Two-carbon homologation of aldehydes and ketones to α,β- unsaturated aldehydes

Article abstract of DOI:10.3390/molecules16065062

Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched α,β- unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2- phosphonate dimethylhydrazone and diethyl ethylformyl-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 1 M HCl and petroleum ether. This robust two-step process worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated aldehyde products ranged from 71% to 86% after the condensation and deprotection steps.

Full text of DOI:10.3390/molecules16065062

Molecules 2011, 16, 5062-5078; doi:10.3390/molecules16065062
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Articles
Two-Carbon Homologation of Aldehydes and Ketones to
α,β-Unsaturated Aldehydes
1
2
1,
Richard J. Petroski , Karl Vermillion and Allard A. Cossé *
1
Unit of Crop Bioprotection Research, USDA, Agricultural Research Service, National Center for
Agricultural Utilization Research, 1815 N. University Street, Peoria, IL 61604, USA
2
*
Unit of Functional Food Research, USDA, Agricultural Research Service, National Center for
Agricultural Utilization Research, 1815 N. University Street, Peoria, IL 61604, USA
Author to whom correspondence should be addressed; E-Mail: Allard.Cosse@ars.usda.gov;
Tel.: +1-309-681-6217; Fax: +1-309-681-6693.
Received: 28 April 2011; in revised form: 31 May 2011 / Accepted: 13 June 2011 /
Published: 17 June 2011
Abstract: Phosphonate reagents were developed for the two-carbon homologation of
aldehydes or ketones to unbranched- or methyl-branched α,β-unsaturated aldehydes. The
phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl
ethylformyl-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 1 M HCl and petroleum ether. This robust two-step process
worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated
aldehyde products ranged from 71% to 86% after the condensation and deprotection steps.
Keywords: aldehyde homologation; ketone to aldehyde homologation; diethyl methylformyl-
phosphonate dimethylhydrazone; diethyl ethylformyl-2-phosphonate dimethylhydrazone
1
. Introduction
A recurring theme in the synthesis of various polyketide natural products and other compounds is
two-carbon homologation of aldehydes or ketones to unbranched or branched (e.g., α-methyl or
β-methyl) α,β-unsaturated aldehydes. A typical approach based on the Horner-Wadsworth-Emmons
condensation [1] uses a phosphonate ester, such as triethyl-2-phosphonoacetate or triethyl-2-

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Molecules 2011, 16
phosphonopropionate, and involves three synthetic steps: The phosphonate condensation step extends
the chain by two carbons while introducing an (E) double bond, an α-alkyl branch (size depending on
the choice of phosphonate reagent), and a terminal ester group. The ester is then reduced to an
α,β-unsaturated alcohol, and the alcohol is partially oxidized to the desired α,β-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 α-formylethylidene
triphenylphosphorane are known [2,3], but in our hands the reagent was not reactive toward
α,β-branched unsaturated aldehydes, such as (2E)-2-methyl-2-butenal [4]. Phosphonate anions are
generally more reactive toward aldehydes or ketones than the analogous phosporanes [5]. Aldehyde
phosphonates (where the ester group is replaced by an aldehyde) can be readily prepared [6], but using
them directly in Wittig-Horner reactions is not practicable because of self-condensation. Reactions
using aldehyde phosphonates protected as imines and acetals have been reported, but these reagents
also have problems with side reactions, insufficient reactivity, and lability of products [7]. The
silylaldimines are the functional equivalents of protected aldehyde phosphonates and have been used
in Wittig-Horner-like reactions [8,9]; however, reaction conditions to form and use silylaldimines are
not operationally convenient [9]. Solid base-promoted cross-aldol condensations have been successful,
but only aromatic or heteroaromatic aldehydes were suitable as reactants [10]. Recently, acidic ionic
liquid-catalyzed homologation of α,β-enals was reported, but the scope of the reaction did not include
aliphatic aldehydes [11].We chose to further explore phosphonate chemistry with a better carbonyl
protective group because the scope of the reaction would include a variety of aldehydes and ketones.
Protection of carbonyl compounds as dimethylhydrazones is a common practice, and the incorporation
and removal of this group have been studied extensively [12-14].
This paper describes work detailing the preparation (Scheme 1) and use (Scheme 2) of diethyl
methylformylphosphonate dimethylhydrazone (1) and diethyl 1-ethylformyl-2-phosphonate dimethyl-
hydrazone (2) for the two-carbon homologation of a variety of aldehydes or ketones to α,β-unsaturated
aldehydes after deprotection.
Scheme 1. Preparation of phosphonate reagents 1 and 2.
O
O
P
OEt
OEt
O
P
EtO
EtO
EtO
EtO
a
EtO
EtO
b
P
N
N
O
1
82%
O
O
O
P
EtO
EtO
EtO
EtO
c, d, e
EtO
EtO
b
P
N
P
N
O
R
R
R
R = H or R = Me
1 R = H, 50%
R = Me, 97%
R = H or R = Me
2
Reagents and conditions: Preparation of phosphonate 1: (a) diethyl-2,2-(diethoxy)ethylphosphonate,
acetone, 1.5% water, p-toluenesulfonic acid, 25 °C, 96 h; (b) H N-NMe , MgSO , CH Cl , 25 °C,
2
2
4
2
2
4
8 h. Alternative preparation of 1: (c) diethyl methylphosphonate, THF, BuLi; (d) Me NCHO;
2
(
e) 3 M HCl, 1a–1c in one pot; (b) H N-NMe , MgSO , CH Cl , 25 °C, 48 h. Preparation of
2 2 4 2 2
phosphonate 2: (c) diethyl ethylphosphonate, THF, BuLi; (d) Me NCHO; (e) 3 M HCl, 1a–1c in
2
one pot; (b) H N-NMe , MgSO , CH Cl , 25 °C, 48 h.
2
2
4
2
2

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Molecules 2011, 16
Scheme 2. Reaction pathways and products.
O
O
3
18
a
a
N
N
N
N
19
99 %
R
R
4 R = H 88 %
R = Me 89 %
b
b
5
O
O
6
7
R = H 90 %
R = Me 91 %
20 86 %
O
O
21
8
a
a
N
N
N
N
O
2
2
94 %
R
9 R = H 77 %
10 R = Me 82 %
b
b
O
2
3 90 %
R
1
1
1 R = H 89 %
2 R = Me 89 %
O
O
13
24
a
a
N
N
N
N
1
1
4 R = H
88 %
5 R = Me 88 %
R
R
2
5 85 %
b
b
O
O
1
1
6 R = H 81 %
7 R = Me 96 %
26 87 %
2
Reagents and conditions: (a) Phosphonate 1 or 2, LiN(iPr) , THF, 25 °C, 3 to 20 h, time varies with
compound; (b) 1 M HCl and Pet ether, 25 °C, 5 to 48 h, time varies with compound.
2
. Results and Discussion
2
.1. Preparation of Phosphonate Dimethylhydrazone Reagents
Reagent 1 could be prepared (Scheme 1) from commercially available diethyl-2,2-(diethoxy)
ethylphosphonate by deprotection to give ethylformyl-2-phosphonate, then the aldehyde functional
group could be protected as the dimethylhydrazone derivative [13]. Acetals of aldehydes have been
deprotected by transfer to acetone, in the presence of certain catalysts [15-18]; therefore, deprotection of
commercially available diethyl-2,2-(diethoxy)ethylphosphonate [7] would yield the required diethyl
formylmethylphosphonate, a deprotection procedure, which needed only a small amount of water,

