based on mechanistic studies of a variety of carbon-carbon bond-forming
reactions catalyzed by low-valent cobalt, notably [4+2+2],[29] cross-
coupling,[30] hydrovinylation,[31] as well as [2+4][20] or [2+6][32-34] cycloaddi-
tion reactions, we propose the catalytic cycle depicted in Scheme 7. As a
first step, the Co(II)(dppe) complex[35] is being reduced to Co(I)(dppe) by
electron transfer from zinc, producing active cationic species A. The re-
quirement of an activation agent such as ZnI2 or TMSCl is attributed to the
removal of a passivated layer on the surface of metallic zinc, but the
exchange of the counteranion of the low-valent cobalt ate complex or the
formation of a dinuclear intermediate complex cannot be excluded.[29] In a
next step, coordination of the diene takes place producing intermediate
Experimental Section
diene complex B, as already described by Schäfer and co-workers for a
similar system.[20]
Further coordination of the alkyne moiety delivers C,
[30]
which undergo a metallocyclization forming complex D which in turn
undergoes olefin insertion to E followed by reductive elimination to the
final cycloaddition product 6. Alternatively, intermediate C can undergo a
direct [2+4]-cycloaddition delivering cyclohexadiene complex D’ which
can then release 6 and the active catalyst A as described through quantum
chemical calculations in the gas phase by Schäfer and co-workers.[12d]
General Procedures
Commercially available reagents were used without further purification.
Anhydrous solvents (acetonitrile and ethyl acetate) were purchased from
Sigma-Aldrich. Column Chromatography was performed on silica gel 60
Merck, particle size 40-63 m, Silicaflash P60 silica gel (40-60 mm) or a
4
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Biotage Isolera system SNAP Ultra prepacked cartridges. Mixtures of
hexane and ethyl acetate (EtOAc) were used as eluent. Thin layer chroma-
tography was performed on commercial 60-mesh silica gel plates, visuali-
zation was effected with short wavelength UV light (254 nm) and KMnO4
or Ceric sulfate staining reagent. 1H-NMR and 13C-NMR spectra were
recorded on a Bruker Avance III HD (400 MHz) spectrometer or Bruker
Avance DPX-500 spectrometer; δ in ppm, J in Hz. Chemical shifts are given
in ppm relative to internal TMS, while coupling constants are reported in
hertz (Hz). Deuterated chloroform and benzene were used as solvent. The
multiplicity signals were indicated with the common abbreviations: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad)
and the combinations thereof. In 13C-NMR spectra the solvent itself served
as the internal standard: CDCl3 ((C) = 77.00 ppm, t, JCD = 31.5 Hz). HPLC
high resolution mass spectra (LC-HRMS) were recorded on a Q-Exactive
Orbitrap (Thermo Scientific) instrument or on a JEOL AccuTof 4G spec-
trometer coupled to a GC HP Agilent 7890 in electrospray ionisation mode
(ESI).
Unless otherwise stated, a 25 mL 3-necked flask was charged under nitro-
gen atmosphere with Zn (33 mg, 0.5 mmol, 0.2 equiv.), ZnI2 (200 mg, 0.625
mmol, 0.25 equiv.) in 2.5 mL of DCM to which CoBr2(dppe) (77 mg, 0.125
mmol, 5 mol%) was added, yielding a green solution which gradually turns
to clear blue. Diene 4 (5.0 mmol , 2.0 equiv.) followed by propiolate 5 (2.5
mmol, 1.0 equiv.) were added via syringe, and the reaction mixture heated
to 40 °C over the course of 2 hours. The reaction mixture is filtered over a
plug of silica, washed with DCM and the volatiles evaporated. The product
was purified by flash column chromatography over silica gel as eluent to
yield the desired product.
Ethyl 2-ethyl-6-methylcyclohexa-1,4-diene-1-carboxylate (6a)
The product was synthesized according to General Procedure A using 0.5
mL of penta-1,3-diene (341 mg, 5.0 mmol, 2.0 equiv.) and 315 mg of ethyl
pent-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using
a gradient from 0-10% EtOAc in heptane, the title product was obtained as
yellowish oil in 59 % yield (288 mg, 1.48 mmol).
Not commercially available ethyl propiolates were synthesized according
to literature reference.[36]
The product was synthesized according to General Procedure B using 0.5
mL of penta-1,3-diene (341 mg, 5.0 mmol, 2.0 equiv.) and 315 mg of ethyl
pent-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using
hexane/MTBE (100:1) as eluent, the title product was obtained as slightly
yellow oil in 85 % yield (412 mg, 2.13 mmol).
