Direct aldehyde homologation utilized to construct a conjugated-tetraene hydrocarbon insect pheromone

Article abstract of DOI:10.1021/jf063337e

New phosphonate reagents were developed for the two-carbon homologation of aldehydes to methyl-or ethyl-branched unsaturated aldehydes and used in the practical synthesis of (2E,4E,6E,8E)-3,5-dimethyl-7-ethyl-2,4,6,8-undecatetraene (1), a pheromone of the beetle Carpophilus lugubris. The phosphonate reagents, diethyl ethylformyl-2-phosphonate dimethylhydrazone and diethyl 1-propylformyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde, followed by removal of the dimethylhydrazone protective group with a biphasic mixture of dilute HCl and petroleum ether. This robust two-step process replaces the standard three-step aldehyde homologation route using ester-based Horner-Wadsworth-Emmons reagents. The new synthesis of compound 1 from (2E)-2-methyl-2-butenal was run on a 10-g scale and required just five steps (two cycles of condensation and deprotection, followed by a final Wittig olefination) instead of the usual seven. In addition, the Wittig olefination step was simplified and its E-isomer selectivity was improved. The overall yield for the entire synthetic pathway was increased from 20% to 37%, enhancing the commercial potential of Carpophilus pheromones.

Full text of DOI:10.1021/jf063337e

2282 J. Agric. Food Chem. 2007, 55, 2282−2287
Direct Aldehyde Homologation Utilized To Construct a
Conjugated-Tetraene Hydrocarbon Insect Pheromone
RICHARD J. PETROSKI* AND ROBERT J. BARTELT
Crop Bioprotection Research Unit, National Center for Agricultural Utilization Research, Agricultural
Research Service, U.S. Department of Agriculture, 1815 North University Street,
Peoria, Illinois 61604
New phosphonate reagents were developed for the two-carbon homologation of aldehydes to methyl-
or ethyl-branched unsaturated aldehydes and used in the practical synthesis of (2E,4E,6E,8E)-3,5-
dimethyl-7-ethyl-2,4,6,8-undecatetraene (1), a pheromone of the beetle Carpophilus lugubris. The
phosphonate reagents, diethyl ethylformyl-2-phosphonate dimethylhydrazone and diethyl 1-propyl-
formyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual
ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde,
followed by removal of the dimethylhydrazone protective group with a biphasic mixture of dilute HCl
and petroleum ether. This robust two-step process replaces the standard three-step aldehyde
homologation route using ester-based Horner-Wadsworth-Emmons reagents. The new synthesis
of compound 1 from (2E)-2-methyl-2-butenal was run on a 10-g scale and required just five steps
(two cycles of condensation and deprotection, followed by a final Wittig olefination) instead of the
usual seven. In addition, the Wittig olefination step was simplified and its E-isomer selectivity was
improved. The overall yield for the entire synthetic pathway was increased from 20% to 37%,
enhancing the commercial potential of Carpophilus pheromones.
KEYWORDS: Aldehyde homologation; diethyl ethylformyl-2-phosphonate dimethylhydrazone; diethyl
1-propylformyl-2-phosphonate dimethylhydrazone; sap beetle; Carpophilus lugubris; Nitidulidae
INTRODUCTION
practicable because of self-condensation. Reactions with alde-
hyde phosphonates protected as imines and acetals have been
reported, but these reagents also have problems with side
reactions, insufficient reactivity, and lability of reagents or
products (4, 6). The silylaldimines are the functional equivalents
of protected aldehyde phosphonates and have been used in
Horner-Wadsworth-Emmons-like reactions (7, 8); however,
reaction conditions to form and use silylaldimines are not
operationally convenient (8), and we chose to further explore
phosphonate chemistry.
A recurring theme in the synthesis of various polyketide
natural products and other compounds is two-carbon homolo-
gation of aldehydes to R-alkyl-R,â-unsaturated aldehydes. A
typical approach based on the Horner-Wadsworth-Emmons
condensation (1) uses a phosphonate ester and involves three
synthetic steps: The phosphonate condensation step extends the
chain by two carbons while introducing an (E) double bond, an
R-alkyl branch (size depending on the choice of phosphonate
reagent), and a terminal ester group. The ester is then reduced
to an R,â-unsaturated alcohol, and the alcohol is partially
oxidized to the desired R,â-unsaturated aldehyde. One way to
shorten this scheme would be to use a homologating reagent
that keeps the oxidation state of an aldehyde throughout.