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Molecules 2011, 16
would be preferable because the product, diethyl formylmethyl-2-phosphonate, is difficult to extract
from water. Also, hydrolysis of the ethyl esters on phosphorous can occur in water [19].
The deprotection of diethyl-2,2-(diethoxy) ethylphosphonate was successfully carried out with a
p-toluenesulfonic acid catalyst in acetone [18] containing only 1.5% water. The product contained 8%
unused starting material, diethyl-2,2-(diethoxy)ethylphosphonate, but deprotection of the acetal with
aqueous HCl also resulted in unreacted starting material [17].
The aldehyde functional group was then protected as the dimethylhydrazone derivative, with
N,N-dimethylhydrazine, as done previously [19]. Phosphonate 1 was prepared in 82% overall yield
from the starting material. The product still contained about 8% unused starting material, carried
through the synthesis. The presence of starting material did not pose a problem when the phosphonate
reagent was used for aldehyde homologation or ketone to aldehyde homologation.
Phosphonate reagent 1, could also be prepared from commercially available diethyl methyl-
phosphonate, by lithiation of diethyl methylphosphonate, formylation with dimethylformamide [19],
followed by protection of the aldehyde function as the dimethylhydrazone derivative [13]. The overall
yield for this synthetic pathway was only 50% (because of difficulty extracting water-soluble
ethylformyl-2-phosphonate), so the other preparative route was preferred.
Phosphonate reagent 2 was prepared from diethyl ethylphosphonate by formylation, to prepare
diethyl 1-propylformyl-2-phosphonate [19], and then the aldehyde functional group was protected as
the dimethylhydrazone derivative. The overall yield was usually greater than 95%.
The new method requires the phosphonate reagents to be synthesized, whereas those for the original
method are available commercially. Nevertheless, 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.
Diethyl methylformylphosphonate can also be named (2-oxo-ethyl)-phosphonic acid diethyl ester and
diethyl ethylformyl-2-phosphonate can also be named (1-methyl-2-oxo-ethyl)-phosphonic acid diethyl
ester. Diethyl methylformylphosphonate dimethylhydrazone can also be named [2-(dimethyl-
hydrazino)-ethyl]-phosphonic acid diethyl ester.and diethyl ethylformyl-2-phosphonate dimethylhydrazone
can also be named [2-(dimethyl-hydrazino)-1-methyl-ethyl]-phosphonic acid diethyl ester. Alternative
names for the aldehyde phosphonates and aldehyde phosphonate dimethylhydrazones 1 and 2 are given,
but the simpler, and more intuitive, names were used in this paper.
2.2. Use of the Phosphonate 1 and 2 Reagents in Synthesis
Both 1 and 2 were readily converted to their corresponding anions with the base LDA and reacted
smoothly with aldehydes or ketones, added in excess, to give unbranched- or methyl-branched,
unsaturated aldehyde dimethylhydrazones with chains having two additional carbons (Scheme 2).
Yields for the condensation step ranged from 77%–99%.
Deprotection of unsaturated aldehyde dimethylhydrazones was accomplished in 81%–96% yield,
using a biphasic mixture of 1 M HCl and petroleum ether [14]. In the deprotection reaction, the
dimethylhydrazone is initially converted to a water-soluble hydrochloride salt, and the free aldehyde
then forms under the acidic conditions. Successful deprotection requires immediate migration of the
liberated, but sometimes labile, aldehyde from the aqueous phase to the neutral petroleum ether phase.

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Molecules 2011, 16
In the absence of petroleum ether, deprotection of unsaturated aldehyde dimethylhydrazones 9 and 10
gave a complex mixture of reaction products.
Using these reagents led to a two-step aldehyde homologation cycle (condensation and deprotection)
instead of the previous three-step cycle. Overall yields, of unsaturated aldehyde products, for the two-step
sequence ranged from 71% to 86%. Homologation of unbranched aldehyde starting materials with
phosphonate 1 resulted in disubstituted α,β-unsaturated aldehyde products whereas homologation of
unbranched aldehyde starting materials with phosphonate 2 resulted in trisubstituted α,β-unsaturated
aldehyde products, with a methyl group at the 2-position. Homologation of methyl ketones with
phosphonate 1 resulted in trisubstituted α,β-unsaturated aldehyde products, with a methyl group at the
3
-position. The two-step homologation procedure gave a favorable (9.5:1 to 170:1) ratio of 2E to 2Z
products from aldehyde starting materials and a ratio (2.0:1 to 2.2:1) of 2E to 2Z products from ketone
starting materials. Homologation of cycloheptanone with phosphonate 2 resulted in an improved
synthesis of cycloheptylidene-acetaldehyde 26. The overall yield for the preparation of 26 increased
from 42% [20] to 74%.
2
.3 Assignment of Double-Bond Configuration
The major isomer configuration, at the α,β-double bond of disubstituted alkene compounds 4, 6, 9,
1, 14 and 16 (Scheme 2) was readily determined to be E by the coupling constant of J2-3 =15.1 to
1
J
2-3 = 16.1 Hz. The major isomer configuration of all trisubstituted double bonds, of compounds 5, 7,
0, 12, 15 and 17, was determined by nuclear Overhauser enhancement (nOe) NMR methods.
1
Irradiation at either H-1 or H-3 caused a nuclear Overhauser enhancement of 2.1% to 4.3% at H-1 or
H-3 for compounds 5, 7, 10, 12, 15 and 17, but only a nOe of 0% to 0.2% was observed for the methyl
group protons for any of the compounds. Irradiation of the methyl group protons caused a nOe of just
0% to 0.5% for either H-1 or H-3. The data support the assignment of 2E configuration for compounds
5
, 7, 10, 12, 15 and 17, because the H-1 and H-3 protons are closer to each other than to the protons of
the methyl group, attached to C-2.
The proportion of 2Z-isomer product was identified by its shorter GC retention time and nearly
identical mass spectra, compared to the 2E-isomer [21], for compounds 19, and 20. The major isomer
configuration of the trisubstituted double bonds, of compounds 19, and 20 was determined to be E
because of the later GC retention time, previously observed for (2E)-N,N-Dimethyl-N’-(dec-2-
enylidene)-hydrazine and (2E)-2-Decenal [19]. Also, the reported proton NMR chemical shifts more
closely matched the E-isomer of 20 reported previously [22]. We could not use nuclear Overhauser
enhancement (nOe) NMR methods for additional verification because the proton chemical shifts for
the methyl branch and protons on adjacent carbons were too close together for the both isomers.
The major isomer configuration of the trisubstituted double bonds, of compounds 22 and 23,
derived from methyl ketone starting materials, 6, and 7 was determined by nuclear Overhauser
enhancement (nOe) NMR methods. A moderate nOe enhancement was observed (2D NOESY
experiments) between the methyl group protons and H-2, in the case of the minor isomer for both
compounds. Only weak nOe enhancement was observed between the methyl group protons and H-2, in
the case of the major isomer of compound 6 and no nOe enhancement was observed between the
methyl group protons and H-2, in the case of the major isomer of compound 23. The data support the