1H NMR (400 MHz, CDCl3) δ = 5.71 – 5.66 (m, 1H), 5.66 – 5.61 (m, 1H), 4.28
– 4.18 (m, 2H), 3.29 – 3.16 (m, 1H), 2.87 – 2.77 (m, 1H), 2.73 – 2.61 (m, 1H),
2.34 – 2.23 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.07 (t, J =
7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ = 169.1, 144.0, 130.4, 128.1, 121.5,
60.0, 32.0, 30.8, 27.9, 21.4, 14.2, 13.0. HR-MS (ESI+): 195.1379 ([M + H]+,
C12H19O2+, calc. 195.1380), 193.1224 ([M + H – H2]+, C12H17O2+, calc.
193.1223).
1,2-Bis(diphenylphosphino)ethanedibromocobalt(II), CoBr2(dppe)
Cobalt(II) bromide (5.49 g, 25.10 mmol) was dissolved in tetrahydrofuran
(300 mL) in a 500 mL two-neck round-bottom flask equipped with a nitro-
gen bubbler. Ethylenebis(diphenylphosphine) (10 g, 25.10 mmol) was
added at once and the reaction mixture let to stir for 4 hours during which
the solution turned dark green. After 4 hours, the volatiles were evapo-
rated until only 50 ml of THF remained. 200 mL of hexane were added to
the mixture to fully precipitate the product. The resulting suspension was
filtered and the filtrate washed with hexane (blue washings). The green
product was then dried under vacuum at 40 °C, to afford CoBr2(dppe) (14.7
g, 23.82 mmol, 95 % yield) as a deep green solid. The product was used as
such, without further characterization nor purification.
Ethyl 2,6-dimethylcyclohexa-1,4-diene-1-carboxylate (6b)
The product was synthesized according to General Procedure A using 0.5
mL of penta-1,3-diene (341 mg, 5.0 mmol, 2.0 equiv.) and 280 mg of ethyl
but-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using a
gradient from 0-10% EtOAc in heptane, the title product was obtained as
yellowish oil in 62 % yield (278 mg, 1.54 mmol).
General Procedure A (TMSCl)
Unless otherwise stated, a 25 mL 3-necked flask was charged under nitro-
gen atmosphere with Zn (33 mg, 0.5 mmol, 0.2 equiv.), TMSCl (0.625
mmol, 0.25 equiv.) in 2.5 mL of DCM to which CoBr2(dppe) (77 mg, 0.125
mmol, 5 mol%) was added, yielding a green solution which gradually turns
to clear blue. Diene 4 (5.0 mmol , 2.0 equiv.) followed by propiolate 5 (2.5
mmol, 1.0 equiv.) were added via syringe, and the reaction mixture heated
to 40 °C over the course of 2 hours. The reaction mixture is filtered over a
plug of silica, washed with DCM and the volatiles evaporated. The product
was purified by flash column chromatography over silica gel to yield the
desired product.
The product was synthesized according to General Procedure B using 0.5
mL of penta-1,3-diene (341 mg, 5.0 mmol, 2.0 equiv.) and 280 mg of ethyl
but-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using
hexane/MTBE (100:1) as eluent, the title product was obtained as slightly
yellow oil in 52 % yield (234 mg, 1.30 mmol).
1H NMR (400 MHz, CDCl3) δ = 5.72 – 5.60 (m, 1H), 5.63 – 5.56 (m, 1H), 4.28
– 4.13 (m, 2H), 3.28 – 3.17 (m, 1H), 2.83 – 2.72 (m, 1H), 2.70 – 2.59 (m, 1H),
1.94 – 1.93 (m, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.06 (d, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ = 169.0, 139.3, 130.6, 128.4, 121.2, 59.9, 33.8, 31.9, 21.5,
21.0, 14.3. HR-MS (ESI+): 181.1221 ([M + H]+, C11H17O2+, calc. 181.1223),
179.1066 ([M + H – H2]+, C11H15O2+, calc. 179.1067).
General Procedure B (ZnI2)
5
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Ethyl 2-isopropyl-6-methylcyclohexa-1,4-diene-1-carboxylate (6c)
Ethyl 2-ethyl-1,4-dihydro-[1,1'-biphenyl]-3-carboxylate (6f) and
Ethyl 3-ethyl-1,4-dihydro-[1,1'-biphenyl]-2-carboxylate (6f’)
The product was synthesized according to General Procedure B using 0.5
mL of penta-1,3-diene (341 mg, 5.0 mmol, 2.0 equiv.) and 350 mg of ethyl
4-methylpent-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatog-
raphy using hexane/MTBE (100:1) as eluent, the title product was obtained
as a yellowish oil in 39 % yield (200 mg, 0.97 mmol).
