Applications of olefin cross metathesis to commercial products

Article abstract of DOI:10.1002/1615-4169(200208)344:6/7<728::AID-ADSC728>3.0.CO;2-4

In this paper, we will demonstrate the value of olefin cross metathesis as an effective synthetic tool for applications in the agrochemical and pharmaceutical industries. First, we will demonstrate the usefulness of cross metathesis reactions in the efficient synthesis of the major component of the Peach Twig Borer pheromone and the of Omnivorous Leafroller pheromone, insect pheromones are environmentally friendly pest-controlling agents. Second, we will demonstrate highly efficient cross metathesis routes into novel α,β-unsaturated carbonyl intermediates. These novel α,β-unsaturated carbonyl intermediates can be further functionalized into pharmaceutical compounds that are difficult to prepare by the traditional synthetic methodologies. This paper highlights key catalyst-substrate reactivity variations with different ruthenium olefin metathesis catalysts, highlights cross metathesis reactions and techniques and highlights an efficient ruthenium catalyst removal technique.

Full text of DOI:10.1002/1615-4169(200208)344:6/7<728::AID-ADSC728>3.0.CO;2-4

FULL PAPERS
Applications of Olefin Cross Metathesis to Commercial Products
Richard L. Pederson,* Ingrid M. Fellows, Thay A. Ung, Hiroki Ishihara,
Sharad P. Hajela
Materia, Inc., 60 N. San Gabriel Blvd., Pasadena, CA 91107, USA
Fax: ( ‡ 1)-626-584-4272, e-mail: rpederson@materia-inc.com
Received: February 1, 2002; Accepted: May 18, 2002
Abstract: In this paper, we will demonstrate the value can be further functionalized into pharmaceutical
of olefin cross metathesis as an effective synthetic tool compounds that are difficult to prepare by the
for applications in the agrochemical and pharmaceut- traditional synthetic methodologies. This paper high-
ical industries. First, we will demonstrate the useful- lights key catalyst-substrate reactivity variations with
ness of cross metathesis reactions in the efficient different ruthenium olefin metathesis catalysts, high-
synthesis of the major component of the Peach Twig lights cross metathesis reactions and techniques and
Borer pheromone and the of Omnivorous Leafroller highlights an efficient ruthenium catalyst removal
pheromone, insect pheromones are environmentally technique.
friendly pest-controlling agents. Second, we will
demonstrate highly efficient cross metathesis routes Keywords: cross metathesis; insect pheromones; or-
into novel a,b-unsaturated carbonyl intermediates. ganocatalysis; pharmaceuticals; ruthenium catalyst
These novel a,b-unsaturated carbonyl intermediates removal
Introduction
yl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenyl-
methylene)ruthenium(II) (5); [1,3-bis(2,4,6-trimethyl-
Applications of olefin metathesis in the synthesis of phenyl)-2-imidazolidinylidene)dichloro(phenylmethy-
biologically relevant targets are growing rapidly,[1] lene)(triphenylphosphine)ruthenium(II) (6).
however, most efforts to date involve ring-closing
metathesis as the key synthetic transformation.[2] The
exploitation of olefin cross metathesis is just beginning Insect Pheromones
to emerge as a valuable synthetic tool for fine chemical
synthesis. For example, cross metathesis methodologies The use of ruthenium-based metathesis methodology
have recently been shown to be highly effective routes in has been of particular success in the synthesis of
the synthesis of insect pheromones,[3,4] flavor and Lepidopteran insect pheromones.[2,3,4,8,9] Insect phero-
fragrance compounds,[5] and valuable synthetic inter- mones are biologically active compounds used by the
mediates such as novel a,b-unsaturated carbonyl sys- same species for communication. The use of the female×s
tems.[6,7] In this paper, we will describe several cross sex attractant to confuse the male and disrupt mating is
metathesis routes to biologically active compounds for an effective and environmentally friendly technique in
agrochemical and pharmaceutical applications.
controlling insect populations.[10] Lepidopteran insect
Results and Discussion
PCy3
PCp3
PCy3
Cl
Cl
Cl
Ru
Ru
Ru
PCy3 = tricyclohexylphosphine
PCp3 = tricyclopentylphosphine
PPh3 = triphenylphosphine
Many of the olefin metathesis catalysts used in this
article are available from Materia, Strem, or Aldrich.
