Polyunsaturated alkyl amides from echinacea: Synthesis of diynes, enynes, and dienes

Article abstract of DOI:10.1021/jo200289f

The synthesis of 20 alkyl amides, including 15 naturally occurring polyunsaturated alkyl amides previously identified from Echinacea spp. (1-13 and 62) or from Achilla sp. (55) and five previously unknown geometric isomers (23, 28, 67, 73, and 80), is described. Importantly, these amides include all of the major alkyl amides present in commercially used Echinacea extracts. The syntheses demonstrate methodology used for constructing alkyl amides containing conjugated diyne and isomerically pure enyne and diene moieties and may be adapted easily for the preparation of other alkyl amides present in Echinacea spp. Terminal-conjugated diynes were prepared by a Cadiot-Chodkiewitz coupling/deprotection sequence utilizing a protected bromoacetylene, and methyl-substituted diynes were made via a base-catalyzed rearrangement of terminal-skipped diynes. Conjugated dienes were prepared conveniently and with high stereoselectivity by the reduction of enynes or diynes with Rieke zinc. With the exception of 1-2 and 11-12, the alkyl amides are synthesized here for the first time, and their NMR data are consistent with that of the reported isolated natural compounds.

Full text of DOI:10.1021/jo200289f

ARTICLE
pubs.acs.org/joc
Polyunsaturated Alkyl Amides from Echinacea: Synthesis of Diynes,
Enynes, and Dienes
Nicholas J. Matovic,† Patricia Y. Hayes,† Kerry Penman,‡ Reginald P. Lehmann,‡ and James J. De Voss*,†
†School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia
‡Integria Healthcare, 35 Miles Platting Road, Eight Mile Plans Queensland 4113, Australia
S Supporting Information
b
ABSTRACT: The synthesis of 20 alkyl amides, including 15
naturally occurring polyunsaturated alkyl amides previously
identified from Echinacea spp. (1ꢀ13 and 62) or from Achilla
sp. (55) and five previously unknown geometric isomers (23,
28, 67, 73, and 80), is described. Importantly, these amides
include all of the major alkyl amides present in commercially
used Echinacea extracts. The syntheses demonstrate methodol-
ogy used for constructing alkyl amides containing conjugated diyne and isomerically pure enyne and diene moieties and may be
adapted easily for the preparation of other alkyl amides present in Echinacea spp. Terminal-conjugated diynes were prepared by a
CadiotꢀChodkiewitz coupling/deprotection sequence utilizing a protected bromoacetylene, and methyl-substituted diynes were
made via a base-catalyzed rearrangement of terminal-skipped diynes. Conjugated dienes were prepared conveniently and with high
stereoselectivity by the reduction of enynes or diynes with Rieke zinc. With the exception of 1ꢀ2 and 11ꢀ12, the alkyl amides are
synthesized here for the first time, and their NMR data are consistent with that of the reported isolated natural compounds.
’ INTRODUCTION
amides as well as some 2-methylbutyl alkyl amides (see Figure 1).
We have recently reported that the (8E,10Z)-tetraene 9 is a
previously unreported component of Echinacea extracts.6 Typically,
alkyl amides of E. purpurea contain a dienamide moiety,9 and alkyl
amides from E. angustifolia contain a monenamide moiety,10 but the
tetraene isomers 5 and 8 are the major constituents in both species.
The lipophilic extract from E. pallida has been shown to
contain alkyl amides but in lower quantities and also contains
significant amounts of acetylenic ketones 16 and 17.11 As part of
our investigation of various Echinacea preparations, we required
authentic alkyl amide standards in quantities ranging from 100
mg to several grams. Herein we report efficient and cost-effective
total syntheses of the major alkyl amides that have been used as
authentic standards and for biological assays.6,8,12
The alkyl amides from Echinacea sp. (Figure 1) present two
areas of functionality that need to be addressed: the enamide or
dienamide moiety with differing stereochemistries and the diyne,
diene, or enyne unsaturations distal to the amide functionality.
Robust, modular methods for construction of all of these
structural motifs and the total synthesis of 14 naturally occurring
alkyl amides from Echinacea sp. are presented.
Echinacea sp. is a perennial herb from the Composite family,
which is native to the central plains of the United States. The Native
Americans first documented its use as a phytomedicine, and today,
extracts from the plant’s leaves, roots, or flowers are frequently used
as a nonspecific immunostimulant for the treatment of bacterial and
viral infection,1 attracting significant scientific and economic inter-
est. E. purpurea, E. angustifolia, and E. pallida are the three medi-
cinally preferred Echinacea species which may show potential
biological activity,2 and ethanolic extracts of the roots, leaves, and
flowers are among the most popular form of the commercial
preparations. In 2002, the Echinacea industry was reported to be
worth US$500 million in the United States of America alone.3
Despite its widespread use for attempting to reduce the severity and
duration of the common cold, the efficacy of Echinacea preparations
is controversial, with clinical trials reporting negative results.4 This
might be caused to some degree by the erratic phytochemical profile
of many Echinacea products, which depends on the species, the part
of the plant used, the method of extraction, and even the geographic
location of the plant’s origin.5,6 Thus, there is a need for chemically
pure, authentic reference compounds, both for the standardization
of the natural extracts and for biological evaluation. Ethanol/
aqueous extracts commonly contain mostly polysaccharides and
caffeic acid derivatives, whereas pure ethanolic extracts and extracts
with less polar solvents are rich in alkyl amides. There is a growing
belief that the alkyl amides are indeed the active constituents, owing
to their anti-inflammatory properties7 and their ability to cross the
intestinal barrier,8 which is an important factor for the efficacy of
orally administered remedies. To date, the number of alkyl amides
identified from extracts is about 20, comprising mostly isobutyl
’ RESULTS AND DISCUSSION
Enamides and Dienamides via Wittig Condensation. An
(E)-enamide or dienamide is common to most of the alkyl
amides found in Echinacea spp. (1ꢀ10). The phosphonium salt
Received: February 7, 2011
Published: April 18, 2011
r
2011 American Chemical Society
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Figure 1. Some examples of the major liphophillic compounds isolated from extracts of (a) E. purpurea, (b) E. angustifolia, and (c) E. pallida.
20 has previously been used mainly for the construction the
(E)-enamide alone13 but surprisingly only once in the synthesis
of dienamides.14 A number of methods have been reported for
the preparation of this dienamide moiety, some of which have
been used to prepare the amide 13, but most required a some-
what elaborate reaction scheme.15 We established through the
synthesis of the known 13 that the (E,E)-diene amide moiety
could be robustly constructed from an appropriate aldehyde by a
sequence of four reactions, including a final Wittig reaction that
utilized phosphonium salt 20 to install the amide moiety
(Scheme 1). Initially, the final Wittig condensation was con-
ducted employing the literature method of NaOMe/methanol,14
giving the (2E,4E)- and (2Z,4E)-isobutyl amides 13 and 21 in 42
and 22% yields, respectively. By exploring different solvents for
this reaction, it was found that using KOt-Bu as the base in THF
at 0 °C resulted in the highest yield and greatest E/Z ratio
(approx 10:1) for the newly formed olefin, providing 13 in 66%
yield (as well as 6.6% of 21). We then used this methodology to
synthesize for the first time the trienamide 10, previously isolated
from the roots of E. purpurea.9 10 was synthesized in four steps
from known aldehyde 2216 in an overall yield of 20% (along with
3% of previously unknown minor 2Z-isomer 23).
Scheme 1. Preparation of the (E,E)-Diene Amide Moietya
a (A) Synthesis of amides 13 and 21. Reagents and conditions:
(a) (EtO)2POCH2COOEt, NaH, Et2O, 0 °C, 94%; (b) DIBAL, Et2O,
0 °C, 91%; (c) (ClCO)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N; (di) 20,
KOtBu, THF, 66% (13) and 6.6% (21). (B) Synthesis of amides 10 and
23. Reagents and conditions: (e) (EtO)2POCH2COOEt, NaH, Et2O,
0 °C, 74%; (f) DIBAL, Et2O, 0 °C, 80%; (g) (ClCO)2, DMSO, CH2Cl2,
ꢀ78 °C, then Et3N; (dii) 20, KOtBu, THF, 31% (10) and 3% (23).
1H NMR data obtained for this crystalline trienamide are
consistent with that of the reported (2E,4E,8Z)-N-isobutyldo-
deca-2,4,8-trienamide (10) which had previously been isolated as
a yellow oil.9
Conceivably the (2E,4E)-N-isobutyl dienamide moiety could
also be installed in a single step by adopting a more complex
Wittig precursor, reducing the number of linear synthetic steps
and hopefully increasing the overall yield. Preparation of the
phosphonium salt 26 was achieved simply from crotonic acid, via
bromoacid 2417 and bromoamide 2518 (Scheme 2). Phosphonate
ester 27 was also prepared from bromoamide 25. However,
preliminary results obtained from the reaction of 26 or 27 with
octanal (Scheme 2) were disappointing. When reacted with
octanal, both reagents gave moderate yields of diene amide
product as an approximately 5:1 mixture of the E- and Z-isomers
at the newly formed olefin (13 and 28). Separation of these
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Scheme 2. Synthesis of 13 via Wittig Reagents 26 and 27a
Scheme 3. Preparation of 1 and 2a
a (A) Reagents and conditions: (a) NBS, BzOOH, benzene, reflux, 80%;
(b) (i) SOCl2, (ii) i-BuNH2, ether, 61%; (c) Ph3P, benzene, 25 °C, 52%;
(d) P(OEt)3, 100 °C, 76%. (B) Reagents and conditions: (e) 26, THF,
KOt-Bu, 0 °C; (f) 27, ether, NaH, 0 °C.
a Reagents and conditions: (a) nBuLi, THF, HMPA, 0 °C, 64%; (b)
NaOH, PhMe, reflux, 91%; (c) TsOH, MeOH, 93%; (d) nBuLi, THF,
MeI, 0 °C, 91%; (e) (ClCO)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N; (f)
20, KOtBu, THF, 1: 53%, 2: 51%.
isomers by chromatography was difficult, and thus these reagents
were not pursued for larger scale syntheses. Previously unknown
28 was isolated here as a colorless oil and fully characterized for
the first time.
acetylenes to methyl-substituted alkynes with KOtBu in DMSO
had previously been reported.22 We postulated that the isomer-
ization of terminal-skipped diynes such as 42 might provide a
unique, practical method for preparation of methyl-substituted,
conjugated diynes. Thus, we investigated the synthesis of methyl
diyne 33 via rearrangement of skipped diyne 42.
As the doubly propargylic methylene of a skipped diyne is
considerably more acidic than the corresponding hydrogens of a
simple terminal acetylene, increased reactivity to the reported
isomerization conditions (20 mol % of KOt-Bu, DMSO) was
expected. Potential side reactions included the formation of
allenes or isomerization of the internal triple bond.23 Thus a
model system easily derived from propargyl alcohol 36 was
examined initially (Scheme 4A). After considerable optimization
of the reaction conditions, it was found that by using low con-
centrations of DMSO in THF as solvent at lower temperatures
(ꢀ40 °C, 10% DMSO in THF, 20 mol % of KOt-Bu, 10 min) the
skipped diyne 37 smoothly isomerized to the methyl-substituted
diyne 38 in 90% yield. We therefore applied this methodology to
the synthesis of 1 (Scheme 4B).
Synthesis of the required 42 (Scheme 4B) began with treat-
ment of 1-hexyne with butyllithium followed by reaction with
paraformaldehyde to give 39.24 Isomerization of 39 under
conditions for the modified “zipper” reaction25 (NaH/ethylene-
1,2-diamine, 60 °C) gave hept-6-yn-1-ol (40)22 in excellent
overall yield. Protection of the primary alcohol 40 as a THP ether
gave 41 which, following deprotonation with EtMgBr in THF,
underwent cuprate-catalyzed coupling with propargyl bromide26
to yield 42. Attempts to avoid the use of a protecting group and
prepare the skipped diyne directly from 40 using 2 equiv of
EtMgBr were unsuccessful, resulting in allene impurities that
were inseparable from the desired product. Treatment of the
skipped diyne 42 with KOt-Bu/DMSO under the conditions
reported for alkyne isomerization (20 °C, DMSO, 20 mol % of
KOt-Bu) instantly returned only black polymeric material.
However, when the conditions developed for the model system
above were employed (ꢀ40 °C, 10% DMSO in THF, 20 mol %
of KOt-Bu, 10 min), the skipped diyne 42 smoothly isomerized
Preparation of Diyne Containing Alkyl Amides. With
methodology for installation of the dienamides in hand, we
turned to the construction of the unsaturations at the end of
the long acyl chain in 1ꢀ9 and 11ꢀ12. Reasoning that a diyne
would provide a useful precursor for various dienes, our initial
targets became 1 and 2 for investigating diyne construction.
Initial trials were based on a modification of the protocol
developed by Kraus.19 This had employed the addition of the
anion of a TMS-protected terminal diyne to an aldehyde, with
the formed propargyl alcohol able to undergo tin-mediated
deoxygenation and elaboration into the alkyl amides 1 and 2.
We explored the use of a preformed diyne to generate an anion
that might be alkylated directly, thus avoiding the tin-mediated
deoxygenation step (Scheme 3). Attempts at alkylating the
protected diyne 29, available via a two-step procedure from
commercially available 2-methylbut-3-yn-2-ol,20 with bromide
3021 were only successful when 10% HMPA was used as
cosolvent. Refluxing the product 31 in toluene in the presence
of NaOH effectively liberated the terminal diyne 32. This 32 was
either used directly for the preparation of 2 or methylated
(methyl iodide) giving the methyl diyne 33 required for prepar-
ing alkyl amide 1. After acid-catalyzed cleavage of the THP ethers
32 or 33, the diyne containing alcohols 34 and 35 were subjected
to Swern oxidation and subsequent Wittig condensation with the
anion derived from phosphonium salt 20. We found purification
of the aldehydes after Swern oxidation unnecessary, and higher
overall yields of alkyl amide were obtained simply by treating the
crude oxidation product with the Wittig reagent. While the
synthesis was successful, we found this scheme was not easily
adapted to large-scale work in our laboratory. The use of large
quantities of HMPA, which required rigorous drying prior to use
and poses health and safety concerns, was unattractive. In
addition, the synthesis of the diyne precursor 29 was somewhat
tedious, and it had to be freshly prepared as required.
In searching for more general methodology for the syntheses
of these diynes, we noted that the isomerization of terminal
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Scheme 4a
Scheme 6. Preparation of Alkyl Amide 4a
a Reagents and conditions: (a) (i) (ClCO)2, DMSO, CH2Cl2, ꢀ78 °C,
then Et3N, (ii) (PhO)2POCH2CO2Et, NaH, Et2O, 0 °C, 91%; (b)
DIBAL, Et2O, 0 °C, 92%; (c) 43, nPrNH2, H2O, CuCl, NH2OH HCl,
3
88%; (d) NaOH, PhMe, reflux, 83%; (e) (i) TPAP, NMO, DCM,
3 Å mol sieves, (ii) 20, KOtBu, THF, 56%.
CadiotꢀChodkiewicz conditions.27 The diyne alcohol 34 was
then released from 44 by treatment with NaOH in refluxing
toluene and secured in only two steps and 76% overall yield from
40. The usual Swern/Wittig protocol then delivered 2 in good
yield from 34 and in 42% overall yield from 43 in four steps. We
have found that bromoalkyne 43 is easy and inexpensive to
prepare, gives very good yields of coupled products, and can be
stored at ꢀ20 °C for extended periods.
a (A) Model system based on propargyl alcohol, used for developing a
method for the conversion of skipped diynes to methyl diynes. Reagents and
conditions: (a) (i) EtMgBr, THF, (ii) propargyl bromide, CuCl, 50 °C,
75%; (b) KOt-Bu (20 mol %), THF/DMSO (10:1), ꢀ40°C, 90%.
(B) Improved synthesis of methyl diyne 33 and alkyl amide 1. Reagents
and conditions: (a) BuLi, Et2O, (CHO)n, 0 °C, 89%; (b) (NH2CH2)2,
NaH, 60°C, 88%; (c) TsOH, DHP, CH2Cl2, 86%; (d) (i) EtMgBr,
THF, 50 °C, (ii) propargyl bromide, CuCl, 50 °C, 75%; (e) KOtBu,
THF, DMSO, ꢀ40 °C, 88%; (f) TsOH, MeOH, 93%; (g) (ClCO)2,
DMSO, CH2Cl2, ꢀ78 °C, then Et3N; (h) 20, KOtBu, THF, 59%.
Preparation of the (2E,4Z)-Diene Amide Moiety. Alkyl
amides 3 and 4 occur in both E. purpurea and E. angustifolia
and are analogous to 1 and 2 but contain the (2E,4Z)-dienamide
moiety. By incorporating the methodology established for the
preparation of terminal and methyl-substituted diynes, both
compounds were synthesized from commercial pent-4-yn-1-ol
(Scheme 6). Swern oxidation of this alcohol gave the correspond-
ing aldehyde which underwent, without purification, Wittig
condensation under cis-selective HornerꢀWadsworthꢀEmmons
conditions.28 This generated the R,β-unsaturated ester 45 as
an 89:11(Z/E) mixture, with the pure cis-isomer (Z)-45 available
in 69% overall yield after flash chromatography. DIBAL reduc-
tion of (Z)-45 gave desired alkynol 46. The allylic alcohol 46 was
then subjected to the conditions developed above for the
preparation of terminal conjugated diynes. Thus, CadiotꢀChod-
kiewicz coupling of 46 with bromoalkyne 43 to yield 47 followed
by deprotection (toluene/NaOH/reflux) gave the terminal
diyne 48 in 73% over the two steps. With the immediate pre-
cursor to alkyl amide 4 now in hand, the transformation of the
(Z)-allyl alcohol 48 to the (E,Z)-dienamide 4 by the Swern
oxidation/Wittig reaction protocol was attempted. However,
treatment of the (Z)-allyl alcohol 48 under Swern conditions
resulted in considerable Z/E isomerization of the newly formed
R,β-unsaturated aldehyde. A number of other oxidants were
investigated for the oxidation of the allyl alcohol 48, including
DessꢀMartin periodinane, MnO2, and PCC, but these also
resulted in significant isomerization. Pleasingly, however, the
TPAP oxidation/Wittig sequence suggested by Ley for the
transformation of sensitive aldehydes29 produced negligible Z/E
isomerization and gave 4 in 56% yield from 48 (Scheme 6).
For the synthesis of alkyl amide 3, pent-4-yn-1-ol was first
converted to the corresponding THP ether and thence to
skipped diyne 49 via copper-mediated alkylation with propargyl
bromide. The methyl-substituted diyne 50 was subsequently
smoothly produced via isomerization (89%), adopting the pro-
tocol developed previously (vide supra). The key (Z)-allyl
Scheme 5. Revised Synthesis of Rerminal Diynesa
a Reagents and conditions: (a) KOH, H2O, Br2, 0 °C, 71%; (b) 40,
n-PrNH2, H2O, CuCl, NH2OH HCl, 90%; (c) NaOH, PhMe, reflux,
3
85%; (d) (ClCO)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N; (e) 20,
KOtBu, THF, 53%.
and the methyl-substituted diyne 33 could be isolated in 88%
yield. Methanolic cleavage of the THP protecting group pro-
cured the alcohol 22, which was subjected to the usual Swern
oxidation/Wittig sequence employing phosphonium salt 20.
This completed the synthesis of 1 in eight steps and 22% overall
yield from 1-hexyne. We have found that this methodology,
which avoids the use of HMPA, is easily scaled in our laboratory,
and we have synthesized alkyl amide 1 in multigram quantities.
Alternative methodology was also devised for the synthesis
of conjugated terminal diynes (Scheme 5), such as 34 required
for the synthesis of 2. The protected diyne 44 was made
directly by coupling bromoalkyne 43 with alkyn-ol 40 under
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Scheme 7. Preparation of Alkyl Amide 3a
Scheme 9. Synthesis of Alkyl Amides 11 (and 2)a
a Reagents and conditions: (a) SOCl2, Δ, 2h, 64%;(b) i-BuNH2, THF, ꢀ10
°C, 94%; (c) (OEt)P(OPh)2, 100 °C, 12 h, 52%; (d) (COCl)2, DMSO,
CH2Cl2, ꢀ78 °C, then Et3N; (e) 57, NaHMDS, THF, ꢀ20 °C, 64%.
a Reagents and conditions: (a) DHP, TsOH, DCM, 78%; (b) (i) EtMgBr,
THF, 50°C, (ii) propargyl bromide, CuCl, 50 °C, 77%; (c) KOtBu, THF,
DMSO, ꢀ40 °C, 89%; (d) TsOH, MeOH, 90%; (e) (i) (ClCO)2, DMSO,
CH2Cl2, ꢀ78 °C, then Et3N, (ii) (PhO)2POCH2CO2Et, NaH, Et2O, 0 °C,
78%; (f) DIBAL, Et2O, 0 °C, 92%; (g) (i) TPAP, NMO, DCM, 3 Å mol
sieves, (ii) 20, KOtBu, THF, 60%.
of amide 3 from the methyl diyne precursor 51, avoiding the
isomerization problems experienced with 48 and 53. Thus,
reaction of an equimolar mixture of bromoamide 25 with
ethyldiphenylphosphite (purified by distillation from the crude
mixture prepared from triphenylphosphite) at 100 °C for 8 h
produced the desired phosphonate reagent 54 in 46% yield
(Scheme 7). Following deprotonation of phosphonate 54 with
sodium hydride in THF, and subsequent reaction with the crude
aldehyde obtained from Swern oxidation of 51 (Scheme 8), a
23% yield of amides 3 and 55 was obtained as a mixture in the
ratio 3.6:1, respectively. The Z-selectivity exhibited by the
reagent 54 was acceptable, but the relatively poor yield of
product, coupled with the additional steps required to prepare
54, meant this methodology was not competitive with the
TPAP/Wittig route developed above. Although 55 has not been
isolated from Echinacea sp., it has been identified from Achillea
species31 and from Chrysanthemum frutesce,32 and full character-
ization is reported here for the first time.
Scheme 8. Use of a Phosphonate 54 for the Attempted
Preparation of Alkyl Amide 3a
Synthesis of (2Z)-Enamide and Dienamide Alkyl Amides.
A number of alkyl amides have been reported from Echinacea sp.
which possess a 2Z-configured unsaturation, such as 11 and 12
(see Figure 1).
a Reagents and conditions: (A) (a) (OEt)P(OPh)2, 100 °C, 8 h, 46%;
(B) (b) (i) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N, (ii) 54,
NaH, THF, ꢀ20 °C.
We sought to access these via the synthesis of a Z-selective
Wittig reagent, (diphenylphosphonato)acetamide reagent 57
(Scheme 9), successfully employed by Kraus33 in the synthesis
of 12. Swern oxidation of alcohol 34 was followed by a Wittig
reaction employing (diphenylphosphonato)acetamide reagent
57 (synthesized in two steps from bromoacetic acid via bromoa-
mide 56)34 (Scheme 9). Pleasingly, the desired (2Z)-alkyl amide
11 (isolated from E. angustifolia)10 was obtained predominantly
(39%) along with the corresponding (2E)-alkyl amide 2 (25%) in
an overall yield of 64% from 34.
Alkyl amide 12 occurs in E. purpurea and E. pallida and
contains a (2Z,4E)-dienamide moiety. 12 was synthesized from
commercial pent-4-yn-1-ol (Scheme 10) using similar methodol-
ogy to that employed for the synthesis of 4 (2E,4E-isomer of 12).
Thus, pent-4-yn-1-ol underwent Swern oxidation followed by the
classical trans-selective HornerꢀWadsworthