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SYNLETT0936-52141437-2096

© Georg Thieme Verlag Stuttgart · New York


2015, 26, 2462–2466 2462
letter

Syn lett C. R. Larsen et al. Letter

A Facile, Convenient, and Green Route to (E)-Propenylbenzene Fla-


vors and Fragrances by Alkene Isomerization
Casey R. Larsen
Erik R. Paulson1
Gulin Erdogan1
Douglas B. Grotjahn*

San Diego State University, Department of Chemistry and Biochemistry,


5500 Campanile Drive, San Diego, CA, 92182-1030, USA
dbgrotjahn@mail.sdsu.edu

This article is dedicated to Peter Vollhardt with gratitude for his creative,
scientific, and mentoring influences, and his love of one-pot reactions

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Received: 30.03.2015 is the major volatile component in sassafras12 and long pep-
Accepted after revision: 30.07.2015
per oil.23 Isosafrole is an important intermediate for the
Published online: 08.09.2015
DOI: 10.1055/s-0035-1560205; Art ID: st-2015-b0231-l synthesis of pharmaceutical compounds, such as strigol,24
amphetamines,25 and piperonal fragrance.2,26
Abstract (E)-Propenylbenzene flavors and fragrances can be made Early manufacture of valuable phenylpropenoids on
and isolated in high yield and selectivity by using bifunctional catalyst
1, and the heterogenized analogues. Multigram-scale reactions can be
commercial scale was done using stoichiometric or excess
performed neat and the products isolated either by distillation, using base at temperatures over 200 °C,27 but with modest E/Z se-
homogeneous catalyst 1 (0.1–0.5 mol%, r.t., 10–45 min), or by decan- lectivity (82:18). According to food regulations, exceeding
tation from heterogeneous catalysts PS-1 or PSL-1 (0.5 mol%, 70 °C, 24 h; any more than 1% cis isomer cannot be tolerated due to its
catalyst separation and re-use shown for 3–4 cycles; 10 cycles using dis- toxicity and unpleasant taste.28–31 Transition-metal cata-
tilled eugenol feedstock). Both purified starting materials and essential
oil feedstocks could be used. Z Isomers were present at very low levels
lysts generally isomerize allyl benzene flavors and fragranc-
(from 0.4% to less than 0.1%) in the products. es to their phenylpropene analogues at moderate tempera-
tures, but high E/Z selectivity remains a challenge, as re-
Key words alkenes, isomerization, flavors, fragrances, homogeneous ported for complexes of titanium,32 iron,33 nickel,34
catalysis, heterogeneous catalysis
ruthenium,35–38 rhodium,39 and platinum,40 where a compi-
lation of such has been documented in a recent review.41
The flavor and fragrance industry continues to grow, Basic ligands,42 bases grafted onto zeolite43,44 and metals in-
with a total worldwide market of $16 billion annually in tegrated into hydrotalcites,35,45 have also been reported for
2002,2 estimated at $25 billion in 2014.3 Allyl benzenes, the isomerization of these compounds. A platinum catalyst
such as estragole, eugenol, and safrole are major constitu- converts allyl benzenes at 50 °C into moderate yields (38–
ents of essential oils. Commercial processes convert the 60%) and insufficient E/Z selectivity (63:37 to 97:3).40 Mi-
compounds into their propenyl analogues, anethole, isoeu- crowave isomerization of allyl benzenes using KF/Al2O3 al-
genol, and isosafrole. trans-Anethole is an important com- lows for high conversions (>96%) with variable E/Z selectivi-
modity with an annual global production of 750,000 tons ty (<91:6).46 As far as we are aware, the most promising
per year4 and is produced on the largest scale from star an- combinations of yield and selectivity come from [RuCl2(η6-
ise and anise2,5 and fennel oils.2 trans-Anethole is produced C6H5OCH2CH2OH)(L)] [L = P(OMe)3] for the conversion of
by the isomerization of estragole and finds applications in estragole into anethole in 99% yield with >99% E selectivity
the perfumery industry,6 food and beverage industries,7 for- at 80 °C in 15 minutes.37 [RuCl2(η6-cymene)(P(OMe)3)]
mulation of oral sanitation products,8 and as an important formed in situ achieved similar yield, but the distilled prod-
intermediate in the synthesis of pharmaceutical com- uct was insufficient in E selectivity (98%) to comply with
pounds.9–11 Eugenol is the major constituent of volatile oils regulations cited above.47 Chemical companies Rhone-
derived from cloves12–14 and cinnamon,15 whereas isoeuge- Poulenc48 and Givaudan49 explored catalysts for isomeriza-
nol is minor.5 Isoeugenol is used in perfumes2,16 and vanil- tion of these compounds, where the best afforded 10% and
lin,17 and used for antioxidant,18,19 anxiolytic, antidepres- 6% (Z)-propenylarene, respectively; the latter product also
sant,20 insecticidal,21 and antimicrobial22 properties. Safrole contained some unreacted starting material.