A variety of options were considered. Aldehyde Wittig
reagents such as R-formylethylidenetriphenylphosphorane are
known (2, 3), but in our hands the reagent was not reactive
toward R,â-branched unsaturated aldehydes, such as (2E)-2-
methyl-2-butenal (R.J.P., unpublished results). Phosphonate
anions are generally more reactive toward aldehydes than the
analogous phosphoranes (4). Aldehyde phosphonates (where the
ester group is replaced by an aldehyde) can be readily prepared
(5), but using them directly in Wittig-Horner reactions is not
Protection of carbonyl compounds as dimethylhydrazones is
a common practice, and the incorporation and removal of this
group have been studied extensively (9-11). However, to our
knowledge, the use of aldehyde phosphonates protected as
dimethylhydrazones in Horner-Wadsworth-Emmons-type re-
actions had not been exploited previously. The dimethylhydra-
zone phosphonates were prepared without difficulty, were stable
enough to be distilled, and readily entered condensation reac-
tions; subsequent removal of the dimethylhydrazone protective
group could be easily accomplished, even for delicate product
aldehydes. Using these reagents led to a two-step homologation
cycle (condensation and deprotection), instead of the previous
three-step cycle.
Here, the new approach was applied to the preparation of
* Corresponding author: e-mail petrosrj@ncaur,usda.gov.
pheromones for Carpophilus sap beetles (Coleoptera: Nitidul-
10.1021/jf063337e This article not subject to U.S. Copyright. Published 2007 by the American Chemical Society
Published on Web 02/24/2007

Construction of Insect Pheromone by Direct Aldehyde Homologation
J. Agric. Food Chem., Vol. 55, No. 6, 2007 2283
compound 1 was prepared on a 10-g scale in just five steps
(two condensation/deprotection cycles, plus a final Wittig
olefination) from commercially available (2E)-2-methyl-2-
butenal (Scheme 1), while the previous method (14) required
seven steps. The Wittig olefination was further optimized during
this study, by taking advantage of the observation that lithium
cation (from n-butyllithium base) and increased concentration
of the reactants can both lead to increased proportions of
E-alkene (15). The overall yield and final purity of compound
1 were better than previously obtained (14). Further applications
of the aldehyde dimethylhydrazone phosphonates are discussed.
Scheme 1. Comparison of Synthetic Pathways to Compound 1 via
Ester-Based Phosphonate Reagents (Previous Method) and
Protected-Aldehyde-Based Phosphonate Reagents (New Method)a
MATERIALS AND METHODS
Chemicals and General Methods. Dry tetrahydrofuran (THF) was
prepared by distillation from sodium benzophenone ketyl. Diethyl
ethylphosphonate and diethyl 1-propylphosphonate were purchased from
Alfa Aesar (Ward Hill, MA), but these compounds were also prepared
in the laboratory (see below). Other organic reagents were obtained
from Aldrich and were used without further purification. Nonaqueous
reactions were performed under an atmosphere of dry argon in oven-
dried glassware. Removal of solvent, during workups, was accomplished
by rotary evaporation at water aspirator vacuum.
Analysis of Reaction Products. Progress of synthetic reactions was
monitored by gas chromatography (GC) and GC mass spectrometry
(GC-MS). The unwanted Z-isomer products were recognized by their
shorter GC retention times but nearly identical mass spectra, compared
to the all-E-isomers (14). Reported yields included only the all-E
isomers. All structures and double-bond configurations were additionally
verified by NMR.
The Hewlett-Packard (HP) 5890 Series II gas chromatograph was
equipped with flame ionization detector and split/splitless inlet and was
interfaced to an HP ChemStation data system. The column was a DB-5
capillary (30 m × 0.25 mm, 0.25-µm film thickness, J&W Scientific,
Folsom, CA). Carrier gas was He. The oven temperature was
programmed from 50 to 280 °C at 10 °C/min, and the detector
temperature was 280 °C. The inlet temperature was 120 °C, and 1.0
µL sample injections were made in splitless mode. Considerable
degradation of unsaturated aldehyde dimethylhydrazones was obser-
ved during GC runs with higher inlet temperatures, especially for
compound 6.
Electron impact mass spectra (70 eV) were obtained with an HP
5973 MSD instrument, interfaced to an HP 6890 GC, equipped with a
splitless inlet. Several columns were used, but all gave comparable
results to that used for GC. The oven temperature was programmed
from 50 to 250 °C at 10 °C/min; the inlet temperature was 120 °C and
the transfer line temperature was 250 °C.
1H NMR, 13C NMR, and 2D NMR spectra were collected on a
Bruker (Bellerica, MA) Avance 500 spectrometer using a 5 mm inverse
broadband probe. Samples were dissolved in CDCl3 or C6D6 (compound
1), and all spectra [1H and correlation spectroscopy (COSY) at 500
MHz, 13C and distortionless enhancement by polarization transfer
(DEPT) at 125 MHz] were acquired at 300 K. Configurations of
trisubstituted double bonds were assigned as E or Z, on the basis of
one-and two-dimensional pulsed field gradient nuclear Overhauser
enhancement spectroscopic (1D and 2D PFG-NOESY) experiments.
Chemical shifts are reported as parts per million from tetramethylsilane.