These catalysts are shown in Scheme 1: dichloro(3-
methyl-1,2-butenylidene)bis(tricyclopentylphosphine)-
ruthenium(II) (1); dichloro(3-methyl-1,2-butenylidene)-
bis(tricyclohexylphosphine)ruthenium(II) (2); dichloro-
(phenylmethylene)bis(tricyclohexylphosphine)ruthenium-
(II) (3); [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidi-
nylidene)dichloro(phenylmethylene)(tricyclohexylphos-
Cl
Cl
Cl
PCy3
PCp3
PCy3
1
2
3
N
N
Cl
N
Cl
N
N
N
Cl
Ru
Ru
Ru
Cl
Cl
Cl
PPh3
O
PCy3
4
6
5
phine)ruthenium(II) (4); [1,3-bis(2,4,6-trimethylphen- Scheme 1. Structures of Materia×s olefin metathesis catalysts.
728
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/3446+7-728 735 $ 17.50-.50/0
Adv. Synth. Catal. 2002, 344, No. 6+7

Applications of Olefin Cross Metathesis to Commercial Products
FULL PAPERS
pheromones are traditionally defined as straight 10.5% to 33.4% of 9 after 6hours. Second, 4- and 6-
chained alcohols, aldehydes, or acetates containing 10 catalyzed reactions rapidly formed impurities, 3.4% to
to 18 carbons and 1 to 3 double bonds. The current 6.5% impurities after 10 minutes, and up to 17.5%
worldwide market for insect pheromones is approxi- impurities after 20 hours.[18]
mately US $250 million and is projected to grow at an
Several techniques were investigated to maintain the
high yield of 9 while keeping the impurity formation to a
annual rate of 11% for the next decade.[11]
The advantages of using olefin metathesis to produce minimum. Ultimately, running the metathesis reaction
insect pheromones include: most of the starting materi- at low temperatures proved to be successful. As
als are commodity materials (e.g., seed oils and alpha- depicted in Figure 2, cross metathesis of equal moles
olefins), the reactions are run neat, the reactions can of 7 and 8, neat, with 0.2 mol % catalyst 4, at 5 8C for
provide up to 50% reactor efficiencies, the unreacted 18 hours produces a 49% yield of 9 with < 0.1% double
starting materials are recycled, very little waste is bond migration impurity.
produced, and the reactions are run under near ambient
temperature ranges. These factors make insect phero- synthesis of the Omnivorous Leafroller (OLR) pher-
mones attractive targets for commercialization. omone, as described in Scheme 3. OLR is a pest of
The low-temperature technique has been used in the
Two attractive pheromone targets are those of the apples, grapes, pears, peaches, and nectarines. The OLR
Peach Twig Borer (Anarsia lineatella) and Omnivorous pheromone is an 82:18 ratio of E- to Z-11-tetradecenyl
Leafroller (Platynotastultana). PeachTwig Borer(PTB) acetate (14).[19]
is a pest of peaches, plums, nectarines, and almonds. The
The synthesis of OLR pheromone is a particularly
PTB pheromone is an 83:17 ratio of (E)-5-decenyl attractive target for metathesis because the metathesis
acetate (9) and (E)-5-decenol;[12] modest amounts of the reaction produces the pheromone with the desired
(Z)-isomers have no effect on efficacy. Synthesis of 9 has isomeric (E to Z) ratio. The two starting materials, 3-
been reported in the patent literature using ruthenium hexene (11) and 11-eicosenyl acetate (13), were derived
olefin metathesis but these routes are low yielding or from commodity materials: 11 was produced by homo-
difficult to scale up beyond 72-L reaction flasks.[3,13] Our coupling 1-butene (10), and 13 was produced from
goal was to develop a convenient, high yielding process Jojoba oil (12). Starting material 12 is a seed oil used in
that could be scaled up into commercial reactors. A key
requirement of any synthetic route is the formation of
< 0.1% double bond migrated impurities (i.e., forma-
tion of E-4-decenyl acetate or E-6-decenyl acetate,
which are known to be inhibitors in the PTB pheromone
to the moths).[14] The reaction sequence to 9 is shown in
Scheme 2.
Catalysts 1, 2, 3, 4, and 6[15] were screened for the cross
metathesis reactions of 5-decene (7)[3,16] with 1,10-
diacetoxy-5-decene (8)[17] to identify the optimal cata-
lyst. Reactions were run with equal molar concentration
of 7 and 8 using 0.2 mol % metathesis catalysts, at 45 8C,
for 20 hours. Metathesis reactions produce equilibrium
mixtures; therefore, using a 1:1 molar ratio of 7:8 will
produce a maximum yield of 50% of 9. Unreacted 7 and
Figure 1. Formation of 9 by cross metathesis of 7, 1.67 M, and
8 are readily recovered by vacuum distillation and 8, 1.67 M, in CH2Cl2 with 0.2 mol % catalyst at 45 8C.
recycled. Figure 1 depicts the time course of the catalyst
screening reactions.