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2462–2466
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Syn lett C. R. Larsen et al. Letter

Industrial demand for phenylpropenoids such as trans- stituent of rhizome63 and Russian tarragon64 oils. Catalyst 1
anethole, isoeugenol, and isosafrole has increased, prompt- interacts selectively with the allyl moiety of allyl tiglate (7),
ing more efficient and green processes for their production, a flavoring,65 leaving the tiglate moiety untouched. In sum-
with minimal use of energy, excess reagent base, solvent for mary, at low loadings and ambient temperatures, homoge-
reaction or extraction, or fractional distillation because of neous catalyst 1 in acetone solvent very easily converts fla-
isomeric mixtures. vors and fragrances into the desired E products.
We have previously shown that homogeneous catalyst 1 Heterogeneous isomerization catalysts PS-1 and PSL-1
(Figure 1) isomerizes many types of substrates, moving ter- show the same high selectivity as 1 (Table 1). For example,
minal alkenes on unhindered chains extensively (up to 30 estragole (2) is completely converted into (E)-anethole (2a)
bonds), with high E selectivity.50,51 In addition, hydrogen– using 2 mol% PS-1 and PSL-1 in 20 minutes. Looking at the
deuterium exchange occurs in the presence of D2O under other entries of Table 1, in a few cases 70 °C was used, but
isomerization conditions using 1.52,53 The bifunctional li- most reactions could be conducted at room temperature.
gand basic nitrogen has been shown to lead to >3000-fold Comparing rates of homogeneous and heterogeneous cata-
increases in catalytic activity.54 Finally, we reported the lysts in entry 1 (Table 1), 40 times more heterogeneous cat-
synthesis and application of heterogenized isomerization alyst was used but the reaction time for completion was