5
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Molecules 2011, 16
assignment of 2Z configuration for the minor isomer of compounds 22 and 23 because the H-2 protons
are closer to the protons of the methyl group, attached to C-3. Therefore, the major isomer has the
E-configuration. The GC retention time for the major isomer was also later than that observed for the
minor isomer, consistent with the assignment of E-configuration for the major isomer. Compound 23
has been prepared previously [23-25] and the chemical shift for the methyl branch carbon, attached to
C-3, was δ 16.4 for the major E-isomer and δ 26.4 for the minor Z-isomer, consistent with reported
1
3
C-NMR data [25].
3. Experimental
General
Diethyl-2,2-(diethoxy)ethylphosphonate, diethyl methylphosphonate and diethylethylphosphonate
were purchased from Alfa Aesar (Ward Hill, MA, USA). Diethyl ethylphosphonate can also be
prepared in 98% yield by refluxing a mixture of triethyl phosphite and ethyl iodide for 3 h [26]. THF
was purified by distillation from sodium benzophenone ketyl. Lithium diisopropylamide (LDA) was
purchased from the Aldrich Chemical Co (Milwaukee, WI, USA) as a 2 M solution in a mixture of
heptane/THF/ethylbenzene. Other organic reagents were obtained from Aldrich and were used without
further purification. Non-aqueous reactions were performed under an atmosphere of dry argon in
oven-dried glassware. Removal of solvent was accomplished by rotary evaporation at water
aspirator pressure.
Progress of synthetic reactions was monitored by gas chromatography (GC). All reaction products
were identified by GC/MS and the structures were additionally verified by NMR. Yields were
corrected for purity. Both 2E and 2Z isomers were considered to be the product for all product
compounds; however, the 2E:2Z isomer ratios are reported.
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, USA).
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 220 °C, and 1.0 µL sample injections were
made in splitless mode. The inlet temperature was 120 °C, and 1.0 µL sample injections were made in
splitless mode for analysis for compounds 9 and 10 because considerable degradation of unsaturated
aldehyde dimethylhydrazones was observed during GC runs with higher inlet temperatures.
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 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 220 °C and the transfer line temperature was 250 °C. The inlet temperature
was 120 °C for compounds 9 and 10.
1
13
H-NMR, C-NMR and 2D NMR spectra were collected on a Bruker (Bellerica, MA, USA)
Avance 500 spectrometer using a 5 mm broadband probe. Samples were dissolved in either CDCl or
C D (where indicated) and all spectra ( H and COSY at 500 MHz, C and DEPT at 125 Mhz) were
3
1
13
6
6
o
acquired at 300 K. Trisubstituted double-bond “E” or “Z” assignments were based on 1D PFG-NOE
experiments and 2D PFG-NOESY experiments. Chemical shifts are reported as parts per million from

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Molecules 2011, 16
tetramethylsilane based on the lock solvent. Coupling constants (J) are in Hertz. Assignments were
made with the help of NMR prediction software from Advanced Chemistry Development, Inc.
(
ACD/Labs) [27] and by analogy to known compounds. Although compounds 6, 7, 20, 22, 23 and 26
are known, spectral data are given because MS and NMR data are very difficult to find in the older
chemical literature. Methyl branches are reported by the point of attachment to the carbon chain
(
e.g., CH at C-2).
3
Diethyl methylformylphosphonate dimethylhydrazone (1). Diethyl-2,2-(diethoxy)ethylphosphonate
5.31 g, 20.9 mmol) was added to acetone (200 mL), followed by water (3 mL) and p-toluenesulfonic
(
acid (1.3 g, 6.8 mmol). The mixture was stirred at r.t., under an argon atmosphere for 4 days. A
solution of NaHCO (570 mg, 6.8 mmol in 6 mL water) was added with stirring to quench the reaction
3
and neutralize acid present. The pH was checked and found to be 7. After removal of solvent, aqueous
oil remained. The oil was saturated by the addition of NaCl (25 g). The aqueous oil was repeatedly
extracted with CH Cl (100 mL then 2 × 50 mL), and the combined CH Cl extracts were dried over
2
2
2
2
anhydrous Na
-phosphonate. Without further purification, the crude product was converted to the dimethylhydrazone
DMH) derivative by adding it to a mixture of CH Cl (75 mL) containing anhydrous MgSO (5.3 g,
2 4
SO and filtered. Solvent was removed to afford 5.59 g of crude diethyl methylformyl-
2
(
2
2
4
4
4 mmol) then N,N-dimethylhydrazine (1.76 g, 2.2 mL, 22 mmol) 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 62 °C,
0
.05 Torr) afforded 4.41 g of oil containing 1 (purity 86%, yield corrected for purity 82%). The oil also
contained 8% starting material, diethyl-2,2-(diethoxy)ethylphosphonate. MS of product: (EI) m/z (%)
+
2
22 (M , 32), 180 (9), 152 (91), 125 (100), 122 (74), 108 (27), 97 (37), 85 (85), 71 (15), 58 (8), 44
1
(
91). H-NMR δ 1.30 (6H, t, J = 7.0, CH
3
–CH
–O), 6.47 (1H, br d, J1-2 = 5.8, H-1). C-NMR δ 16.4 (CH
), 61.9 (CH –CH –O), 126.1 (C-1). The MS and NMR spectral data were
2 3
–O), 2.77 (6H, s, N–CH ), 2.81 (1H, dt, J1-2 = 5.8, H-2),
1
3
4
.09, (4H, q, J = 7.0, CH
3
–CH
2
3 2
–CH –O),
3
1.3 (C-2), 42.9 (N–CH
3
3
2
consistent with the reference spectral data from previous work [19].
Alternative preparation of diethyl methylformylphosphonate dimethylhydrazone (1). A solution of
n-butyllithium (2.5 M, 25 mL, 0.213 mol, slight excess) was added to dry THF (80 mL) and the
mixture was cooled in an argon atmosphere to dry ice-ethanol bath temperature (approx −78 °C).
Diethyl methylphosphonate (9.13 g, 8.8 mL, 0.06 mol) was added dropwise and the mixture was stirred
2
for an additional hr before dry dimethylformamide (DMF, distilled from CaH , 4.8 mL, 0.066 mol) was
added. After warming to 20 °C, ice cold 3 M aqueous HCl (300 mL) was added and the mixture was
stirred 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 10 mL of alkaline brine solution (0.5 % NaHCO
dried over anhydrous MgSO , and filtered. The acidic aqueous phase was repeatedly extracted with
CH Cl (5 × 50 mL), and the combined CH Cl extracts were washed with alkaline brine solution
3
in saturated aqueous NaCl),
4
2
2
2
2
(
2 × 10 mL). The alkaline brine washes were combined and extracted again with CH
All CH Cl extracts were combined, dried over anhydrous MgSO , and filtered. Solvent was removed
from the dried organic phase and all dried CH Cl extracts to afford 9.8 g of crude diethyl
2 2
Cl (4 × 15 mL).
2
2
4
2
2

5
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Molecules 2011, 16
methylformyl-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
2 2 4
CH Cl (200 mL) containing anhydrous MgSO (14.4 g, 0.12 mol) then N,N-dimethylhydrazine
(
4.7 g, 6 mL, 0.08 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 44 °C, 0.02 Torr) afforded 7.1 g of 1 (purity 93%, yield
+
corrected for purity 50%). MS (EI) m/z (%) 222 (M , 32), 180 (9), 152 (91), 125 (100), 122 (74), 108
(
27), 97 (37), 85 (85), 71 (15), 58 (8), 44 (91). EI-HRMS C
8
H
19
N
2
O
3
P calcd. for 222.1133 (obs.
), 2.81 (1H, dt, J1-2 = 5.8,
1
2
22.1133). H-NMR δ 1.30 (6H, t, J = 7.0, CH
3
–CH
2
–O), 2.77 (6H, s, N–CH
3
13
H-2), 4.09, (4H, q, J = 7.0, CH –CH –O), 6.47 (1H, br d, J = 5.8, H-1). C-NMR δ 16.4 (CH –CH –O),
3
2
1-2
3
2
31.3 (C-2), 42.9 (N–CH
3
), 61.9 (CH
3
–CH
2
–O), 126.1 (C-1).
Diethyl ethylformyl-2-phosphonate dimethylhydrazone (2). A solution of n-butyllithium (2.5 M, 85 mL,
.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 (approx −78 °C). Diethyl ethylphosphonate (33.2 g,
2.4 mL, 0.20 mol) was added dropwise and the mixture was stirred for an additional hr before dry
0
3
DMF (20 mL, 0.26 mol) was added. After warming to 20 °C, ice cold 3 M aqueous HCl (300 mL) was
added and the mixture was stirred 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%
NaHCO
phase was repeatedly extracted with CH
washed with 30 mL of alkaline brine solution. The alkaline brine washes were combined and extracted
again with CH Cl (4 × 15 mL). All CH Cl extracts were combined, dried over anhydrous MgSO
and filtered. Solvent was removed from the dried organic phase and all dried CH Cl extracts to afford
4 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 CH Cl (600 mL) containing anhydrous MgSO (48g, 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
3
in saturated aqueous NaCl), dried over anhydrous MgSO
4
, and filtered. The acidic aqueous
2
Cl (5 × 150 mL), and the combined CH
2
2
Cl extracts were
2
2
2
2
2
4
,
2
2
4
2
2
4
(
4
7.6 g of 3 (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
1
(
12), 72 (11), 56 (12), 44 (36). EI-HRMS C
.19 and 1.20 (6H, overlapping t, J = 7.0, CH
1-2 = 4.1 and J2-3 = 7.3, H-2), 2.66 (6H, s, N–CH
9
H
21
N
2
O
3
P calcd. for 236.1290 (obs. 236.1293) H-NMR δ
1
3
–CH
2
–O), 1.26 (3H, d, J2-3 = 7.3, H-3), 2.76 (1H, dt,
), 3.99 and 4.00, (4H, overlapping q, J = 7.0,
CH –CH –O), 6.38 (1H, br d, J = 4.1, H-1). C-NMR δ 12.7 (C-3), 16.4 (CH –CH –O), 36.0 and
J
3
1
3
3
2
1-2
3
2
3
7.1 (C-2, isomers), 43.1 (N–CH ), 62.0 (CH –CH –O), 132.6 (C-1).
3 3 2
(
2E)-N,N-Dimethyl-N’-(dec-2-enylidene)-hydrazine (4). A commercial 2.0 M solution of LDA (5.2 mL,
0.4 mmol, slight excess) was added dropwise (reaction exothermic) to a 250 mL round-bottomed
flask containing dry THF (25 mL), 1 (2.22 g, containing 2.06 g of 1, 9.3 mmol) and a few mg of
1

5
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Molecules 2011, 16
ethyl(triphenyl)phosphonium bromide, as an indicator, and the mixture was stirred in an argon
atmosphere at r.t. 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 phosphonate to its anion.
Then, n-octanal (1.67 g, 13 mmol) was added dropwise; final color was yellow-orange. The mixture
was stirred at r.t. for 5 h. Consumption of the phosphonate 1 was monitored by GC. Water (6 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 (5 × 25 mL). The combined extracts were
washed with saturated aqueous NaCl solution (15 mL), dried over anhydrous Na SO and filtered.
2
4
Removal of solvent left a yellow oil. Kugelrohr distillation (oven temperature 59 °C, 0.05 Torr)
afforded 1.80 g of 4 (89% purity by GC, yield corrected for purity 88%). By GC and GC-MS, the
+
2
1
1
E/2Z isomer ratio was 8.5 to 1. MS (EI) m/z (%) 196 (M , 72), 181 (8), 167 (2), 152 (19), 140 (7),
25 (14), 111 (100), 82 (40), 59 (21), 44 (32), 42 (19). EI-HRMS C H N calcd. for 196.1939 (obs.
1
2
24
2
1
96.1940). H-NMR δ 0.89 (3H, t, J9-10 = 6.9, H-10), 1.27-1.30 (8H, m, H-6 to H-9), 1.42 (2H, m,
H-5), 2.15 (2H, m, J3-4 = 7.8, H-4), 2.84 (6H, s, N–CH ), 5.87 (1H, dd, J = 7.8 and J2-3 = 15.5, =CH,
3
3-4
1
3
H-3), 6.20 (1H, dd, J1-2 = 9.1 and J2-3 = 15.5, =CH, H-2), 7.11 (1H, d, J1-2 = 9.1, =CH, H-1). C-NMR
δ 13.3 (C-10), 22.6 (C-9), 29.0 (C-5, C-6 and C-7), 31.7 (C-8), 32.6 (C-4), 43.0 (N–CH ), 128.6 (C-2),
36.4 (C-3), 137.6 (C-1).
3
1
(
2E)-2-Decenal (6). Deprotection was initiated by stirring 4 (1.10 g, containing 0.98 g 4, 5.0 mmol)
with 1 M HCl (50 mL) at room temperature for 5 min (4 dissolves as the hydrochloride salt forms),
and then petroleum ether (b.p. 35 °C to 60 °C, 50 mL) was added and stirring continued. After 4 h, the
phases were separated and the aqueous phase was returned to the reaction vessel. Petroleum ether
(
30 mL) was added and the mixture was stirred at r.t. for an additional 1 h before the phases were
separated. The combined petroleum ether phases were washed with alkaline brine solution (2 × 10 mL),
and the brine phase was back-extracted once with petroleum ether (20 mL). The combined organic
phases were dried, filtered, and removal of solvent afforded 0.75 g of the free aldehyde 6. Purity by
GC was 92%, and yield corrected for purity was 90%. The 2E:2Z isomer ratio was 25 to 1. The MS
and NMR spectral data were consistent with the reference spectral data from previous work [9].
(
2E)-N,N-Dimethyl-N’-(2-methyl-dec-2-enylidene)-hydrazine (5). Compound 5 was prepared in a way
similar to compound 4. The phosphonate anion was prepared from 2 (2.36 g, containing 2.31 g of 2,
.8 mmol) in THF (25 mL) by treatment with LDA (2.0 M, 5.2 mL, 10.4 mmol, slight excess), and
n-octanal (1.92 g, 15 mmol) was subsequently added and the mixture was stirred at r.t. for 20 h. Water
3 mL) was added to quench the reaction and the reaction was worked up as before. Kugelrohr
9
(
distillation (oven temperature 69 °C, 0.1 Torr) afforded 2.04 g of 5. (90% purity by GC, yield corrected
+
for purity 89%). By GC and GC-MS, the 2E/2Z isomer ratio was 8.2 to 1. MS (EI) m/z (%) 210 (M ,
6
8), 195 (24), 180 (3), 166 (82), 125 (100), 111 (13), 96 (29), 82 (37), 59 (18), 44 (31), 42 (15).
1
EI-HRMS C H N calcd. for 210.2096 (obs. 210.2093). H-NMR δ 0.90 (3H, t, J
= 7.0, H-10),
1
3
26
2
9-10
1
.28-1.31 (8H, m, H-6 to H-9), 1.41 (2H, m, H-5), 1.84 (3H, s, CH
3
attached to C-2), 2.20 (2H, m,
1
3
H-4), 2.83 (6H, s, N–CH ), 5.61 (1H, dd, J3-4 = 6.9, =CH, H-3), 7.15 (1H, s, =CH, H-1). C-NMR
3