Several interesting observations are seen from the
data. First, 4- and 6-catalyzed reactions were completed
within 10 minutes, while catalysts 1, 2 and 3 yielded only
AcO
+
OAc
7
8
a
OAc
9
Scheme 2. Screening metathesis catalysts in the production of
9 by cross metathesis; a) equal molar ratio of 7 and 8,
0.2 mol % metathesis catalyst, 45 8C, 20 h.
Figure 2. Formation of 9 by cross metathesis of neat 7 and 8
(1:1 mole ratio) with 0.2 mol % catalyst 4 at 5 8C.
Adv. Synth. Catal. 2002, 344, 728 735
729

Richard L. Pederson et al.
FULL PAPERS
R2
+
OAc
O
O
11
13
N
O
Catalysts 4 or 5
R1
+
R1
H
H
R3
R1
R1
a,b,c
novel substrates
for catalyst 15
CHO
O
OAc
O
14
N CH3
NH
N
O
Scheme 3. Formation of 14 by cross metathesis: a) 5 8C,
0.2 mol % catalyst 4 to 13, 4:1 mole ratio of 11:13, 16h, 84%
conversion; b) TKC, NaHCO3, 70 8C, 20 h; c) vacuum
distillation, 50% yield, > 95% purity.
HX
N
CH3
R1
H
15
Scheme 4. Efficient cross metathesis routes into novel sub-
strates for 15.
the cosmetic industry and primarily comprises a mixture
Organocatalysts have been around for over 40 years.
of oleyl, eicosenyl and docosenyl esters, with ꢀ 60% of In 1960 the first organocatalytic reaction was reported
the oil being the 11-eicosenyl moiety. Reduction, by Pracejus,[25] who described quinuclidine-catalyzed
purification, and acetylation of 12 produce 13 in high methanolysis of ketenes. In the 1970×s Hajos[26] reported
yields. Cross metathesis of 11 and 13 (4:1 mole ratio) proline-catalyzed intramolecular aldol reactions. More
produced an 84% yield of 14. The metathesis catalyst recently List[27] and Barbas[28] developed organocatalyst
was removed by the in-situ formation of tris(hydroxy- reaction conditions that yield products with up to 97%
methylphosphine) (THP)[4] from tetrakis(hydroxyme- ee. Numerous groups have developed and examined
thyl)phosphonium chloride (TKC), followed by vacuum asymmetric organocatalyst reactions; their work will not
distillation of 14 in 50% overall yield and > 95% purity. be covered here, refer to Dalko[29] for an excellent
This methodology has been the basis for the continuing review of enantioselective organocatalysis. Even though
scale-up efforts related to the commercialization of 9 organocatalysts have numerous advantages over their
and 14.
metal-containing counterparts, a major drawback is that
they work well for only a relatively small class of
substrates. MacMillan×s asymmetric imidazolidinone
catalyst overcomes this drawback.
Pharmaceuticals and Intermediates
Attractive pathways to pharmaceutical intermediates
The demand for chiral intermediates and drugs has available from cross metathesis and OrganoCatalysisTM
grown rapidly over the past several years. Chiral drugs include chiral 1,3-nitrone additions, indole alkylations
represent almost one third of all drug sales worldwide.[20] and pyrrole alkylations, as recently described by Mac-
The demand for single enantiomer molecules for Millan.[19,22] Two attractive targets are the enantiomeric
À
commercial applications has accelerated the develop- synthesis of ( )Ketorolac (20) and Paxil (23), which are
ment of asymmetric catalysis. Recently David W.C. depicted in Scheme 5.
MacMillan of Caltech has developed a new and novel
Compound 20 is a non-steroidal anti-inflammatory
class of asymmetric metal-free organic molecules. drug (NSAID) and is the primary drug used in post-
MacMillan×s group has developed imidazolidinone- operative pain prevention. [Racemic Ketorolac is mar-
based chiral organocatalysts that exhibit broad reaction keted in the Unites Stated under the trade names of
class capabilities and routinely produce chiral products Acular by Allergan and Toradol IM by Roche.] It is
in > 90% ee and > 85% yields.[21] MacMillan×s imida- currently marketed as the racemate with the (‡)-
zolidinone-based catalysts, (2S,5S)-2-(t-butyl)-3-meth- enantiomer being associated with undesirable gastro-
yl-5-(phenylmethyl)-4-imidazolidinone (catalyst 15), intestinal side effects.[30] Therefore an enantiomerically
trade named OrganoCatalysisTM, uses a,b-unsaturated pure synthesis of 20 would be valuable in increasing
aldehydes as key substrates in these reactions.[21,22,23,24]
Cross metathesis is a powerful tool to produce a,b-
patient comfort by reducing side effects.