1H NMR (400 MHz, CDCl3) δ = 5.37 – 5.77 (m, 1 H), 5.15 – 5.31 (m, 1 H), 4.24
(td, J=7.09, 2.20 Hz, 2 H), 3.22 (spt, J=7.34 Hz, 1 H), 3.12 – 3.19 (m, 1 H),
2.99 – 3.09 (m, 2 H), 1.31 (t, J=7.09 Hz, 3 H), 1.05 (t, J=3.42 Hz, 6 H), 0.99 (d,
J=6.85 Hz, 3 H). 13C NMR (101 MHz, CDCl3) δ = 169.99, 144.19, 131.49,
130.12, 121.85, 60.07, 32.30, 31.32, 24.20, 21.21, 20.67, 14.25. HR-MS
(ESI+): 209.1534 ([M + H]+, C13H21O2+, calc. 209.1536), 207.1378 ([M + H –
H2]+, C13H19O2+, calc. 207.1380).
The product was synthesized according to General Procedure A using 0.5
mL of buta-1,3-dien-1-ylbenzene (380 mg, 2.92 mmol, 1.17 equiv.) and 315
mg of ethyl pent-2-ynoate (2.5 mmol, 1.0 equiv.). After column chroma-
tography using a gradient from 0-10% EtOAc in heptane, the title product
was obtained as clear oil in 25 % yield (160 mg, 0.62 mmol) as a 1.6 to 1
ratio of both regioisomers 6f and 6f’.
The product was synthesized according to General Procedure B using
buta-1,3-dien-1-ylbenzene (651 mg, 5.0 mmol, 2.0 equiv.) and 315 mg of
ethyl pent-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatography
using hexane/MTBE (100:1) as eluent and bulb-to-bulb distillation (150 °C,
0.19 mbar), the title product was obtained as a yellow ishoil in 90 % yield
(575 mg, 2.27 mmol) as a mixture of both regioisomers 6f and 6f’ in a 1.6 to
1 ratio.
Ethyl 6-methyl-2-pentylcyclohexa-1,4-diene-1-carboxylate (6d)
1H NMR (400 MHz, CDCl3, major + minor) δ = 7.33 – 7.10 (m, 5Hmaj + 5Hmin),
The product was synthesized according to General Procedure A using 0.5
mL of penta-1,3-diene (341 mg, 5.0 mmol, 2.0 equiv.) and 421 mg of ethyl
oct-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using a
gradient from 0-10% EtOAc in heptane, the title product was obtained as
yellowish oil in 57 % yield (336 mg, 1.42 mmol).
1H NMR (400 MHz, CDCl3) δ = 5.70 – 5.59 (m, 2H), 4.28 – 4.16 (m, 2H), 3.27
– 3.16 (m, 1H), 2.79 – 2.74 (m, 1H), 2.72 – 2.67 (m, 1H), 2.32 – 2.19 (m, 2H),
1.53 – 1.38 (m, 2H), 1.36 – 1.24 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (d, J =
6.9 Hz, 3H), 0.92 – 0.86 (m, 3H). 13C NMR (101 MHz, CDCl3) δ = 169.2,
142.7, 130.5, 128.6, 121.6, 59.9, 34.7, 32.1, 31.9, 31.4, 28.2, 22.5, 21.4, 14.3,
14.0. HR-MS (ESI+): 237.1847 ([M + H]+, C15H25O2+, calc. 237.1849).
5.83 – 5.66 (m, 2Hmaj + 2Hmin), 4.42 – 4.36 (m, 1Hmaj), 4.28 – 4.14 (m, 2Hmin),
4.05 – 3.92 (m, 2Hmaj +1Hmin), 3.19 – 3.08 (m, 1Hmin), 3.07 – 2.95 (m, 1Hmaj
+
1Hmin), 2.85 - 2.75 (m, 1Hmaj), 2.60 (dq, J = 13.0, 7.5 Hz, 1Hmin), 2.52 - 2.29
(m, 2Hmaj), 1.96 – 1.84 (m, 1Hmin), 1.31 (t, J = 7.1 Hz, 3Hmin), 1.13 (t, J = 7.5 Hz,
3Hmaj), 1.05 (t, J = 7.1 Hz, 3Hmaj), 0.96 (t, J = 7.5 Hz, 3Hmin). 13C NMR (101
MHz, CDCl3, major) δ =168.0, 145.8, 144.1, 129.0, 128.3, 128.1, 126.3,
126.0, 121.2, 59.8, 44.1, 31.2, 27.9, 13.9, 13.1. 13C NMR (101 MHz, CDCl3,
minor) δ =168.4, 149.6, 143.6, 128.6, 128.5, 128.1, 126.7, 122.9, 122.4, 60.2,
47.1, 28.2, 25.9, 14.2, 13.1 ppm. HR-MS (ESI+): 257.1535 ([M + H]+,
C17H21O2+, calc. 257.1536).