5
071
Molecules 2011, 16
δ 11.6 (CH
3
attached to C-2), 14.1 (C-10), 22.6 (C-9), 28.1 (C-4), 29.3 (C-6 and C-7), 29.9 (C-5), 31.9
(
C-8), 43.0 (N–CH ), 132.4 (C-2), 134.2 (C-3), 141.2 (C-1).
3
(
2E)-2-Methyl-2-Decenal (7). Deprotection procedure was similar to that used for 6. A solution
containing 5 (1.15 g, containing 1.04 g 3c, 5.0 mmol) and 1 M HCl (60 mL), to which petroleum ether
b.p. 35 °C to 60 °C, 60 mL) was added after 5 min, was stirred at room temperature for 6 h. The
(
phases were separated and the aqueous phase was returned to the reaction vessel. Petroleum ether (40 mL)
was added and the mixture was stirred at r.t. for an additional 1 h before the phases were separated.
Workup of the reaction as for 6 resulted in 0.85 g of the free aldehyde 7 (purity by GC showed 90%,
yield corrected for purity 91%). The 2E:2Z isomer ratio was 24 to 1. The MS and NMR spectral data
were consistent with the reference spectral data from previous work [28].
(
2E,4E)-N’-(Undeca-2,4-dienylidene)-N,N-dimethyl-hydrazine (9). Compound 9 was prepared in a
way similar to compound 4. The phosphonate anion was prepared from 1 (2.22 g, containing 2.06 g of
, 9.3 mmol) in THF (25 mL) by treatment with LDA (2.0 M, 5.2 mL, 10.4 mmol, slight excess), and
2E)-2-nonenal (1.68 g, 12 mmol) was subsequently added and the mixture was stirred at r.t. for 3 h.
1
(
Water (6 mL) was added to quench the reaction and the reaction was worked up as before. Kugelrohr
distillation (oven temperature 70 °C, 0.05 Torr) afforded 1.62 g of 9. (92% purity by GC, yield
corrected for purity 77%). By GC and GC-MS, the 2E/2Z isomer ratio was 16 to 1. MS (EI) m/z (%)
+
2
08 (M , 18), 137 (3), 123 (100), 108 (2), 94 (8), 80 (11), 67 (5), 44 (7), 42 (3). EI-HRMS C13
H
24
N
2
1
calcd. for 208.1939 (obs. 208.1944). H-NMR δ 0.90 (3H, t, J10-11 = 7.2, H-11), 1.29–1.31 (6H, m, H-8
3
to H-10), 1.41 (2H, m, H-7), 2.12 (2H, m, J5-6 = 7.2, H-6), 2.87 (6H, s, N–CH ), 5.75, (1H, dt, J5-6 = 7.2
and J4-5 = 15.0, =CH, H-5), 6.13 (1H, dd, J3-4 = 10.0 and J4-5 = 15.0, =CH, H-4), 6.28 (1H, m, J3-4 = 10.0
and J2-3 = undeterminable in CDCl
CDCl
3
, =CH, H-3), 6.28 (1H, m, J1-2 = 6.0 and J2-3 = undeterminable in
1
3
, =CH, H-2), 7.05 (1H, d, J1-2 = 6.0, =CH, H-1). H-NMR in C
D
6 6
δ 0.98 (3H, t, J10-11 = 7.8, H-11),
),
1
5
6
7
.29–1.31 (6H, m, H-8 to H-10), 1.41 (2H, m, H-7), 2.10 (2H, m, J5-6 = 7.2, H-6), 2.63 (6H, s, N–CH
3
.77, (1H, dt, J5-6 = 7.2 and J4-5 = 15.1, =CH, H-5), 6.22 (1H, dd, J3-4 = 10.4 and J4-5 = 15.1, =CH, H-4),
.41 (1H, dd, J3-4 = 10.4 and J2-3 = 15.1, =CH, H-3), 6.72 (1H, dd, J1-2 = 8.5 and J2-3 = 15.1, =CH, H-2),
1
3
.14 (1H, d, J1-2 = 8.5, =CH, H-1). C-NMR δ 14.0 (C-11), 22.6 (C-10), 28.9 (C-8), 29.2 (C-7), 31.6
), 128.6 (C-2), 130.3 (C-4), 133.2 (C-3), 135.8 (C-5), 136.2 (C-1).
(
C-9), 32.8 (C-6), 42.9 (N–CH
3
(
2E,4E)-2,4-undecadienal (11). Deprotection procedure was similar to that used for 6. A solution
containing 9 (1.16 g, containing 1.07 g 9, 5.1 mmol) and 1 M HCl (50 mL), to which petroleum ether
b.p. 35 °C to 60 °C, 50 mL) was added after 5 min, was stirred at room temperature for 24 h. The
(
phases were separated and the aqueous phase was returned to the reaction vessel. Petroleum ether (40 mL)
was added and the mixture was stirred at r.t. for an additional 1 h before the phases were separated.
Workup of the reaction as for 6 resulted in 0.81 g of the free aldehyde 11 (purity by GC showed 93%,
+
yield corrected for purity 89%). The 2E:2Z isomer ratio was 9.5 to 1. MS (EI) m/z (%) 166 (M , 6),
1
1
37 92), 123 (4), 109 (5), 95 (12), 81 (100), 67 (15), 55 (11), 43 (10), 41 (18). H-NMR δ 0.91 (3H, t,
J10-11 = 6.9, H-11), 1.30-1.32 (6H, m, H-8 to H-10), 1.47 (2H, m, J6-7 = 7.2, H-7), 2.24 (2H, dt, J5-6 = 6.6
and J6-7 = 7.2, H-6), 6.09 (1H, dd, J1-2 = 7.9 and J2-3 = 15.1, =CH, H-2), 5.79 (minor 2Z isomer, 1H, dd,
J
3
1-2 = 7.9 and J2-3 = 11.2, =CH, H-2), 6.31, (1H, m, J5-6 = 6.6 and J4-5 = undeterminable in CDCl ,

5
072
Molecules 2011, 16
=
CH, H-5), 6.31 (1H, d, J3-4 = 9.8 and J4-5 = undeterminable in CDCl
isomer: 1H, dd, J3-4 = 9.8 and J2-3 = 15.1, =CH, H-3), 6.93 (minor 2Z isomer, 1H, dd, J3-4 = 9.8 and
2-3 = 11.2, =CH, H-3), 9.55 (1H, d, J1-2 = 7.9, O=CH, H-1), 10.19 (minor 2Z isomer, 1H, d, J1-2 = 7.9,
O=CH, H-1). The sample also contained about 6% of the 2E,4Z isomer: δ 6.16 (1H, dd, J1-2 = 7.9 and
3
, =CH, H-4), 7.10 (major 2E
J
J
2-3 = 15.4, =CH, H-2), 6.30 (1H, dd, J4-5 = 11.3, =CH, H-4), 7.45 1H, dd, J3-4 = 9.8 and J2-3 = 15.1,
1
=
CH, H-3), 9.63 (1H, d, J1-2 = 7.9, O=CH, H-1). H-NMR in C
6
D
6
δ 0.99 (3H, t, J10-11 = 7.1, H-11),
1
.27–1.32 (8H, m, H-7 to H-10), 1.91 (2H, m, J5-6 = 7.0, H-6), 5.79, (1H, dt, J5-6 = 7.0 and J4-5 = 15.1,
=
CH, H-5), 5.90 (1H, dd, J3-4 = 10.7 and J4-5 = 15.1, =CH, H-4), 6.03 (1H, dd, J1-2 = 7.8 and J2-3 = 15.4,
CH, H-2), 6.55 (1H, dd, J3-4 = 10.7 and J2-3 = 15.4, =CH, H-3), 9.54 (1H, d, J1-2 = 7.8, O=CH, H-1).
C-NMR δ 14.0 (C-11), 22.5 (C-9), 28.5 (C-7), 28.8 (C-8), 31.6 (C-10), 33.2(C-6), 128.6 (C-4), 130.0
C-2), 147.4 (C-5), 152.8 (C-3), 193.9 (C-1).
=
1
3
(
(
2E, 4E)-N’-(2-Methyl-undeca-2,4-dienylidene)-N,N-dimethyl-hydrazine (10). Compound 10 was
prepared in a way similar to compound 4. The phosphonate anion was prepared from 2 (2.36 g,
containing 2.31 g of 2, 9.8 mmol) in THF (25 mL) by treatment with LDA (2.0 M, 5.2 mL, 10.4 mmol,
slight excess), and (2E)-2-nonenal (1.68 g, 12 mmol) was subsequently added and the mixture was
stirred at r.t. for 20 h. Water (3 mL) was added to quench the reaction and the reaction was worked up
as before. Kugelrohr distillation (oven temperature 78 °C, 0.06 Torr) afforded 2.09 g of 10. (85%
purity by GC, yield corrected for purity 82%). By GC and GC-MS, the 2E/2Z isomer ratio was 39 to 1.
+
MS (EI) m/z (%) 222 (M , 14), 137 (100), 108 (7), 94 (13), 44 (4), 43 (5). EI-HRMS C14
H
26
N
2
calcd.
1
for 222.2096 (obs. 222.2102). H-NMR δ 0.91 (3H, t, J10-11 = 7.0, H-11), 1.29-1.31 (6H, m, H-8 to H-10),
3 3
1.43 (2H, m, H-7), 1.96 (CH attached to C-2), 2.16 (2H, m, J5-6 = 7.2, H-6), 2.87 (6H, s, N–CH ),
5
.77, (1H, dt, J5-6 = 7.2 and J4-5 = 15.1, =CH, H-5), 6.12 (1H, d, J3-4 = 11.2, =CH, H-3), 6.44 (1H, dd,
1
3
J
3-4 = 11.2 and J4-5 = 15.1, =CH, H-4), 7.08 (1H, s, =CH, H-1). C-NMR δ 11.8 (CH
4.1 (C-11), 22.6 (C-10), 28.9 (C-8), 29.4 (C-7), 31.7 (C-9), 33.2 (C-6), 43.2 (N–CH
31.2 (C-2), 133.2 (C-3), 135.8 (C-5), 140.0 (C-1).
3
attached to C-2),
1
1
3
), 126.7 (C-4),
(2E, 4E)-2-Methyl-2,4-undecadienal (12). Deprotection procedure was similar to that used for 6. A
solution containing 10 (1.29 g, containing 1.10 g 10, 5.0 mmol) and 1 M HCl (50 mL), to which
petroleum ether (b.p. 35 °C to 60 °C, 50 mL) was added after 5 min, was stirred at room temperature
for 48 h. The phases were separated and the aqueous phase was returned to the reaction vessel.
Petroleum ether (40 mL) was added and the mixture was stirred at rt for an additional 1 h before the
phases were separated. Workup of the reaction as for 6 resulted in 0.91 g of the free aldehyde 12
(
purity by GC showed 88%, yield corrected for purity 89%). The 2E:2Z isomer ratio was 30 to 1. MS
+
(
1
EI) m/z (%) 180 (M , 11), 109 (6), 95 (100), 81 (10), 79 (9), 67 (12), 55 (5), 53 (5), 43 (5), 41 (10).
H-NMR δ 0.91 (3H, t, J10-11 = 6.8, H-11), 1.32–1.34 (6H, m, H-8 to H-10), 1.48 (2H, m, H-7), 1.85
(
CH
3
attached to C-2), 2.26 (2H, dt, J5-6 = 7.2, H-6), 6.26, (1H, dt, J4-5 = 15.0 and J5-6 = 7.2, =CH, H-5),
.54 (1H, dd, J3-4 = 11.2 and J4-5 = 15.0, =CH, H-4), 6.84 (1H, d, J3-4 = 11.2, =CH, H-3), 9.44 (major
E isomer, 1H, s, O=CH, H-1), 10.28 (minor 2Z isomer, 1H, s, O=CH, H-1), The sample also
6
2
contained a trace amount of the 2E,4Z isomer: δ 6.13 (1H, d, J3-4 = 11.2, =CH, H-3), 6.85 (1H, dd,
1
3
J
3-4 = 11.2 and J4-5 = 11.3, =CH, H-4), 9.51 (1H, s, O=CH, H-1). C-NMR δ 14.0 (C-11), 22.5 (C-9),

5
073
Molecules 2011, 16
2
8.5 (C-7), 28.8 (C-8), 31.6 (C-10), 33.2(C-6), 128.6 (C-4), 130.0 (C-2), 147.4 (C-4), 152.8 (C-3),
93.9 (C-1).
1
(
2E)-N,N-Dimethyl-N’-(3-phenyl-allylidene)-hydrazine (14). Compound 14 was prepared in a way
similar to compound 4. The phosphonate anion was prepared from 1 (2.22 g, containing 2.06 g of 1,
.3 mmol) in THF (25 mL) by treatment with LDA (2.0 M, 5.2 mL, 10.4 mmol, slight excess), and
9
benzaldehyde (1.11 g, 10.5 mmol) was subsequently added and the mixture was stirred at r.t. for 5 h.
Water (3 mL) was added to quench the reaction and the reaction was worked up as before. Kugelrohr
distillation (oven temperature 61 °C, 0.1 Torr) afforded 1.62 g of 14. (88% purity by GC, yield
corrected for purity 88%). By GC and GC-MS, the 2E/2Z isomer ratio was 50 to 1. The MS and NMR
spectral data were consistent with the reference spectral data from previous work [13].
(
2E)-Cinnamaldehyde (16). Deprotection procedure was similar to that used for 6. A solution
containing 14 (0.98 g, containing 0.86 g 14, 4.9 mmol) and 1 M HCl (50 mL), to which petroleum
ether (b.p. 35 °C to 60 °C, 50 mL) was added after 5 min, was stirred at room temperature for 18 h. The
phases were separated and the aqueous phase was returned to the reaction vessel. Petroleum ether (50 mL)
was added and the mixture was stirred at r.t. for an additional 1 h before the phases were separated.
Workup of the reaction as for 6 resulted in 0.61 g of the free aldehyde 16 (purity by GC showed 86%,
yield corrected for purity 81%). The 2E:2Z isomer ratio was 170 to 1. The MS and NMR spectral data
were consistent with the reference spectral data from previous work [9].
(
2E)-N,N-Dimethyl-N’-(2-methyl-3-phenyl-allylidene)-hydrazine (15). Compound 15 was prepared in a
way similar to compound 4. The phosphonate anion was prepared from 2 (2.36 g, containing 2.31 g of
, 9.8 mmol) in THF (25 mL) by treatment with LDA (2.0 M, 5.2 mL, 10.4 mmol, slight excess), and
2
benzaldehyde (1.11 g, 10.5 mmol) was subsequently added and the mixture was stirred at r.t. for 20 h.
Water (3 mL) was added to quench the reaction and the reaction was worked up as before. Kugelrohr
distillation (oven temperature 69 °C, 0.1 Torr) afforded 1.82 g of 15. (89% purity by GC, yield
corrected for purity 88%). By GC and GC-MS, the 2E/2Z isomer ratio was 25 to 1. The MS and NMR
spectral data were consistent with the reference spectral data from previous work [13].
(
2E)-Methyl cinnamaldehyde (17). Deprotection procedure was similar to that used for 6. A solution
containing 15 (1.12 g, containing 1.00 g 15, 5.3 mmol) and 1 M HCl (50 mL), to which petroleum
ether (b.p. 35 °C to 60 °C, 50 mL) was added after 5 min, was stirred at r.t. for 48 h. The phases were
separated and the aqueous phase was returned to the reaction vessel. Petroleum ether (40 mL) was
added and the mixture was stirred at r.t. for an additional 1 hr before the phases were separated.
Workup of the reaction as for 6 resulted in 0.78 g of the free aldehyde 17 (purity by GC showed 96%,
yield corrected for purity 96%). The 2E:2Z isomer ratio was 56 to 1. The MS and NMR spectral data
were consistent with the reference spectral data from previous work [9].
N,N-Dimethyl-N'-(3-methyl-non-2-enylidene)-hydrazine (19). A commercial 2.0 M solution of LDA,
(
4.4 mL, 8.8 mmol, slight excess) was added dropwise (reaction exothermic) to a 250 mL round-bottomed
flask containing dry THF (24 mL), 1 (1.78 g, 8 mmol) and a few mg of ethyl(triphenyl)phosphonium
bromide, as an indicator, and the mixture was stirred in an argon atmosphere at r.t. for 1.5 h to ensure

5
074
Molecules 2011, 16
complete formation of the phosphonate ylide. A persistent red color developed in the solution when
sufficient base was added to convert the phosphonate to its anion. Then, 2-octanone (18, 1.44 g,
11.2 mmol) was added dropwise; final color was yellow-orange. The mixture was stirred at r.t. for 22 h.
Consumption of the phosphonate 1 was monitored by GC. Water (6 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 (5 × 25 mL). The combined extracts were washed with saturated aqueous
NaCl solution (15 mL), dried over anhydrous Na SO and filtered. Yellow oil remained after removal
2
4
of solvent. Kugelrohr distillation (oven temperature 60 °C, 0.10 Torr) afforded 1.95 g of 19 (82%
purity by GC, yield corrected for purity >99%). By GC and GC-MS, the 2E/2Z isomer ratio was 2.2 to 1.
+
+
MS (EI) m/z (%) 197, (M 1, 197, 14), 196 (M , 100), 181 (27), 166 (7), 154 (17), 139 (13), 125 (58),
1
1
10 (21), 96, (75), 94 ((48), 82 (36), 67 (18), 59 (38), 44 (41). H-NMR, major 2E-isomer, δ 0.89 (3H,
t, J8-9 = 6.8, H-9), 1.29 (6H, m, H-6, H-7, and H-8) 1.45 (2H, m, H-5), 1.83 (3H, s, H-10 which is the
CH attached to C-3), 2.09 (2H, t, J4-5 = 7.6, H-4), 2.85 (6H, s, N–CH , H-11), 5.99 (1H, d, J1-2 = 9.3, H-2),
.26 (1H, br, H-1). C-NMR δ 14.1 (C-9), 17.0 (C-10), 22.6 (C-3), 27.6 (C-5), 28.9 (C-6), 31.7 (C-7),
3
3
1
3
7
4
1
0.0 (C-4), 43.3 (C-11), 122.5 (C-2), 128.2 (C-1), 141.3 (C-3). H-NMR, minor 2Z-isomer,
δ 0.89 (3H, t, J8-9 = 6.8, H-9), 1.29 (6H, m, H-6, H-7, and H-8) 1.45 (2H, m, H-5), 1.81 (3H, s, H-10
which is the CH attached to C-3), 2.22 (2H, t, J4-5 = 7.5, H-4), 2.84 (6H, s, N-CH , H-11), 5.99 (1H, d,
1-2 = 9.3, H-2), 7.16 (1H, br, H-1). C-NMR δ 14.1 (C-9), 22.6 (C-8), 24.0 (C-10), 28.0 (C-5), 29.1
C-6), 31.7 (C-7), 32.5 (C-4), 43.3 (C-11), 123.5 (C-2), 128.4 (C-1), 135.2 (C-3).
3
3
1
3
J
(
3
-Methyl-non-2-enal (20). Deprotection was initiated by stirring 19 (1.80 g, containing 1.48 g 19,
.5 mmol) with 1 M HCl (100 mL) at room temperature for 5 min (19 dissolves as the hydrochloride
7
salt forms), and then hexane (100 mL) was added and stirring continued. After 3 h, the phases were
separated and the aqueous phase was returned to the reaction vessel. Hexane (100 mL) was added and
the mixture was stirred at r.t. for an additional 1 h before the phases were separated. The combined
hexane phases were washed with alkaline brine solution (2 × 10 mL), and the brine phase was back-
extracted once with hexane (20 mL). The combined organic phases were dried, filtered, and removal of
solvent afforded 1.04 g of the free aldehyde 20. Purity by GC was 95%, and yield corrected for purity
+
was 86%. The 2E:2Z isomer ratio was 2.0 to 1. MS (EI) m/z (%) 154 (M , 5), 139 (17), 125 (11), 111
1
(
5), 97, (100), 84 (61), 69 (22), 55 (23), 41 (36). H-NMR, major 2E-isomer, δ 0.89 (3H, t, J8 = 6.6,
-9
H-9), 1.29 (2H, m, H-7), 1.30 (4H, m, H-6 and H-8), 1.50 (2H, m, H-5), 2.16 (3H, s, H-10 which is the
CH attached to C-3), 2.21 (2H, t, J4-5 = 7.5, H-4), 5.88 (1H, d, J1-2 = 8.2, H-2), 9.99 (1H, d, J1-2 = 8.2,
3
1
3
H-1). C-NMR δ 14.1 (C-9), 17.5 (C-10), 22.5 (C-8), 27.1 (C-5), 28.8 (C-6), 31.5 (C-7), 40.6 (C-4),
1
1
27.3 (C-2), 164.4 (C-3), 191.1 (C-1). H-NMR, minor 2Z-isomer, δ 0.89 (3H, t, J8-9 = 6.6, H-9), 1.29
(
2H, m, H-7), 1.30 (2H, m, H-8), 1.32 (2H, m, H-6), 1.54 (2H, m, H-5), 1.97 (3H, s, H-10 which is the
CH attached to C-3), 2.57 (2H, t, J4-5 = 7.6, H-4), 5.87 (1H, d, J1-2 = 8.2, H-2), 9.96 (1H, d, J1-2 = 8.2,
H-1). C-NMR δ 14.0 (C-9), 22.5 (C-8), 25.0 (C-10), 28.8 (C-5), 29.0 (C-6), 31.5 (C-7), 32.6 (C-4),
28.4 (C-2), 164.9 (C-3), 190.7 (C-1). The MS and NMR spectral data were consistent with the
reference spectral data from previous work [22].
3
1
3
1

5
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Molecules 2011, 16
N,N-Dimethyl-N'-(3-phenyl-but-2-enylidene)-hydrazine (22). Compound 22 was prepared in a way
similar to compound 19. The phosphonate anion was prepared from 1 (1.78 g, 8 mmol) in THF (25 mL) by
treatment with LDA (2.0 M, 4.4 mL, 8.8 mmol, slight excess), and acetophenone (21, 1.35 g, 11.2 mmol)
was subsequently added and the mixture was stirred at r.t. for 22 h. Water (6 mL) was added to quench
the reaction and the reaction was worked up as before. Kugelrohr distillation (oven temperature 69 °C,
0
.1 Torr) afforded 1.64 g of 22. (86 % purity by GC, yield corrected for purity 94%). By GC and
+
+
GC-MS, the 2E/2Z isomer ratio was 2.1 to 1. MS (EI) m/z (%) 189 (M 1, 14), 188 (M , 100), 173
1
(15), 158 (15), 144 (84), 128 (22), 115 (61), 103 (9), 91 (18), 77 (15), 58 (15), 42 (13). H-NMR,
3
major 2E-isomer, δ 2.25 (3H, d, J2-10 = 1.2, H-10 which is the CH attached to C-3), 2.85 (6H, s,
N-CH , H-11), 6.68 (1H, dq, J = 9.3 and J2-10 = 1.1, H-2), 7.12 (1H, d, J = 9.3, H-1), 7.26 (1H, m,
3
1-2
1-2
1
3
H-7), 7.35 (2H, t, J5-6 = 8.0, H-6), 7.51 (2H, d, J5-6 = 8.1, H-5). C-NMR δ 16.0 (C-10), 43.0 (C-11),
1
1
25.0 (C-2), 125.4 (C-5), 127.1 (C-7), 128.3 (C-6), 135.6 (C-1), 139.4 (C-4), 142.6 (C-3). H-NMR,
minor 2Z-isomer, δ 2.18 (3H, d, J2-10 = 1.3, H-10 which is the CH attached to C-3), 2.78 (6H, s,
3
N–CH
H-6), 7.41 (1H, d, J1-2 = 9.3, H-1), 7.51 (2H, d, J5-6 = 8.1, H-5). C-NMR δ 25.6 (C-10), 43.0 (C-11),
25.4 (C-2 and C-5), 127.2 (C-7), 128.3 (C-6), 133.3 (C-1), 139.4 (C-4), 141.4 (C-3). This compound
has been prepared previously [23].
3
, H-11), 6.30 (1H, dq, J1-2 = 9.4 and J2-10 = 1.3, H-2), 7.26 (1H, m, H-7), 7.35 (2H, t, J5-6 = 8.0,
1
3
1
3
-Phenyl-but-2-enal (23). The deprotection procedure was similar to that used for 19. A solution
containing 22 (1.49 g, containing 1.28 g 22, 6.8 mmol) and 1 M HCl (100 mL), to which hexane (100 mL)
was added after 5 min, was stirred at room temperature for 3 h. The phases were separated and the
aqueous phase was returned to the reaction vessel. Hexane (100 mL) was added and the mixture was
stirred at r.t. for an additional 1 h before the phases were separated. Workup of the reaction as for 19
resulted in 0.95 g of the free aldehyde 23 (purity by GC showed 93%, yield corrected for purity 90%).
+
The 2E:2Z isomer ratio was 2.1 to 1. MS (EI) m/z (%) 146 (M , 46), 145 (100), 131 (24), 115 (42), 103
1
(
15), 91 (17), 77 (11), 63 (6), 51 (10). H-NMR, major 2E-isomer, δ 2.59 (3H, s, H-10 which is the
3
CH attached to C-3), 6.42 (1H, d, J1-2 = 7.7, H-2), 7.42 (1H, m, H-7), 7.43 (1H, m, H-6), 7.43 (1H, dd,
1
3
J5-6 = 6.0 and J5-7 = 2.5, H-5), 10.20 (1H, d, J1-2 = 7.9, H-1). C-NMR δ 16.4 (CH attached to C-3),
3
1
1
26.3 (C-5) 127.3 (C-2), 128.8 (C-6), 130.1 (C-7), 140.6 (C-4), 157.6 (C-3), 191.1 (C-1), H-NMR,
minor 2Z-isomer, δ 2.33 (3H, s, H-10 which is the CH
3
attached to C-3), 6.15 (1H, d, J1-2 = 8.1, H-2),
7
.31 (1H, dd, J5-6 = 7.1 and J5-7 = 3.3, H-5), 7.42 (2H, m, H-6 and H-7), 9.49 (1H, d, J1-2 = 8.2, H-1).
1
3
3
C-NMR δ 26.4 (CH attached to C-3), 128.4 (C-5 and C-6), 129.2 (C-2 and C-7), 138.4 (C-4), 162.1
(C-3), 193.4 (C-1). The MS and NMR spectral data were consistent with the reference spectral data
from previous work [24,25].
N'-(2-Cycloheptylidene-ethylidene)-N,N-dimethyl-hydrazine (25). Compound 25 was prepared in a
way similar to compound 19. The phosphonate anion was prepared from 1 (1.78 g, 8 mmol) in THF
(
25 mL) by treatment with LDA (2.0 M, 4.4 mL, 8.8 mmol, slight excess), cycloheptanone (24, 1.68 g,
1.2 mmol) was subsequently added and the mixture was stirred at r.t. for 22 h. Water (6 mL) was
1
added to quench the reaction and the reaction was worked up as before. Kugelrohr distillation (oven
temperature 61 °C, 0.1 Torr) afforded 1.40 g of 25. (88% purity by GC, yield corrected for purity 85%)
+
+
MS (EI) m/z (%) 181 (M 1, 13), 180 (M , 100), 165 (64), 138 (38), 136 (37), 123 (22), 112 (41), 94

5
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Molecules 2011, 16
1
(
41), 80 (50), 67 (26), 59 (26), 44 (30). H-NMR δ 1.52 (2H, m, H-6), 1.54 (2H, m, H-7), 1.62 (2H, m,
H-5), 1.64 (2H,m , H-8), 2.32 (2H, t, J4-5 = 5.8, H-4), 2.46 (2H, td, J8-9 = 6.1 and J2-9 = 1.0, H-9), 2.85
1
3
(6H, s, N-CH
3
, H-10), 5.98 (1H, dp, J1-2 = 6.0 and J2-9 = 1.0, H-2), 7.30 (1H, br, H-1). C-NMR δ 27.1
(C-8), 28.8 (C-5), 29.0 (C-6), 29.7 (C-7), 30.6 (C-9), 43.2 (C-10), 123.1 (C-2), 128.2 (C-1), 146.9 (C-3).
Cycloheptylidene-acetaldehyde (26). The deprotection procedure was similar to that used for 19. A
solution containing 25 (1.27 g, containing 1.11 g 25, 5.1 mmol) and 1 M HCl (100 mL), to which
hexane (100 mL) was added after 5 min, was stirred at room temperature for 3 h. The phases were
separated and the aqueous phase was returned to the reaction vessel. Hexane (100 mL) was added and
the mixture was stirred at r.t. for an additional 1 h before the phases were separated. Workup of the
reaction as for 19 resulted in 0.76 g of the free aldehyde 26 (purity by GC showed 98%, yield
+
corrected for purity 87%). MS (EI) m/z (%) 138 (M , 41), 137 (12), 123 (18), 110 (48), 109 (51), 95,
1
(
100), 81 (66), 67 (66), 55 (35), 41 (46).. H-NMR δ 1.55 (2H, m, H-6), 1.57 (2H, m, H-7), 1.69 (2H,
m, H-5), 1.73 (2H,m , H-8), 2.45 (2H, t, J = 6.0, H-4), 2.84 (2H, t, J = 6.0, H-8), 5.85 (1H, d, J = 8.1,
4-5
8,9
1-2
13
H-2), 9.9 (1H, d, J1-2 = 8.1, H-1). C-NMR δ 27.4 (C-5, C-8), 28.6 (C-6), 29.3 (C-7), 30.5 (C-9), 38.9
C-4), 127.6 (C-2), 170.2 (C-3), 191.1 (C-1), The MS and NMR spectral data were consistent with the
reference spectral data from previous work [20].
(
4
. Conclusions
The new phosphonate reagents 1 and 2 were prepared without difficulty from sufficiently
inexpensive starting materials and were stable enough to be distilled. The starting materials are thus
inexpensive and the homologation reactions are sufficiently robust, so use of this two-step process can
be commercially viable. Subsequent removal of the dimethylhydrazone protective group could be
easily accomplished, even for delicate product aldehydes. Furthermore, the new method eliminates the
use and disposal of some metal-containing reagents (powerful reducing agents such as lithium
aluminum hydride or diisobutylaluminum hydride or oxidants such as pyridinium dichromate or
manganese dioxide). This more concise homologation chemistry could be applied to the practical
synthesis of a variety of natural products, pharmaceuticals, and other compounds. This new protocol should
replace the usual three-step Horner-Wadsworth-Emmons [1] aldehyde or ketone homologation scheme.
Acknowledgements
The authors thank Karl Vermillion and David Weisleder of NCAUR for acquisition of NMR data,
Robert J. Bartelt for helpful discussions, and the University of Illinois, School of Chemical Sciences,
Mass Spectrometry Laboratory for acquisition of HRMS data.
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Sample Availability: Samples Not Available.
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2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
http://creativecommons.org/licenses/by/3.0/).
(