Coupling constants (J) are in hertz. Assignments for new compounds
a
Reaction conditions: (a) phosphonate 2 or 3, LiN(iPr)2, THF, 25
°
C, 20
h; (b) dilute HCl and petroleum ether, 25
°
C, 4 h for 5 and 17 h for 7; (c)
[Ph3PCH2CH2CH3]+Br-, n-BuLi, THF, <10
°
C, then 25
°
C for 1.5 h; (d) triethyl-
C,
°C, then 25 °C for 4 h; (f) MnO2,
2-phosphonopropionate or triethyl-2-phosphonobutyrate, n-BuLi, THF, <10
then 25
CH2Cl2, 25
°
°
C for 2 h; (e) LiAlH4, Et2O, <15
C, 4 h.
°
idae). These beetles, worldwide pests of a variety of fruits and
grains, have male-produced aggregation pheromones consisting
of conjugated triene and tetraene hydrocarbons, which are
attractive to both sexes (12). One species, the dusky sap beetle,
Carpophilus lugubris Murray, uses (2E,4E,6E,8E)-3,5-dimethyl-
7-ethyl-2,4,6,8-undecatetraene (1) as its major pheromone
component (Scheme 1) (13). Tetraene 1 provided a rather
challenging test for the new synthetic method because it is
relatively labile and because the ethyl branch at the C7-position
can lead to unwanted geometrical isomers and a rather poor
overall yield (14). By use of the new phosphonate reagents
diethyl ethylformyl-2-phosphonate dimethylhydrazone (2) and
diethyl 1-propylformyl-2-phosphonate dimethylhydrazone (3),
1
were made with the help of H- and 13C-Predictive software (16) and
by analogy to known compounds.
Synthetic Details: Diethyl Ethylphosphonate. This compound was
prepared in 98% yield by refluxing a mixture of triethyl phosphite and
ethyl iodide for 3 h as described previously (17).
Diethyl 1-Propylphosphonate. A 250 mL round-bottomed flask
containing 33.2 g (34.3 mL, 0.2 mol) of triethyl phosphite and 61.5 g
(45.4 mL, 0.5 mol) of 1-bromopropane was fitted with a Vigreux
column, thermometer, Dean-Stark trap, and an efficient water-cooled
reflux condenser. The solution was magnetically stirred at reflux
temperature, but only enough heat was applied to distill off the
byproduct bromoethane as it was formed (bp 37-40 °C, compared to

2284 J. Agric. Food Chem., Vol. 55, No. 6, 2007
Petroski and Bartelt
bp 71 °C for 1-bromopropane). The reaction was monitored by GC
and by measuring the volume of bromoethane in the Dean-Stark trap.
The reaction was complete when the triethyl phosphite was consumed,
which took 3-4 days. Kugelrohr distillation (32 °C oven temperature,
0.05 Torr) from two batches afforded 69.3 g (96% isolated yield, 95%
purity). The main product was identical to commercially available
diethyl 1-propylphosphonate in GC retention time and mass spectrum.
The distilled product also contained 2% diethyl ethylphosphonate,
resulting from reaction with byproduct bromoethane.
phosphonate to its anion. Then (2E)-2-methyl-2-butenal (21.0 g, 0.25
mol) was added dropwise; final color was yellow-orange. The mixture
was stirred at rt for 20 h. Consumption of the phosphonate 2 was
monitored by GC. Water (50 mL) was added to quench the reaction
(excess water should be avoided because it leads to problematic
emulsions during subsequent extraction steps). The solvent was removed
by rotary evaporation to give an oily residue, which was extracted with
ethyl acetate (12 × 100 mL, but about 90% of the product was
recovered with just five extractions). The combined extracts were dried
over anhydrous Na2SO4 and filtered, and removal of solvent left a
yellow oil. Kugelrohr distillation (oven temperature 38 °C, 0.05 Torr)
afforded 27.9 g of compound 4 (91% purity by GC, yield corrected
for purity 80%). By GC and GC-MS, the 2E/2Z isomer ratio was 46:1.
MS (EI) m/z (%) 166 (M+, 16), 151 (80), 137 (17), 121 (100), 106
Diethyl Ethylformyl-2-phosphonate Dimethylhydrazone (2). A solu-
tion of n-butyllithium (2.5 M, 85 mL, 0.213 mol, slight excess) was
added to dry THF (250 mL) and the mixture was cooled in an argon
atmosphere to dry ice-ethanol bath temperature (approximately -78
°C). Diethyl ethylphosphonate (33.2 g, 32.4 mL, 0.20 mol) was added
dropwise and the mixture was stirred for an additional hour before dry
dimethylformamide (DMF, distilled from CaH2, 20 mL, 0.26 mol) was
added. After the solution warmed to 20 °C, ice-cold 3 M aqueous HCl
(300 mL) was added and the mixture was stirred for 5 min. A fine
white precipitate formed initially, and then the solution cleared and
separated into two phases (liberation of the free phosphonate aldehyde).