Ethyl 3-pentyl-1,4-dihydro-[1,1'-biphenyl]-2-carboxylate (6g, major)
and ethyl 2-pentyl-1,4-dihydro-[1,1'-biphenyl]-3-carboxylate (6g’,
minor)
Ethyl 2-methyl-1,4-dihydro-[1,1'-biphenyl]-3-carboxylate (6e) and
Ethyl 3-methyl-1,4-dihydro-[1,1'-biphenyl]-2-carboxylate (6e’).
The product was synthesized according to General Procedure A using 0.5
mL of buta-1,3-dien-1-ylbenzene (342 mg, 1.63 mmol, 1.05 equiv.) and 280
mg of ethyl but-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatog-
raphy using a gradient from 0-10% EtOAc in heptane, the title product was
obtained as yellowish oil in 26 % yield (160 mg, 0.66 mmol) in a 2.1:1 ratio
of regisoisomers 6e and 6e’.
The product was synthesized according to General Procedure A using 0.5
mL of buta-1,3-dien-1-ylbenzene (380 mg, 2.92 mmol, 1.17 equiv.) and 350
mg of ethyl oct-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatog-
raphy using a gradient from 0-10% EtOAc in heptane, the title product was
obtained as clear oil in 47% yield (320 mg, 1.18 mmol) as a 1.5 to 1 ratio of
both regioisomers 6g and 6g’.
1H NMR (400 MHz, CDCl3, major + minor) δ = 7.33 – 7.12 (m, 5Hmaj + 5Hmin),
5.80 (dtd, J = 10.0, 3.5, 1.5 Hz, 1Hmaj), 5.77 – 5.72 (m, 1Hmin), 5.71 – 5.63 (m,
1Hmaj + 1Hmin), 4.43 – 4.36 (m, 1Hmin), 4.21 (q, J = 7.1 Hz, 2Hmaj), 4.05 – 3.93
(m, 2Hmin), 3.89 – 3.82 (m, 1Hmaj), 3.11 - 3.05 (m, 2Hmaj), 3.01 – 2.91 (m,
1Hmin), 2.83 – 2.73 (m, 1Hmin), 2.07 – 2.05 (m, 3Hmin), 1.88 (t, J = 1.5 Hz, 3Hmaj),
1.30 (t, J = 7.1 Hz, 3Hmaj), 1.05 (t, J = 7.1 Hz, 1Hmin). 13C NMR (101 MHz, CDCl3,
major) δ = 168.4, 144.5, 143.4, 128.6, 128.4, 127.7, 126.7, 123.0, 122.4, 60.1,
50.1, 28.0, 20.1, 14.3. 13C NMR (101 MHz, CDCl3, minor) δ = 168.0, 144.1,
140.8, 129.1, 128.3, 128.1, 126.4, 126.3, 121.0, 59.8, 44.0, 34.0, 21.1, 13.9.
HR-MS (ESI+): 243.1379 ([M + H]+, C16H19O2+, calc. 243.1380).
1H NMR (400 MHz, CDCl3, major + minor) δ = 7.35 – 7.10 (m, 5Hmaj + 5Hmin),
5.83 – 5.66 (m, 2Hmaj + 2Hmin), 4.43 – 4.37 (m, 1Hmaj), 4.26 – 4.16 (m, 2Hmin),
4.04 – 3.92 (m, 2Hmaj + 1Hmin), 3.19 – 2.94 (m, 1Hmaj + 2Hmin), 2.85 – 2.76 (m,
1Hmaj), 2.64 – 2.55 (m, 1Hmin), 2.52 – 2.30 (m, 2Hmaj), 1.87 – 1.78 (m, 1Hmin),
1.62 – 1.20 (m, 6Hmaj + 6Hmin), 1.30 (t, J = 7.1, 3Hmin), 1.05 (t, J = 7.1 Hz,
3Hmaj), 0.90 (t, J = 7.0 Hz, 3Hmaj), 0.84 (t, J = 7.0 Hz, 3Hmin). 13C NMR (101
MHz, CDCl3, major) δ = 168.0, 144.5, 144.1, 129.0, 128.3, 128.1, 126.4,
126.3, 121.2, 59.8, 44.1, 34.8, 32.0, 31.7, 28.4, 22.5, 14.0, 14.0. 13C NMR
(101 MHz, CDCl3, minor) δ = 168.5, 148.4, 143.7, 128.6, 128.5, 128.1, 126.7,
6
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10.1002/hlca.202000175
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HELVETICA
123.1, 122.4, 60.1, 47.5, 32.7, 32.1, 28.5, 28.3, 22.4, 14.3, 14.0. HR-MS
(ESI+): 299.2002 ([M + H]+, C20H26O2+, calc. 299.2006).