Compound 23[31] is a selective serotonin (5-HT)
unsaturated carbonyl-containing molecules,[6,7] many of reuptake inhibitor with a market value of US $2.4 billion
which are difficult to prepare by traditional synthetic per year. [Paxil (Paroxetine) is marketed in the Unites
techniques. Cross metathesis offers complementary Stated under the trade name Seroxat by Glaxo Smith
technologies to MacMillan×s asymmetric organocata- Kline.] Having an efficient and enantioselective route to
lysts, see Scheme 4. Asymmetric metal-free organo- 23 would position one for a share of the generic drug
catalyst-catalyzed reactions offer several advantages market, when 23 goes off patent.
over their transition metal-containing counterparts.
The key syntheticstepsto 20 are depicted in Scheme 6.
Advantages include that the reactions are run under 4-(Benzoyloxy)-2-butenal (18) was produced in 63%
aerobic conditions and in polar protic solvents, they are yield in 30 minutes by the cross-metathesis of allyl
inexpensive and stable and there is no disposal of toxic benzoate (16) and crotonaldehyde (17) with catalyst
metal waste.
5.[32,33,34] Repeating the experiment with catalyst 4
730
Adv. Synth. Catal. 2002, 344, 728 735

Applications of Olefin Cross Metathesis to Commercial Products
FULL PAPERS
O
Conclusion
O
O
OH
O
In this paper we have described the efficient syntheses of
several agrochemical and pharmaceutical compounds
via olefin cross metathesis methodology. The syntheses
of insect pheromones 9 and 14 were demonstrated
without solvent from the cross metathesis of commodity
starting materials. We also described low-temperature
reaction conditions that prevent impurity formation
(arising from double-bond migrations) and the use of an
efficient metathesis catalyst removal agent. We further
demonstrated improved syntheses of two important
pharmaceutical intermediates by tandem cross meta-
thesis and organocatalysis reactions. This combination
of techniques greatly reduces the number of steps
required to directly produce chiral pharmaceutical
intermediates, typically without the need for a chiral
resolution step. These examples demonstrate that olefin
cross metathesis is a powerful synthetic tool to produce
N
F
NH
O
Paxil (23)
(–)Ketorolac (20)
À
Scheme 5. Structures of ( )Ketorolac (20) and Paxil (23).
O
O
BzO
OBz
a
+
H
H
17
18
16
HN
O
b
BzO
20
H
OH
O
OBz
18
19
N CH3
NH
15
Scheme 6. Synthesis of 4-(benzoyloxy)-3-pyrrole-2-butanol
(19). a) 5.0 mol % catalyst 5, RT, 30 min, 68%; b) (i) pyrrole,
20 mol % catalyst 15 dichloroacetic acid; (ii) sodium borohy- carbon-carbon double bonds. In the past decade, olefin
dride, 82% yield, 92% ee.
metathesis has had a huge influence on the field of
organic chemistry and rarely has a new catalyst tech-
nology been so eagerly accepted and used. It will be
exciting to see what another decade of olefin metathesis
will yield.
O
O
O
O
O
H
a
+
H
F
F
F
NH
21
17
22
23
Scheme 7. Synthesis of 22. a) 2.5 mol % catalyst 5, 5 equiv-
alents of 17, 40 8C, 4 h, 73% isolated yield.
Experimental Section
Thefollowingmaterials were usedwithoutfurtherpurification:
5-hexen-1-ol was purchased from CreaNova, 5-hexen-1-ol was
converted to 5-hexen-1-yl acetate under standard acetylation
conditions, 1-hexene was purchased from BP Amoco, 10 was
purchased from Aeriform, Ester X [also known as sodium
bis(2-methoxyethoxy)aluminum hydride] was purchased from
Rohm and Haas, TKC was purchased from Cytec and 12 was
purchased from Desert King International.
produced < 30% yield of 18 after 6hours. A metathesis
route to 18 was desirable over the conventional syn-
thetic route.[35] Conversion of 18 to (3S)-4-(benzoyloxy)-
3-pyrrole-2-butanol (19) was accomplished by using the
dichloroacetic acid salt of (2S,5S)-5-benzyl-2-t-butyl-2-
methyl-3-methyl-4-imidazolidinone (catalyst 15), fol-
lowed by sodium borohydride reduction (82% yield and
91% ee). Compound 19 has been converted to 20 and
will be reported shortly by MacMillan.[36]
5-Decenyl Acetate (9)
Another synthetically useful pharmaceutical target is
p-fluorocinnamaldehyde (22). 22 is a potential key
intermediate in the synthesis of Paxil (23), see Scheme 7.