The phases were separated, and the organic phase was washed with 30
mL of alkaline brine solution (0.5% NaHCO3 in saturated aqueous
NaCl), dried over anhydrous MgSO4, and filtered. The acidic aqueous
phase was repeatedly extracted with CH2Cl2 (5 × 150 mL), and the
combined CH2Cl2 extracts were washed with 30 mL of alkaline brine
solution. The alkaline brine washes were combined and extracted again
with CH2Cl2 (4 × 15 mL). All CH2Cl2 extracts were combined, dried
over anhydrous MgSO4, and filtered. Solvent was removed from the
dried organic phase and all dried CH2Cl2 extracts to afford 44 g of
crude diethyl ethylformyl-2-phosphonate, which still contained some
DMF. Without further purification, the crude product was converted
to the dimethylhydrazone (DMH) derivative by adding it to a mixture
of CH2Cl2 (600 mL) containing anhydrous MgSO4 (48 g, 0.4 mol);
then N,N-dimethylhydrazine (15.6 g, 20 mL, 0.26 mol) was added in
one portion. The mixture was stirred (48 h) until analysis by GC showed
complete protection of the aldehyde as the DMH derivative. Filtration,
removal of solvent, and Kugelrohr distillation (oven temperature 50
°C, 0.04 Torr) afforded 47.6 g of compound 2 (purity 98%, yield
corrected for purity 97%). Isolated yields >95% were routinely
obtained. MS (EI) m/z (%) 236 (M+, 34), 194 (8), 166 (82), 136 (42),
122 (10), 111 (12), 99 (100), 53 (12), 81 (12), 72 (11), 56 (12), 44
(62), 79 (47), 77 (29), 53 (12), 44 (16), 39 (18). EI-HRMS calcd for
1
C10H18N2 166.1470 (obsd 166.1475). H NMR δ 1.74 (d, 3H, J5-6
)
7.2 Hz, H-6, see Figure 1), 1.86 (s, 3H, H-7), 2.03 (s, 3H, H-8), 2.86
(s, 6H, N-CH3), 5.57, (q, 1H, J5-6 ) 7.2 Hz, H-5), 6.02 (s, 1H, H-3),
7.14 (s, 1H, H-1). 13C NMR δ 13.2 (C-8), 13.9 (C-6), 16.6 (C-7), 43.2
(N-CH3), 126.4 (C-5), 132.7 (C-2), 133.8 (C-4), 136.3 (C-3), 141.8
(C-1).
(2E,4E)-2,4-Dimethyl-2,4-hexadienal (5). Deprotection was initiated
by stirring compound 4 (12 g, containing 10.9 g of 4, 0.066 mol) with
1 M HCl (750 mL) at room temperature for 5 min (compound 4
dissolves as the hydrochloride salt forms) and then petroleum ether
(bp 35-60 °C, 750 mL) was added and stirring continued. After 3 h,
the phases were separated and the aqueous phase was returned to the
reaction vessel. Petroleum ether (750 mL) was added and the mixture
was stirred at rt for an additional 1 h before the phases were separated.
The combined petroleum ether phases were washed with alkaline brine
solution (20 mL), and the brine phase was back-extracted once with
petroleum ether (20 mL). The combined organic phases were dried,
and removal of solvent afforded 8.36 g of the free aldehyde 5. Over
two batches, purity by GC was 92-96%, and yield corrected for purity
was 94-98%. The 2E:2Z isomer ratio was 27:1. The MS and NMR
spectral data were consistent with the reference spectral data from
previous work (14).
(2E,4E,6E)-2-Ethyl-4,6-dimethyl-2,4,6-octatrienal Dimethylhydra-
zone (6). Compound 6 was prepared in a way similar to compound 4.
The phosphonate anion was prepared from 3 (38 g, 0.152 mol) in THF
(400 mL) by treatment with LDA (2.0 M, 77 mL, 0.154 mol, slight
excess); aldehyde 5 (18.6 g, containing 17.5 g of aldehyde 5, 0.141
mol) was subsequently added and the reaction was completed as before.
Kugelrohr distillation (oven temperature 56 °C, 0.06 Torr) afforded
32.0 g of compound 6. By GC, minimum purity was 86%; actual purity
may have been higher because some heat-related degradation was
evident in the GC trace. Yield, corrected for purity, was g84%. The
2E:2Z isomer ratio was estimated to be 30:1 by NMR. MS (EI) m/z
(%) 220 (M+, 18), 205 (7), 191 (17), 175 (20), 165 (100), 160 (31),
146 (19), 122 (15), 107 (10), 105 (11), 91 (13), 59 (10), 44 (8). EI-
HRMS calcd for C14H24N2 220.1939 (obsd 220.1939). 1H NMR δ 1.47
(t, 3H, J11-12 ) 7.4 Hz, H-12, see Figure 1), 1.71 (d, 3H, J7-8 ) 6.9
Hz, H-8), 1.82 (s, 3H, H-9), 2.14 (s, 3H, H-10), 2.69 (s, 6H, N-CH3),
3.01 (q, 2H, J11-12 ) 7.4 Hz, H-11), 5.61 (q, 1H, J7-8 ) 6.9 Hz, H-7),
6.15 (s, 1H, H-3), 6.24 (s, 1H, H-5), 7.00 (s, 1H, H-1). 13C NMR δ
13.6 (C-9), 14.9 (C-12), 16.7 (C-8), 18.6 (C-10), 20.6 (C-11), 42.5
(N-CH3), 125.0 (C-7), 132.5 (C-4), 133.7 (C-6), 134.7 (C-5), 135.7
(C-3), 138.1 (C-1), 140.6 (C-2).
1
(36). EI-HRMS calcd for C9H21N2O3P 236.1290 (obsd 236.1293). H
NMR δ 1.19 and 1.20 (overlapping t, 6H, J ) 7.0, CH3-CH2-O),
1.26 (d, 3H, J2-3 ) 7.3 Hz, H-3), 2.76 (dq, 1H, J1-2 ) 4.1 Hz and J2-3
) 7.3 Hz, H-2), 2.66 (s, 6H, N-CH3), 3.99 and 4.00 (overlapping q,
4H, J ) 7.0 Hz, CH3-CH2-O), 6.38 (br d, 1H, J1-2 ) 4.1 Hz, H-1).
13C NMR δ 12.7 (C-3), 16.4 (CH3-CH2-O), 36.0 and 37.1 (C-2,
isomers), 43.1 (N-CH3), 62.0 (CH3-CH2-O), 132.6 (C-1).
Diethyl 1-Propylformyl-2-phosphonate Dimethylhydrazone (3). A
preparation similar to that of compound 2 but with diethyl 1-propyl-
phosphonate (36.2 g, 36 mL, 0.20 mol) afforded 48 g of compound 3
(Kugelrohr oven temperature 68 °C, 0.05 Torr, purity 95%, yield
corrected for purity 91%). MS (EI) m/z (%) 250 (M+, 39), 235 (18),
208 (6), 206 (7), 180 (57), 165 (28), 150 (36), 53 (12), 113 (100), 83
(10), 81 (10), 70 (17), 44 (16). EI-HRMS calcd for C10H23N2O3P
1
250.1446 (obsd 250.1449) H NMR δ0.86 (t, 3H, J ) 7.4 Hz, H-4),
1.18 and 1.19 (overlapping t, 3H, J ) 7.3 Hz, CH3-CH2-O), 1.62
and 1.80 (m, 2H, H-3), 2.58 (m, 1H, H-2), 2.67 (s, 6H, N-CH3), 3.97
and 3.98 (overlapping q, 4H, J ) 7.3 Hz, CH3-CH2-O), 6.26 (br d,
1H, J ) 3.8 Hz, H-1). 13C NMR δ 12.3 (C-4), 16.4 (CH3-CH2-O),
20.8 (C-3), 43.2 (N-CH3), 44.4 (C-2), 61.9 (CH3-CH2-O), 131.9
(C-1).
(2E,4E,6E)-2-Ethyl-4,6-dimethyl-2,4,6-octatrienal (7). Deprotection
procedure was similar to that used for compound 5. A solution
containing compound 6 (9.12 g, containing about 7.84 g of compound
6, 35.6 mmol) and 1 M HCl (420 mL), to which petroleum ether (bp
35-60 °C, 420 mL) was added after 5 min, was stirred at room
temperature for 13 h. After 13 h, the phases were separated and the
aqueous phase was returned to the reaction vessel. Petroleum ether (400
mL) was added and the mixture was stirred at rt for an additional 4 h
before the phases were separated. Completion of the reaction as for
compound 5 resulted in 5.65 g of the free aldehyde 7 (purity by GC
showed 84%, yield corrected for purity 75%). The 2E:2Z isomer ratio
was 23:1. Two batches gave essentially identical results. The MS and
(2E,4E)-2,4-Dimethyl-2,4-hexadienal Dimethylhydrazone (4). A
commercial 2.0 M solution of lithium diisopropylamide (LDA, 102
mL, 0.204 mol, slight excess) was added dropwise (reaction exothermic)
to a 1 L round-bottomed flask containing dry THF (450 mL), compound
2 (47.2 g, 0.20 mol), and a few milligrams of ethyltriphenylphospho-
nium bromide, as an indicator, and the mixture was stirred in an argon
atmosphere at room temperature (rt) for 1.5 h to ensure complete
formation of the phosphonate ylide. A persistent red color developed
in the solution when sufficient base was added to convert the

Construction of Insect Pheromone by Direct Aldehyde Homologation
J. Agric. Food Chem., Vol. 55, No. 6, 2007 2285
NMR spectral data were consistent with the reference spectral data from
previous work (14).
(2E,4E,6E,8E)-3,5-Dimethyl-7-ethyl-2,4,6,8-undecatetraene (1). A
slurry of propyl(triphenyl)phosphonium bromide (25.3 g, 65 mmol)
was prepared in THF (50 mL) and chilled, in an argon atmosphere,
over an ice-water bath. A solution of n-butyllithium (2.5 M in hexane)
was added until the orange color persisted and then an additional 25
mL (62.5 mmol) was added slowly, with the temperature kept under
10 °C. After the solution was stirred for 1 h, crude (2E,4E,6E)-2-ethyl-
4,6-dimethyl-2,4,6-octatrienal (7) (9.09 g, containing 41 mmol of the
2E,4E,6E isomer) was added dropwise, with the temperature kept below
10 °C. The mixture was allowed to warm to rt and was stirred for an
additional 3 h. Methanol (100 mL) was then added; the red solution
became turbid and then cleared and turned a light yellow color. Water
(10 mL) was added and the solvent was removed by rotary evaporation
to afford a viscous oil, which was extracted with hexane (3 × 100
mL). Removal of solvent resulted in a pale yellow oil (9.77 g). Analysis
of two batches by GC showed the purity of compound 1 to be 65-
68%, and the yield of compound 1 from all-E-7, corrected for purity,
was 76-78%. The 8E:8Z isomer ratio for compound 1 was 7.5. The
product contained about 9% 8Z-isomer and about 6% all other isomers
of compound 1 by GC/MS analysis. A portion (2.7 g) of the material
(produced without chromatography and distillation) was chromato-
graphed as described in the earlier synthetic reference (14) and then
Kugelrohr-distilled to determine if any improvement was observed
following either purification step, as observed by GC/MS analysis. The
MS and NMR spectral data were consistent with the reference spectral
data from previous work (13, 14).
The effect of concentration on the E/Z isomer ratio for the final
Wittig reaction was studied on a small scale. Propyl(triphenyl)-
phosphonium bromide (500 mg, 1.3 mmol), 1.25 mmol of nBuLi (0.5
mL), aldehyde 7 (178 mg of the material described above with 82%
2E,4E,6E isomer, 1 mmol), and various amounts of THF were used.
Reactions were conducted as above for the preparation of compound
1. An additional experiment, to study the effect of increasing the ylide
to aldehyde ratio, was conducted with 2.9 mL of THF in which 1.1×
phosphonium salt and 1.05× nBuLi was compared with 1.3× phos-
phonium salt and 1.25× nBuLi.
Figure 1. Observed nuclear Overhauser enhancements (>0.5%) used to
assign configurations of trisubstituted double bonds of compounds 4
and 6.
large batches of the new reagents can be prepared and stored,
and these stocks could subsequently serve for syntheses of a
variety of final products. Alternative names for the aldehyde
phosphonates and aldehyde phosphonate dimethylhydrazones
2 and 3 are given in the reference section (18). We chose to
use the simpler, and more intuitive, names in this paper.
The new phosphonate reagents were readily converted to their
anions with the LDA base and reacted smoothly with aldehydes
to give alkyl-branched, unsaturated aldehyde dimethylhydra-
zones with chains having two additional carbons (4 and 6,
Scheme 1). Spectral data for new compounds 4 and 6 are
reported. The nuclear Overhauser experiment (NOE) results for
compounds 4 and 6 are summarized in Figure 1. These
observations support the assignment of E-configuration at all
the trisubstituted double bonds for compounds 4 and 6.
Deprotection of aldehyde dimethylhydrazone compounds 4
and 6 was accomplished by use of a biphasic mixture of 1 M
HCl and petroleum ether (11). In the deprotection reaction, the
dimethylhydrazone is initially converted to a water-soluble
hydrochloride salt, and the free aldehyde then forms under acidic
conditions. Successful deprotection requires immediate migra-
tion of the liberated, but rather labile, aldehyde from the aqueous
phase to the neutral petroleum ether phase. This procedure gave
a favorable (27:1) ratio of 2E to 2Z products. In the absence of
petroleum ether, dimethylhydrazone 4 gave a complex mixture
of reaction products. Deprotection of compound 4 was also
accomplished with 50% aqueous glyoxylic acid (10), but the
2E:2Z ratio fell to only 7.7:1, and deprotection of 6 with 50%
aqueous glyoxylic acid resulted in a yield of only 18%, along
with a tarlike material.
In our experience, the final Wittig reaction has given variable
results with respect to the E:Z isomer ratio, and efforts were
made to optimize the yield of the E isomers. It is known that
lithium cation (from n-butyllithium base) and increased con-
centration of the reactants can both lead to increased proportions
of E-alkene (15). Therefore, we studied the effect of reactant
concentration on the product 1 isomer ratio (Table 1). The 8E/
8Z isomer ratio increased as the volume of solvent decreased.
The best results were obtained by using a relatively concentrated
solution of reactants (i.e., 1 M aldehyde and 1.25 M phospho-
nium ylide). In a separate experiment, we found that increasing
the amount of excess phosphonium ylide was beneficial. The
8E/8Z isomer ratio increased from 3.5:1 to 5.4:1 when the ylide
to aldehyde ratio was increased from 1.05:1 to 1.25:1.