26.1, 25.7, 17.7, 14.3, 12.9. 13C NMR (101 MHz, CDCl3, minor) δ =168.3,
148.2, 133.4, 131.7, 124.0, 121.5, 117.9, 59.9, 36.6, 35.1, 28.9, 28.0, 25.9,
25.7, 17.7, 14.3, 12.8. HR-MS (ESI+): 263.2005 ([M + H]+, C17H27O2+, calc.
263.2006).
Ethyl 2-ethyl-5-methylcyclohexa-1,4-diene-1-carboxylate (6h) and
ethyl 2-ethyl-4-methylcyclohexa-1,4-diene-1-carboxylate (6h’)
Ethyl 2,4,5-trimethylcyclohexa-1,4-diene-1-carboxylate (6k)
The product was synthesized according to General Procedure B using 0.5
mL of isoprene (341 mg, 5.0 mmol, 2.0 equiv.) and 315 mg of ethyl pent-2-
ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using hex-
ane/MTBE (50:1) as eluent, the title product was obtained as a yellow oil in
70 % yield (340 mg, 1.75 mmol) as a mixture of both regioisomers 6h and
6h’ in a 1 to 1 ratio.
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv.) and 280
mg of ethyl but-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatog-
raphy using a gradient from 0-10% EtOAc in heptane, the title product was
obtained as yellowish oil in 53 % yield (255 mg, 1.37 mmol).
6h: 1H NMR (400 MHz, CDCl3) δ = 5.36 – 5.32 (m, 1H), 4.20 (q, J = 7.1 Hz,
2H), 2.85 – 2.79 (m, 4H), 2.41 (q, J = 7.6 Hz, 2H), 1.71 – 1.69 (m, 3H), 1.31 (t,
J = 7.1 Hz, 3H), 1.07 ppm (t, J = 7.5 Hz, 3H).13C NMR (101 MHz, CDCl3) δ =
168.2, 148.3, 131.3, 121.3, 117.0, 59.9, 32.8, 32.6, 27.7, 22.7, 14.3, 12.9. HR-
MS (ESI+): 195.1378 ([M + H]+, C12H19O2+, calc. 195.1380), 193.1223 ([M + H
– H2]+, C12H17O2+, calc. 193.1223).
6h’: 1H NMR (400 MHz, CDCl3) δ = 5.44 – 5.40 (m, 1H), 4.19 (q, J = 7.1 Hz,
2H), 2.97 – 2.89 (m, 2H), 2.73 – 2.66 (m, 2H), 2.41 (q, J = 7.3 Hz, 2H), 1.69 –
1.67 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.08 ppm (t, J = 7.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ = 168.3, 147.9, 129.6, 121.4, 118.3, 59.9, 36.5, 28.9,
27.8, 22.5, 14.2, 12.8. HR-MS (ESI+): 195.1378 ([M + H]+, C12H19O2+, calc.
195.1380), 193.1223 ([M + H – H2]+, C12H17O2+, calc. 193.1223).
The product was synthesized according to General Procedure B using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv.) and 280
mg of ethyl but-2-ynoate (2.5 mmol, 1.0 equiv.). After column chromatog-
raphy using hexane/MTBE (50:1) as eluent, the title product was obtained
as a yellowish oil in 80 % yield (388 mg, 2.00 mmol).
1H NMR (400 MHz, CDCl3) δ = 4.20 (q, J = 7.1 Hz, 2H), 2.89 – 2.82 (m, 2H),
2.74 – 2.67 (m, 2H), 2.05 – 2.02 (m, 3H), 1.67 – 1.64 (m, 3H), 1.64 – 1.61 (m,
3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3 δ = 168.2, 143.8,
123.2, 121.9, 121.4, 59.8, 41.8, 34.5, 20.8, 18.0, 17.7, 14.3. HR-MS (ESI+):
195.1378 ([M + H]+, C12H19O2+, calc. 195.1380), 193.1223 ([M + H – H2]+,
C12H17O2+, calc. 193.1223).
Ethyl 2-isopropyl-4,5-dimethylcyclohexa-1,4-diene-1-carboxylate
(6l)
Ethyl
2-ethyl-5-(4-methylpent-3-en-1-yl)cyclohexa-1,4-diene-1-
carboxylate (6i) and Ethyl 2-ethyl-4-(4-methylpent-3-en-1-
yl)cyclohexa-1,4-diene-1-carboxylate (6i’)
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv and 350
mg of ethyl 4-methylpent-2-ynoate (2.5 mmol, 1.0 equiv.). After column
chromatography using a gradient from 0-10% EtOAc in heptane, the title
product was obtained as a pale yellow oil in 65 % yield (361 mg, 1.62
mmol).