Unsatisfactory yields of 22 were obtained by a
conventional synthetic methodology.[37] But 22 was
synthesized efficiently by the cross metathesis of p-
To a 3-L flask was added 1.00 kg (3.8 mol, 97%) 8, 0.53 kg
(3.8 mol) 7[4] and 100 mg of BHT. The solution was cooled to
5 8C and sparged with argon for 20 minutes. Catalyst 4 (6.44 g,
7.6mmol, 0.2 mol %) was added, the flask was sealed with a
rubber septa and stirring was continued for 20 hours. GC
analysis indicated a 49% yield of 9 with < 0.1% double bond
fluorostyrene (21) with 5 equivalents of 17 in 73% yield, migrated impurities. The metathesis catalyst was removed with
THP as described below. Compound 7 was removed by rotovap
under high vacuum,[16] the remaining solution was flashed
distilled followed by packed bed vacuum distillation using a
2 in  36in distillation column packed with 0.16in stainless
Pro-PakTM distillation packing. Product 9 (677 g, 3.42 mol,
45% isolated yield in > 98% chemical purity) was collected at
0.20 mmHg over a boiling point range of 75 8C to 78 8C, in an
84:16 E:Z isomeric ratio.[39] 1H NMR (300 MHz, CDCl3): d ˆ
0.92 (t, 3H, CH3), 1.34 (m, 6H, CH2), 1.58 (m, 2H, CH2), 1.97
using catalyst 5. Under the same conditions, the use of
catalyst 4 produced mainly p,p×-difluorostilbene (52%
yield). Work is under way to complete the synthesis of 23
from 22. Other groups have also reported similar
reactivity variations between catalyst 4 and 5.[38] The
differences in the catalyst specificities are presumed to
be associated with the presence of the tricyclohexyl-
phosphine, which inhibits productive metathesis of
certain electron-poor olefins.
ˆ
(m, 4H, CH-CH2), 2.02 (s, 3H, CH3), 4.02 (t, 2H, -OCH2), 5.38
ˆ
(m, 2H, -CH ).
Adv. Synth. Catal. 2002, 344, 728 735
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Richard L. Pederson et al.
FULL PAPERS
5.27 mol, > 99% purity) by atmospheric distillation (bp 66 8C
to 71 8C) under argon, through a 2 in  36in Pro-Pak TM
Metathesis Catalyst Removal Procedure: Synthesis of
1 M Solution of Tris(hydroxymethyl)phosphine (THP)
in Isopropyl Alcohol
1
packed distillation column. H NMR (300 MHz, CDCl3): d ˆ
ˆ
0.98 (t, 6H, CH3), 2.05 (m, 4H, CH2-CH ), 5.44 (m, 2H,
CH CH).
The metathesis catalyst was removed by complexing with
THP[3,40] and extracting the metathesis catalyst-THP complex
with water. To a 2-L round-bottomed flask was added 245 g
(1.03 mol) tetrakis(hydroxymethyl)phosphonium chloride
(TKC) and 500 mL isopropyl alcohol (IPA). This mixture
was degassed with nitrogen for 20 minutes, potassium hydrox-
ide (64 g, 1.03 mol, 90% purity, Aldrich) was added slowly over
30 minutes to the vigorously stirring solution, while under a
nitrogen atmosphere (reaction is exothermic!). A white
precipitate (KCl) forms immediately. After the potassium
hydroxide has been added, the reaction was stirred for an
additional 30 minutes. The content of the flask was diluted to
1 L by the addition of IPA. The THP mixture was stored in the
refrigerator or used in the next step without further purifica-
tion.
ˆ
11-Eicosenyl Acetate (13)
Refined grade 12 (5.3 kg, 8.7 mol) was placed in a 12-liter flask
equipped with an overhead stirrer. A 70% solution of Ester X
(2.8 kg, 9.6mol) was slowly added into the reactor at a rate that
kept the pot temperature below 50 8C. After complete addition
of Ester X, the reaction was stirred for an additional two hours
and then quenched with 4.0 L of 50% aqueous sulfuric acid.
The organic layer was separated from the aqueous, washed
with water and dried over sodium sulfate. GC analysis[42]
showed the reaction mixture to be composed of 57.5% 11-
eicosenol, 29.6% 13-docosenol, and 5.7% 9-octadecenol, with
the remainder being trace amounts of smaller and larger fatty
alcohols. 11-Eicosenol was purified by vacuum distillation
(0.20 mmHg) using a 3-in  36in distillation column packed
with 0.24 in stainless Pro-PakTM distillation packing. 11-Eico-
senol was collected over a boiling point range of 155 8C to
160 C. The chemical purity of 11-eicosenol by GC was
determined to be > 95%; yield: 2.7 kg (8.7 mol).
To a metathesis reaction was added at least 25 mole
equivalents of THP per mole of ruthenium metathesis catalyst
and stirred vigorously at 60 8C to 70 8C for 18 to 24 hours,
under nitrogen. The color of the reaction will go from dark
brown to faint yellow or colorless after 18 hours.