RESULTS AND DISCUSSION
The synthetic pathway to pheromone 1 (Scheme 1) was
shortened from seven steps to five steps, and the previous
reduction and oxidation steps are no longer required. The key
advance was the use of the new dimethylhydrazone phosphonate
reagents 2 and 3, which can be made from either laboratory-
prepared or commercially available diethyl ethylphosphonate
and diethyl 1-propylphosphonate. The new phosphonate reagents
were used to accomplish the robust and direct two-carbon
homologation of aldehydes to methyl- and ethyl-branched R,â-
unsaturated aldehydes, protected as dimethylhydrazones, and a
facile deprotection step then liberated the desired aldehyde
products. The final Wittig reaction in the synthesis of 1 was
optimized by using a relatively concentrated solution of the
phosphonium ylide in THF, which maximized the ratio of 8E
to 8Z products, and an improved workup was developed for
removing byproduct triphenylphosphine oxide.
The new phosphonate reagents were synthesized from diethyl
alkylphosphonate starting materials. Diethyl alkylphosphonate
starting materials were formylated, and then the aldehyde
functional group was protected as the dimethylhydrazone
derivative to prepare the new phosphonate reagents. Aldehyde
phosphonates, such as ethylformyl-2-phosphonate and diethyl
1-propylformyl-2-phosphonate, were readily prepared by the
method of Aboujaoude and Collignon (5), and these were
converted essentially quantitatively to the dimethylhydrazone
derivatives 2 and 3 (10). The new method requires the
phosphonate reagents to be synthesized, whereas those for the
original method were available commercially. Nevertheless,

2286 J. Agric. Food Chem., Vol. 55, No. 6, 2007
Petroski and Bartelt
eliminates the use and disposal of some metal-containing
reagents (reducing agents such as lithium aluminum hydride
and oxidants such as manganese dioxide).
Other sap-beetle pheromones, such as compounds 8-11 in
Figure 2, could be prepared by this new chemistry as well,
with the appropriate choice of starting materials, dimethylhy-
drazone phosphonates, number of condensation cycles, and final
Wittig reagents. Overall, the starting materials are sufficiently
inexpensive and the reactions and intermediates are sufficiently
robust so that the pathway can be commercially viable. Beyond
nitidulid pheromones, this more concise chemistry could be
applied to the practical synthesis of a variety of natural products,
pharmaceuticals, and other compounds. An unbranched phos-
phonate, diethyl methylformyl-2-phosphonate dimethylhydra-
zone, will be the subject of a future paper.
Figure 2. Examples of Carpophilus beetle pheromones (12) that could
be prepared via the new synthetic pathway.
Table 1. Effect of Reactant Concentration on Product 1 Isomer Ratioa
ACKNOWLEDGMENT
volume of THF (mL)
8E:8Z ratio
20
5
2.9
1
1.1
2.6
5.4
9.2
We thank Karl Vermillion and David Weisleder of NCAUR
for acquisition of NMR data and the University of Illinois,
School of Chemical Sciences, Mass Spectrometry Laboratory
for acquisition of HRMS data.
a The reactions were run on a 1 mmol scale, with 1.3 mmol of propyl(tri-
phenyl)phosphonium bromide (500 mg), varying amounts of THF, 1.25 mmol
of n-BuLi (0.5 mL), and 1 mmol of (2E,4E,6E)-2-ethyl-4,6-dimethyl-2,4,6-octa-
trienal (7) (178 mg of the material described in text, of which 82% was the
2E,4E,6E isomer). Reactions were conducted as explained for the preparation of
compound 1.
LITERATURE CITED
(1) Wadsworth, W. S., Jr.; Emmons, W. D. The utility of phospho-
nate carbanions in olefin synthesis. J. Am. Chem. Soc. 1961,
83, 1733-1738.
(2) Trippett, S.; Walker, D. M. The phosphobetaines: preparation
and properties. J. Chem. Soc. London 1961, 1266-1272.
(3) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P. The
vinylogation of aldehydes: an improved method for the prepara-
tion of alpha formylethylidenetriphenylphosphorane, and an
improved alpha silyl imine reagent of propionaldehyde. Tetra-
hedron Lett. 1985, 26, 2391-2394.
(4) Boutagy, J.; Thomas, R. Olefin synthesis with organic phos-
phonate carbanions. Chem. ReV. 1974, 74, 87-99.
(5) Aboujaoude, E. E.; Collignon, N. A simple synthesis of dialkyl
1-formylalkanephosphonates. Synthesis 1983, 634-636.
(6) Nagata, W.; Hayase, Y. Formylolefination of organic compounds.
J. Chem. Soc. London (C) 1969, 460-466.
(7) Desmond, R.; Mills, S. G.; Volante, R. P.; Shimkai, I. A highly
selective method for the synthesis of (E)-R-methyl-R,â-unsatur-
ated aldehydes. Tetrahedron Lett. 1988, 29, 3895-3898.
(8) Bellassoued, M.; Majidi, A. A simple and highly stereospecific
route to E-R,â-unsaturated aldehydes. J. Org. Chem. 1993, 58,
2517-2522.
(9) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; pp
350-352.