The product was synthesized according to General Procedure A using 0.86
mL of myrcene (681 mg, 5.0 mmol, 2.0 equiv.) and 315 mg of ethyl pent-2-
ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using a
gradient from 0-10% EtOAc in heptane, the title product was obtained as
yellowish oil in 72 % yield (490 mg, 1.87 mmol) as a mixture of both regioi-
somers 6i and 6i’ in a 1.3 to 1 ratio.
The product was synthesized according to General Procedure B using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv.) and 350
mg of ethyl 4-methylpent-2-ynoate (2.5 mmol, 1.0 equiv.) and the reaction
was run for 24 hours. After column chromatography using hexane/MTBE
(50:1) as eluent, the title product was obtained as a slightly yellow oil in
59% yield (330 mg, 1.48 mmol).
1H NMR (400 MHz, CDCl3) δ = 4.19 (q, J = 7.1 Hz, 2H), 3.44 – 3.32 (m, 1H),
2.87 – 2.81 (m, 2H), 2.69 – 2.63 (m, 2H), 1.67 – 1.64 (m, 6H), 1.30 (t, J = 7.1
Hz, 3H), 1.03 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3 δ = 169.0, 149.0,
122.7, 121.8, 121.7, 60.0, 35.0, 31.9, 30.4, 20.7, 18.1, 17.9, 14.3. HR-MS
(ESI+): 223.1691 ([M + H]+, C14H23O2+, calc. 223.1693).
The product was synthesized according to General Procedure B using 0.86
mL of myrcene (681 mg, 5.0 mmol, 2.0 equiv.) and 315 mg of ethyl pent-2-
ynoate (2.5 mmol, 1.0 equiv.). After column chromatography using hex-
ane/MTBE (100:1) as eluent, the title product was obtained as a yellow oil
in 95 % yield (0.62 mg, 2.36 mmol) as a mixture of both regioisomers 6i
and 6i’ in a 1.1 to 1 ratio.
1H NMR (400 MHz, CDCl3, major + minor) δ = 5.46 – 5.42 (m, 1Hmin), 5.38 –
5.34 (m, 1Hmaj), 5.15 – 5.05 (m, 1Hmaj + 1Hmin), 4.20 (q, J = 7.1 Hz, 2Hmaj), 4.19
(q, J = 7.1 Hz, 2Hmin), 2.99 – 2.91 (m, 2Hmin), 2.89 – 2.78 (m, 4Hmaj), 2.75 –
2.68 (m, 2Hmin), 2.46 – 2.35 (m, 2Hmaj + 2Hmin), 2.16 – 2.07 (m, 2Hmaj
2Hmin), 2.04 – 1.96 (m, 2Hmaj + 2Hmin), 1.68 (s, 3Hmaj + 3Hmin), 1.61 (s, 3Hmaj
+
+
Ethyl 2-(tert-butyl)-4,5-dimethylcyclohexa-1,4-diene-1-carboxylate
3Hmin), 1.31 (t, J = 7.1 Hz, 3Hmaj), 1.29 (t, J = 7.1 Hz, 3Hmin), 1.08 (t, J = 7.5 Hz,
3Hmin), 1.07 (t, J = 7.5 Hz, 3Hmaj). 13C NMR (101 MHz, CDCl3, major) δ =
168.3, 148.3, 135.0, 131.6, 124.1, 121.5, 116.6, 60.0, 36.8, 32.8, 31.1, 27.8,
(6m)
7
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10.1002/hlca.202000175
Helvetica Chimica Acta
HELVETICA
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv and 386
mg of ethyl 4,4-dimethylpent-2-ynoate (2.5 mmol, 1.0 equiv.) and the
reaction was run for 24 hours. After column chromatography using a
gradient from 0-10% EtOAc in heptane, the title product was obtained as a
clear yellowish oil in 10 % yield (56 mg, 0.23 mmol).
The product was synthesized according to General Procedure B using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv.) and 435
mg of ethyl 3-phenylpropiolate (2.5 mmol, 1.0 equiv.) and the reaction was
run for 24 hours. After column chromatography using hexane/MTBE
(100:1) as eluent, the title product was obtained as a faint yellow oil in 65
% yield (417 mg, 1.62 mmol).