Nitrogen-degassed water (typically ꢀ 150 mL of water/L
reaction mixture) was added and vigorously stirred for
10 minutes. Stirring was stopped and the phases separated.
The bright orange aqueous phase was removed and 150 mL
water again were added and stirred vigorously for 10 minutes.
Again the phases separated and the aqueous phase was
removed. This procedure was repeated until the aqueous
phase was colorless, usually 2 to 3 washings. The organic phase
was washed with 50 mL of 2.0 M HCl for 5 minutes (pH < 1)
and removed, followed by washing with 50 mL of sodium
bicarbonate saturated water for 5 minutes (pH > 7), removed
and washed with brine. The solution is dried with anhydrous
sodium sulfate.
11-Eicosenol (2.7 kg, 8.7 mol) and acetic acid, (33 g,
0.55 mol) were warmed to 80 8C in a 12-L round-bottom flask.
Acetic anhydride (931 g, 9.1 mol) was slowly added to the flask
while the solution was vigorously stirred. On completion, the
solution was heated to 100 8C, under nitrogen, for an additional
2 hours and then cooled to room temperature. GC analysis
indicated > 99% conversion to 13.[42] The solution was washed
twice with 2 L of water, once with 2 L of a saturated aqueous
sodium bicarbonate solution and dried with anhydrous sodium
sulfate, and filtered to yield 3.0 kg (8.5 mol) of 13 (80 95%
yield based on eicosenyl fraction). 1H NMR (300 MHz, CDCl3):
d ˆ 0.94 (t, 3H, CH3), 1.28 (m, 26H, CH2); 1.60 (m, 2H, CH2),
1.97 (m, 4H, CH2), 2.01 (s, 3H, CH3), 4.05 (t, 2H, CH2-O), 5.38
ˆ
(m, 2H, -CH ). This material was used in the metathesis
3-Hexene (11)
reaction without further purification.
A 5-L jacketed 3-necked flask was equipped with a magnetic
stir bar, gas feeding tube and a packed bed column containing a
dry ice condenser. Catalyst 4 (2.97 g, 0.0035 mol, 0.023 mol %
based on 10 added) and toluene (240 g) were added. The flask
was sparged with argon for 15 min, while being cooled to 15 8C.
Compound 10 (gas) (841 g, 15.0 mol) was added by bubbling
into the toluene solution over 10.5 hours. The rate of addition
was such that the reaction temperature remained above 10 8C.
After 10.5 hours, the packed bed column and the dry ice
condenser were replaced with a Friedrich condenser. The
Friedrich condenser was circulated with 0 8C coolant. The
reaction flask was cooled to 10 8C. An argon purge with a flow
rate of ꢀ 1 L/minute was maintained for 12 hours.[41]
11-Tetradecenyl Acetate (14)
Compounds 11 (443 g, 5.27 mol) and 13 (466 g, 1.32 mol) were
added to a 2-L round-bottomed flask. The mixture was flushed
with nitrogen for 15 minutes and cooled to 5 8C. Catalyst 4
(2.23 g, 2.6mmol) was added and the mixture was stirred for
20 hours. GC analysis showed an 84% yield of 14 with < 0.1%
double bond migrated impurities.[43]
The metathesis catalyst is removed as described above for
product 11, except the reaction was heated to 60 8C for
20 hours. Product 14 was purified by packed-bed vacuum
distillation (0.50 mmHg), collecting material over the boiling
point range of 122 8C to 124 8C to yield 168 g (0.66 mol, 50%
overall yield) chemical purity by GC was > 95%, with an
isomeric ratio of 82.6% E-14 and 17.4% Z-14.[43] 1H NMR
(300 MHz, CDCl3): d ˆ 1.06(t, 3H, C H3), 1.42 (m, 14H, CH2),
1.81 (m, 2H, CH2), 1.96(m, 4H, C H2), 2.01 (s, 3H, CH3), 4.16(t,
The metathesis catalyst was removed by the in-situ gener-
ation of THP. TKC (80% purity, 20.80 g, 25 equivalent to
catalyst) and NaHCO3 (7.35 g, 25 equivalent to catalyst) were
added to the solution. The chiller/heater controlling the
jacketed flask was set to 40 8C and stirred for 18 hours. The
reaction was cooled to 10 8C and washed with water (500 mL)
and brine (500 mL) and dried over anhydrous Na2SO4.
Compound 11 was isolated in 52% overall yield, (443 g,
ˆ
2H, CH2-O), 5.62 (m, 2H, -CH ).
732
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Applications of Olefin Cross Metathesis to Commercial Products
FULL PAPERS
by silica gel chromatography (15% of ethyl acetate in hexane)
to yield 1.09 g (7.30 mmol) 22 in 73% yield and 98% purity.