(10) Petroski, R. J. Preparation and deprotection of aldehyde di-
methylhydrazones. Synth. Commun. 2006, 36 (120), 1727-
1734.
(11) Petroski, R. J. Facile biphasic deprotection of aldehyde dimeth-
ylhydrazones with aqueous hydrochloric acid. Lett. Org. Chem.
2007 (submitted for publication).
The workup of the preparative-scale Wittig reaction was
improved. The reaction was quenched by adding methanol and
a small amount of water, which converts any alkoxide base into
hydroxide base. After the THF is removed by rotary evaporation,
the triphenylphosphine oxide byproduct remains in an oily state,
dissolved in the remaining methanol-water mixture. Extraction
of the resulting oil with hexane and subsequent drying, filtration,
and removal of solvent afforded an oil containing product 1
with almost none of the byproduct triphenylphosphine oxide.
The purity of the product was as high as the product obtained
after silica gel column chromatography, followed by Kugelrohr
distillation (14). No purity improvement was observed (GC/
MS analysis) following the additional purification steps because
the major impurities (e.g., triphenylphosphine oxide) had already
been removed. This new workup also improves the commercial
viability of pheromone production.
Although the diethyl alkylphosphonate starting materials are
commercially available, it is shown here that they can be readily
prepared in the laboratory from less expensive starting materials
(triethyl phosphite and alkyl halides). The preparation of diethyl
1-propylphosphonate requires removal of byproduct bromo-
ethane, as it is formed, because the bromoethane will attack
triethyl phosphite to form diethyl ethylphosphonate (17).
However, attempts to prepare diethyl 1-propylphosphonate from
ethyl phosphate and n-propyllithium (19), prepared in situ from
n-propyl bromide and lithium metal, were not successful in our
hands.
(12) Bartelt, R. J. Sap beetles. In Pheromones of Non-Lepidopteran
Insects Associated with Agricultural Plants; Hardie, J., Minks,
A. K., Eds.; CABI Publishing; New York, 1999; pp 69-89.
(13) Bartelt, R. J.; Dowd, P. F.; Plattner, R. D. Aggregation
pheromone of Carpophilus lugubris new pest management tools
for the nitidulid beetles. In Naturally Occurring Pest Bioregu-
lators; Hedin, P. A., Ed.; ACS Symposium Series 449; American
Chemical Society: Washington, DC, 1991; pp 27-40.
(14) Bartelt, R. J.; Weisleder, D.; Plattner, R. D. Synthesis of nitidulid
beetle pheromones: alkyl-branched tetraene hydrocarbons. J.
Agric. Food Chem. 1990, 2192-2196.
All reactions in the new synthetic pathway were conducted
on a scale large enough (greater than 10 g) to ensure that the
steps could be scaled up for commercial pheromone production.
Yields of products for the five steps in the synthetic pathway
were 4 (80%), 5 (96%), 6 (84%), 7 (75%), and 1 (77%), giving
an overall yield of 37% from (2E)-2-methyl-2-butenal. This is
a substantial improvement over the 20% overall yield for the
previous seven-step pathway (14). Furthermore, the new method

Construction of Insect Pheromone by Direct Aldehyde Homologation
J. Agric. Food Chem., Vol. 55, No. 6, 2007 2287
(15) Reitz, A. B.; Norty, S. O.; Jordon, A. J.; Mutter, M. S.;
Maryanoff, B. E. Dramatic concentration dependence of stereo-
chemistry in the Wittig reaction. Examination of the lithium salt
effect. J. Org. Chem. 1986, 51, 3302-3308.
diethyl 1-propylformyl-2-phosphonate dimethylhydrazone 3 can
also be named [1-(dimethylhydrazinomethyl)propyl]phosphonic
acid diethyl ester.
(19) Teulade, M.-P.; Savignac, P. Direct conversion of phosphates
to alpha-lithio phosphonates with alkyllithiums. Tetrahedron Lett.
1987, 28, 405-408.
1
(16) ACD H- and 13C-Predictive software, version 6.0, is available
from Advanced Chemistry Development, Toronto, Ontario,
Canada.
(17) Ford-Moore, A. H.; Perry, B. J. Diisopropyl methylphosphonate.
Org. Synth. 31, 1951, 33-35.
Received for review November 17, 2006. Revised manuscript received
January 24, 2007. Accepted January 25, 2007. Mention of trade names
or commercial products in this article is solely for the purpose of
providing specific information and does not imply recommendation or
endorsement by the U.S. Department of Agriculture.
(18) Diethyl ethylformyl-2-phosphonate can also be named (1-methyl-
2-oxoethyl)phosphonic acid diethyl ester, and diethyl 1-propyl-
formyl-2-phosphonate can also be named (1-formylpropyl)-
phosphonic acid diethyl ester. Diethyl ethylformyl-2-phos-
phonate dimethylhydrazone 2 can also be named [2-(dimethyl-
hydrazino)-1-methylethyl]phosphonic acid diethyl ester, and
JF063337E