The product was synthesized according to General Procedure B using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv.) and 386
mg of ethyl 4,4-dimethylpent-2-ynoate (2.5 mmol, 1.0 equiv.) and the
reaction was run for 24 hours. After column chromatography using hex-
ane/MTBE (100:1) as eluent, the title product was obtained as a yellowish
oil in 72 % yield (428 mg, 1.81 mmol).
1H NMR (400 MHz, CDCl3) δ = 7.33 – 7.22 (m, 3H), 7.17 – 7.12 (m, 2H), 3.89
(q, J = 7.2 Hz, 2H), 3.06 – 3.00 (m, 2H), 3.00 – 2.93 (m, 2H), 1.73 – 1.70 (m,
3H), 1.67 – 1.65 (m, 3H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3 δ
= 168.9, 143.6, 142.6, 128.0, 127.0, 126.7, 125.1, 122.8, 122.0, 60.0, 40.9,
34.9, 18.0, 17.9, 13.6. HR-MS (ESI+): 257.1531 ([M + H]+, C17H21O2+, calc.
257.1536), 255.1377 ([M + H – H2]+, C17H19O2+, calc. 255.1380).
1H NMR (400 MHz, CDCl3) δ = 4.18 (q, J = 7.2 Hz, 2H), 2.81 – 2.74 (m, 2H),
2.69 – 2.63 (m, 2H), 1.65 – 1.63 (m, 3H), 1.63 – 1.61 (m, 3H), 1.31 (t, J = 7.1
Hz, 3H), 1.14 (s, 9H). 13C NMR (101 MHz, CDCl3 δ = 173.2, 140.2, 123.3,
123.1, 121.5, 60.5, 37.4, 36.1, 34.4, 29.4, 18.2, 17.6, 14.0. HR-MS (ESI+):
237.1846 ([M + H]+, C15H25O2+, calc. 237.1849), 235.1692 ([M + H – H2]+,
C15H23O2+, calc. 235.1693).
Ethyl 4,5-dimethyl-[1,1'-bi(cyclohexane)]-1,4-diene-2-carboxylate
(6p)
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv and 451
mg of ethyl 3-cyclohexylpropiolate (2.5 mmol, 1.0 equiv.) and the reaction
was run for 24 hours. After column chromatography using a gradient from
0-10% EtOAc in heptane, the title product was obtained as yellowish oil in
70 % yield (456 mg, 1.74 mmol).
Ethyl 2-cyclopropyl-4,5-dimethylcyclohexa-1,4-diene-1-carboxylate
(6n)
1H NMR (400 MHz, CDCl3) δ = 4.20 (q, J = 7.2 Hz, 2H), 3.06 – 2.97 (m, 1H),
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv and 345
mg of ethyl 3-cyclopropylpropiolate (2.5 mmol, 1.0 equiv.) and the reac-
tion was run for 24 hours. After column chromatography using a gradient
from 0-10% EtOAc in heptane, the title product was obtained as yellowish
oil in 17 % yield (912mg, 0.42 mmol).
2.88 – 2.81 (m, 2H), 2.71 – 2.64 (m, 2H), 1.80 – 1.59 (m, 6H), 1.65 – 1.63 (m,
6H), 1.36 – 1.25 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3
δ
= 169.0, 149.0, 122.7, 121.8, 121.7, 59.9, 41.6, 35.0, 33.6, 30.9, 26.5, 26.2,
+
18.1, 17.9, 14.3. HR-MS (ESI+): 263.2004 ([M
+
H]+, C17H27O2
,
calc.
263.2006).
The product was synthesized according to General Procedure B using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv.) and 345
mg of ethyl 3-cyclopropylpropiolate (2.5 mmol, 1.0 equiv.) and the reac-
tion was run for 24 hours. After column chromatography using hex-
ane/MTBE (50:1) as eluent, the title product was obtained as a clear oil in
48 % yield (263 mg, 1.19 mmol).
1H NMR (400 MHz, CDCl3) δ = 4.22 (q, J = 7.2 Hz, 2H), 2.88 (br t, J = 7.2 Hz,
2H), 2.60 (tt, J = 8.5, 5.7 Hz, 1H), 2.33 (br t, J = 7.2 Hz, 2H), 1.66 – 1.63 (m,
3H), 1.62 – 1.59 (m, 3H), 1.31 (t, J = 7.1 Hz, 3H), 0.74 - 0.62 (m, 4H). 13C NMR
Ethyl 4,5-dimethyl-2-pentylcyclohexa-1,4-diene-1-carboxylate (6q)
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv and 421
mg of ethyl oct-2-ynoate (2.5 mmol, 1.0 equiv.) and the reaction was run
for 24 hours. After column chromatography using a gradient from 0-10%
EtOAc in heptane, the title product was obtained as yellowish oil in 44 %
yield (275 mg, 1.10 mmol).