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catalysts.55 The linker between the active site and the poly- half as long, indicating that the heterogeneous systems
styrene resin is either a short CH2 bridge (PS-1) or longer were about 20 times slower, but still usefully active; note
(PSL-1) to allow greater distance and mobility between the that even the best homogeneous allylbenzene-to-propenyl-
catalytic active site and polymer (Figure 1). benzene catalysts reported by Cadierno and Crochet require
heating at 80 °C to achieve 15 minutes reaction time (5 min
Cp using microwave irradiation).37
Cp PF6 Isomerization reactions in acetone solvent occur in a
PF6 Ru
Ru MeCN P smooth and facile manner using both 1 and its heteroge-
MeCN P N nized analogues, but the ability to conduct completely sol-
N N X vent-free reactions would make for even more convenient
N
and greener reaction conditions. We examined multigram-
1 scale reactions of neat liquid substrates using the homoge-
PS-1: X = CH2
neous catalyst 1, extending our previous single reported at-
PSL-1: X = (CH2)3OCH2 tempt to several natural oils.
To start, using pure estragole (2) as the starting materi-
Figure 1 Homogeneous alkene isomerization catalyst 1 and support-
al, adding 0.1 mol% 1 led quickly (TOF: 22.2/min) to
ed catalysts PS-1 and PSL-1 (sphere = polystyrene)
(E)-anethole (2a) in 93.0% (4.65 g) isolated yield via vacu-
um distillation (Scheme 1). Similarly, pure eugenol (3) was
Herein, we focus on applications to flavors and fra- isomerized to (E)-isoeugenol (3a) using 0.1 mol% catalyst in
grances, including multigram (up to 15 g) conversions of al- 20 minutes (TOF: 50/min) to obtain 15.76 g of the isolated
lyl benzene starting materials to (E)-propenoid analogues product (Scheme 1). The reactions are somewhat exother-
with complete conversions and exclusive E selectivities de- mic; on the scales mentioned, liquid baths around the
manded by these applications. First, we disclose solution- flasks maintained near-ambient temperatures for compara-
phase reactions, followed by neat reactions.56 tive data. Careful analysis of the distilled product 2a in
As summarized in Table 1, in acetone solution, allyl ben- CDCl3 led us to determine that no detectable Z-isomer had
zenes estragole (2), eugenol (3), methyl eugenol (4), and been formed, with an estimated lower limit of detection of
elemicin (5, Table 1, entries 1–4) were each converted ex- 0.1%. For 3a, 0.4% Z-isomer was seen. Further optimization
clusively into E products 2a–5a using 0.1 mol% of 1 in 10–20 will be done to see if deactivation of catalyst before heating
min. In two cases tried, half as much catalyst could also be during distillation will reduce the levels of Z-isomer further.
used, whereas safrole in sassafras oil (6) required the great- Essential oils are the volatile aromatic compounds
er catalyst loading seen in entry 5 (Table 1). Methyl eugenol found in the many parts of plants, such as flowers, stems,
(4) is a minor constituent of bay leaf oil15 and has been bark, roots, and seeds, where each are unique with regards
known to be an attractant57 and fumigant58 for fly species, to the variation and amount of constituents present in the
in addition to containing antifungal properties59 and being oil. For instance, sassafras oil from Sigma Aldrich is >90%
a food additive. Isomerization of methyl eugenol to methyl safrole (6), along with reported impurities arsenic, cadmi-
isoeugenol, which is a major constituent of pimento um, mercury, and lead.66 The isomerization of safrole or eu-
pseudocaryophyllus leaf oil,20 has been reported in moder- genol in nonpurified sassafras or clove oil feedstocks using a
ate to good yield,40,42,60 and the product is used as food fla- catalyst that is not inhibited by impurities would be attrac-
voring.20 Elemicin (5) is a major constituent of elemi, nut- tive. We found that 0.5 mol% catalyst 1 allows full conver-
meg, and mace oil,61,62 and (E)-isoelemicin is a minor con- sion of 6 in neat sassafras oil in 30 minutes; subsequent

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2462–2466
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Syn lett C. R. Larsen et al. Letter

Table 1 Alkene Isomerization of Allylbenzene to Propenylbenzene Flavors and Fragrancesa

Entry Substrate Product Catalyst mol (%) Time (min) Yield (%)

1 0.05 40 99
0.1 10 100
1
PS-1 2 20 95
MeO MeO
estragole (2) anethole (2a) PSL-1 2 20 91

MeO MeO 1 0.05 20 100


0.1 10 100
2
PS-1 1 45 96
HO HO PSL-1 1 60 94 (2.9)b
eugenol (3) isoeugenol (3a)

MeO MeO
1 0.1 15 100
3 PS-1c 1.1 85 97 (1.8)b
MeO MeO PSL-1c 1.1 220 91 (2.4)b
methyl eugenol (4) methyl isoeugenol (4a)

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MeO MeO
1 0.1 20 98
4 MeO MeO PS-1c 1 130 95 (4.9)b
PSL-1c 1.1 115 96 (3.4)b
OMe OMe
elemicin (5) isoelemicin (5a)

O O
1 0.6 10 98
5d PS-1c 1.9 90 98
O O PSL-1c 2 75 96 (2.7)b
safrole (6) isoafrole (6a)

O O
6 1 0.9 300 96 (2.9)b
O O
allyl tiglate (7) propenyl tiglate (7a)
a
Substrate (0.50 mmol), acetone-d6 solvent, r.t., NMR yield. In cases where NMR yield (est. 1% uncertainty) was measured as slightly above 100, the yield is given
as 100. No starting material detectable, unless otherwise specified.
b
The amount of starting material remaining (%) is in parentheses; when left longer, reactions did proceed further but for comparative data, ca. 95% yield time
points are given here.
c
70 °C.
d
>90% safrole in sassafras oil.

O O
vacuum distillation isolated (E)-6a in 87.9% yield (Scheme 1 (0.5 mol%)
2). Similarly, eugenol (3) in neat clove oil is smoothly con- neat, 30 min 2.86 g
O 6 O 6a 87.9%
verted in 10 minutes using catalyst 1 into (E)-isoeugenol (in sassafras oil)
(3a), isolated in 88.3% yield (Scheme 2). Bifunctional cata- MeO MeO
1 (0.5 mol%)
lyst 1 is an attractive tool for the transformation of essential
neat, 10 min 3a 2.90 g
oils without interference to the catalyst by impurities. HO
3 HO 88.3%
(in clove oil)

1 (0.1 mol%)
Scheme 2 Neat isomerization on essential oils to afford isolated (E)-
propenylbenzene compounds using catalyst 1
2 neat, 45 min 2a 4.65 g
MeO MeO 93.0%
An even greener approach to desirable trans-propenyl-
MeO 1 (0.1 mol%) MeO benzene flavors and fragrances would be executing the re-
action with a heterogeneous catalyst but without any sol-
neat, 20 min
HO 3 HO 3a 15.76 g vent. Separation of liquid product from solid catalyst should
95.9%
be facile, and in addition make possible the reuse of the sol-
Scheme 1 Neat isomerization to isolated (E)-propenylbenzne flavors id catalyst for a subsequent isomerization reaction in batch
and fragrances on large scale using catalyst 1
format. After experimenting with several possible reaction
setups, batch reactions were performed with neat eugenol
(3, ca. 3 g, Scheme 3) as the substrate and a polyethylene
mesh bag containing solid catalyst submerged in the neat

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2462–2466
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Syn lett C. R. Larsen et al. Letter

liquid substrate. After conversion of eugenol to (E)-isoeu- sequent reactions while maintaining reactivity and selec-
genol was complete, as much product as possible was tivity. Z Isomers were present from 0.4% to less than 0.1%
drained from the mesh bag and weighed. Only about 3/4 of levels in the products, highlighting the reliable and superior
product from the first cycle could be obtained in this way, selectivity of the bifunctional catalysts used in this work.
likely because of retention inside as well as on the surface
of the polymer and the porous mesh bag. Fresh eugenol 3
was added for cycles 2 and, later, cycle 3; after completion
Acknowledgment
of isomerization, product was isolated in near quantitative We thank NSF (CHE 1059107, 1464781) for supporting this and relat-
yield, consistent with our explanation that the lower yield ed work.
from cycle 1 is due to mechanical losses, an issue that could
be solved by better reactor engineering. Reasonable reac-
tion rates required heating at 70 °C, perhaps related to the
Supporting Information
degree of swelling and kinetics of substrate and product ac- Supporting information for this article is available online at
cess to the catalyst active sites. Like PS-1, the linker catalyst http://dx.doi.org/10.1055/s-0035-1560205. SuponritIgfmanSuponritIgfman
PSL-1 similarly affords multigram quantities of product

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(Scheme 3); moreover, for the PSL-1 case, a fourth cycle
with twice the amount of substrate (6.57 g) and hence half
References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2462–2466