4-(Benzoyloxy)-2-butenal (18)
To a 50-mL round-bottomed flask was added 1.0 g (0.20 mmol)
1
ˆ
H NMR (300 MHz, CDCl3): d ˆ 6.61 (dd, 1H, CH-CHO),
16, 5.1 mL (6.20 mmol) 17 and 10 mL dry toluene. The reaction
mixture was sparged with argon for 10 minutes. Catalyst 5
(19 mg, 0.03 mmol) was added and stirred at room temperature
for 30 minutes to afford 18 in 68% yield by GC, 9% crotonyl
benzoate, and 7% 16. The reaction was concentrated under
reduced pressure and purified by silica gel chromatography
(25% ethyl acetate in hexane) to yield 730 mg (3.85 mmol) of
18.[35] 1H NMR (300 MHz, CDCl3): d ˆ 5.11 (d, 2H, CH2-O),
ˆ
7.03 (t, 2H, meta-H), 7.48 (d, 1H, Ph-CH ), 7.54 (dd, 2H, ortho-
H), 9.65 (d, 1H, CHO); 13C NMR (75 MHz, CDCl3): d ˆ 116.53
ˆ
(meta-carbons, JCCF ˆ 22.0 Hz; 128.48 (CH CHO), 130.45 (epi-
ˆ
carbons), 130.64 (ortho-carbons), 151.53 (Ph-CH ), 164.50 (JCF
ˆ 251.0 Hz), 193.56( CHO).
ˆ
ˆ
6.40 (dd, 1H, OHC-CH ), 6.95 (dq, 1H, CH CH-CH2), 7.48
(m, 2H, meta-H), 7.62 (m, 1H, para-H), 8.09 (d, 2H, ortho-H),
9.65 (d, 1H, CHO).
Acknowledgements
The authors would like to thank Cindy Lammertink for the
preparation of the manuscript, Brian Kwan for a standard of 18,
Jennifer Love for the sample of catalyst 6, David MacMillan,
Bob Grubbs, Choon Woo Lee, Basil Paulson and Wen-Jing
Xiao for the helpful discussions.
4-(Benzoyloxy)-3-pyrrole-2-butanol (19)
To a 100-mL round-bottom flask equipped with a magnetic stir
bar was added catalyst 15 (246.35 mg, 1.00 mmol, 0.2 equiv.
based on 18) and chloroacetic acid (94.5 mg, 1.0 mmol,
1.0 equiv. based on 15). The two solids were dissolved in
8.05 mL of purified diethyl ether and 0.975 mL of water. The
solution was stirred at 30 8C for 5 minutes, pyrrole (1.74 mL,
25.05 mmol, 5.0 equiv. to 18, freshly distilled from CaH2) was
References and Notes
À
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added via a syringe. The reaction was stirred for another
5 minutes to bring the solution back to 30 8C. Aldehyde 18
À
(951 mg, 5.0 mmol, 1 equiv.) was added by syringe as a solution
À
in 0.5 mL of diethyl ether. The reaction was stirred at 30 8C
and monitored by TLC (70% hexane, 30% ethyl acetate, p-
anisaldehyde stain) until 18 was consumed. The reaction was
warmed to 0 8C and approximately 25 mL of absolute ethanol
were added, followed by NaBH4 (812 mg, 0.756mmol,
0.38 equiv.). The reaction was stirred at 0 8C for 15 minutes.
The mixture was added to a separatory funnel and water
saturated NaHCO3 was added until gas evolution ceased
(about 30 mL total). The product was extracted with 4 Â 25 mL
of CH2Cl2. The organic phases were combined and washed with
brine and dried over anhydrous MgSO4. The solvent was
removed under vacuum to give the crude product. Column
chromatography (70% hexane/30% ethyl acetate) gave 19 as
an oil which solidified on standing to a white solid (1.03 g, 80%
yield, 92% ee).[36] 1H NMR (300 MHz, CDCl3): d ˆ 2.0 (m, 2H,
CH2-CH2OH), 3.38 (m, 1H, chiral proton), 3.65 and 3.75 (2H,
m, CH2OH), 4.5 (2H, s, CH2-OBz), 6.05 (1H, m, pyrrole C-H),
6.05 (1H, m, pyrrole C-H), 6.15 (1H, m, pyrrole C-H), 6.70 (1H,
m, pyrrole C-H), 7.45 (2H, m, aromatic), 7.55 (1H, m, aromatic)
8.00 (2H, m, aromatic), 8.45 (1H, bs, pyrrole N-H). Enantio-
meric excess was determined by normal phase HPLC using a
Chiracel OD 0.46cm ID Â 25 cm column, mobile phase was
10% 2-propanol in n-hexane. The retention times were
19.086min (minor enantiomer) and 20.727 min (major enan-
tiomer).
[3] R. L. Pederson, R. H. Grubbs, (TillieChem, Inc.), U. S.
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p-Fluorocinnamaldehyde (22)
To
a 50-mL round-bottomed flask was added 1.22 g
(10.0 mmol) 21, 3.4 g (48.6mmol) 17 and 20 mL methylene
chloride. The reaction mixture was sparged with argon for
15 minutes. Catalyst 5 (0.156g, 0.25 mmol, 2.5 mol %) was
added and stirred at 40 8C for 4 hours. The crude reaction
mixture was concentrated under reduced pressure and purified
Adv. Synth. Catal. 2002, 344, 728 735
733

Richard L. Pederson et al.
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[35] Compound 18 was synthesized by monobenzoylation of
2-butene-1,4-diol, followed by PCC oxidation with 35
40% yield.
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[37] Compound 22 was synthesized by Wittig coupling with p-
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Reduction with DiBAl resulted in mainly p-fluorocin-
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a complex mixture, which was difficult to purify by silica
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[16] 7: bp 31 8C to 32 8C at 1.0 mmHg, isolated in 60% to
70% yields; 1H NMR (300 MHz, CDCl3): d ˆ 0.86(t, 6H,
ˆ
CH3), 1.26(m, 8H, C H2), 2.05 (m, 4H, CH2-CH ), 5.38
ˆ
(m, 2H, CH CH).
[17] Compound 8 was produced by homocoupling neat 5-
hexenyl acetate with 0.2 mol % catalyst 2 or 3 under
30 mmHg vacuum, heated to 35 8C for 18 hours. The
metathesis catalyst was removed as described in the
synthesis of 9. Product 8 was purified by vacuum
distillation, bp 106 8C to 108 8C at 0.30 mmHg, 80% to
85% isolated yields, as a 4:1 mixture of E:Z isomers (see
ref.[39] for GC conditions and results). 1H NMR
ˆ
(300 MHz, CDCl3): d ˆ 1.34 (m, 4H, CH-CH2-CH2-),
ˆ
1.56(m, 4H, CH-CH2-CH2-), 1.95 (m, 4H, -CH2-CH2-O),
1.98 (s, 6H, CH3), 3.98 (overlapping triplets, 4H,
-CH2-O), 5.32 (m, 2H, CH); 13C NMR (75 MHz,
ˆ
CDCl3): d ˆ 20.61, 25.60, 25.76, 26.53, 27.86, 27.99,
31.88, 63.95, 63.98, 129.28, 129.83, 170.29.
[18] The major impurities were E,Z-4-decenyl acetate, E,Z-6-
decenyl acetate, E,Z-4-nonenyl acetate, E,Z-5-nonenyl
acetate, E,Z-5-undecenyl acetate and E,Z-6-undecenyl
acetate. These impurities were synthesized and co-
injected to verify compounds or characterized by GC-
MS.
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[39] GC analysis with FID detector and J&W DB-225¦
column 30 m  0.25 mm (ID)  0.25 mm film thickness.
GC conditions: Initial temperature 40 8C, hold 1 minute;
first ramp rate 8 8C/minute to 140 8C, hold 5 minutes;
second ramp 20 8C/minute to 210 8C hold 5 minutes. 7
(E- and Z-isomers) Rt 5.76min and 5.86min; 8 (E- and
Z-isomers) Rt 27.31 min and 27.36min; and 9 (E-isomer)
Rt 17.62 min, 9 (Z-isomer) Rt 17.74 min.
[40] H. Maynard; R. H. Grubbs, Tetrahedron Lett. 1999, 40,
4137 4140.
[41] This set-up allows 10 to be removed with < 10% loss of
11.
[42] GC analysis with FID detector and J&W DB-5TM
column 30 m  0.25 mm (ID)  0.25 mm film thickness.
GC conditions: Initial temperature 100 8C, hold 0 mi-
734
Adv. Synth. Catal. 2002, 344, 728 735

Applications of Olefin Cross Metathesis to Commercial Products
FULL PAPERS
nute; ramp rate 25 8C/minute to 240 8C, hold 10 minutes.
Oleyl alcohol Rt 6.103 min; 11-eicosenol Rt 6.920 min;
13-docosenol 8.007 min; oleyl acetate Rt 6.548 min; 13 Rt
7.499 min; 13-docosenyl acetate 8.249 min.
GC conditions: Initial temperature 100 8C, hold 0 mi-
nute; ramp rate 25 8C/minute to 200 8C, hold 15 minutes.
11 (E-isomer) Rt 8.24 min and 11 (Z-isomer) Rt
8.38 min.
[43] GC analysis with FID detector and J&W DB-225¦
column 30 m  0.25 mm (ID)  0.25 mm film thickness.
Adv. Synth. Catal. 2002, 344, 728 735
735