1H NMR (400 MHz, CDCl3) δ = 4.19 (q, J = 7.1 Hz, 2H), 2.90 – 2.82 (m, 2H),
2.76 – 2.69 (m, 2H), 2.41 – 2.34 (m, 2H), 1.66 – 1.64 (m, 3H), 1.64 – 1.62 (m,
3H), 1.51 – 1.42 (m, 2H), 1.37 – 1.27 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H), 0.91 –
0.87 (m, 3H). 13C NMR (101 MHz, CDCl3 δ = 168.2, 147.5, 123.1, 121.9, 121.6,
59.8, 39.5, 34.7, 34.4, 32.1, 28.3, 22.6, 17.9, 17.8, 14.3, 14.0. HR-MS (ESI+):
251.2005 ([M + H]+, C16H27O2+, calc. 251.2006).
(101 MHz, CDCl3 δ = 168.9, 145.6, 123.12, 123.10, 121.0, 60.0, 35.2, 33.0,
+
18.0, 17.9, 14.32, 14.29, 5.2. HR-MS (ESI+): 221.1533 ([M + H]+, C14H21O2
calc. 221.1536), 219.1379 ([M + H – H2]+, C14H19O2+, calc. 219.1380).
,
Ethyl 4,5-dimethyl-3,6-dihydro-[1,1'-biphenyl]-2-carboxylate (6o)
The product was synthesized according to General Procedure A using 0.57
mL of 2,3-dimethylbuta-1,3-diene (411 mg, 5.0 mmol, 2.0 equiv and 435
mg of ethyl 3-phenylpropiolate (2.5 mmol, 1.0 equiv.) and the reaction was
run for 24 hours. After column chromatography using a gradient from 0-
10% EtOAc in heptane, the title product was obtained as yellowish oil in 27
% yield (172 mg, 0.67 mmol).
1-(2-Ethyl-4-(4-methylpent-3-en-1-yl)cyclohexa-1,4-dien-1-
yl)ethan-1-one (10) and 1-(2-ethyl-5-(4-methylpent-3-en-1-
yl)cyclohexa-1,4-dien-1-yl)ethan-1-one (10’)
8
This article is protected by copyright. All rights reserved.

10.1002/hlca.202000175
Helvetica Chimica Acta
HELVETICA
The product was synthesized according to General Procedure A using 0.86
mL of myrcene (681 mg, 5.0 mmol, 2.0 equiv.) and 240 mg of hex-3-yn-2-
one (2.5 mmol, 1.0 equiv.) and the reaction was run for 5 hours. After
column chromatography using a gradient from 0-10% EtOAc in heptane,
the title product was obtained as clear oil in 75 % yield (432 mg, 1.86
mmol) as a mixture of both regioisomers 10 and 10’ in a 1.25 to 1 ratio.
1H NMR (400 MHz, CDCl3, major + minor) δ = 5.48 – 5.43 (m, 1Hmaj), 5.42 –
5.38 (m, 1Hmin), 5.14 – 5.07 (m, 1Hmaj + 1Hmin), 2.97 – 2.90 (m, 2Hmaj), 2.87 –
2.75 (m, 4Hmin), 2.72 – 2.66 (m, 2Hmaj), 2.29 – 2.19 (m, 2Hmaj + 2Hmin), 2.27
(s, 3Hmin), 2.24 (s, 3Hmaj), 2.16 – 2.08 (m, 2Hmaj + 2Hmin), 2.06 – 1.97 (m, 2Hmaj
+ 2Hmin), 1.70 – 1.68 (m, 3Hmaj + 3Hmin), 1.61 (s, 3Hmaj + 3Hmin), 1.07 (t, J = 7.5
Hz, 3Hmaj), 1.06 (t, J = 7.5 Hz, 3Hmin). 13C NMR (101 MHz, CDCl3, major) δ =
203.7, 143.1, 134.4, 134.2, 131.7, 123.9, 117.2, 36.6, 34.2, 29.8, 29.1, 27.5,
25.9, 25.7, 17.7, 12.9. 13C NMR (101 MHz, CDCl3, minor) δ = 203.8, 142.9,
131.7, 130.4, 130.2, 123.9, 117.3, 36.8, 31.8, 31.4, 29.8, 27.3, 26.0, 25.7, 17.7,
13.0. HR-MS (ESI+): 233.1899 ([M + H]+, C16H25O+, calc. 233.1900).
Conflict of Interest
The authors are employees of Givaudan S.A., a commercial producer of
perfumes and perfume ingredients.
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Synthesis of cyclohexa-1,4-diene carboxylates through a low-valent cobalt catalyzed [2+4] cycloadditions with substituted propiolates as
dienophiles.
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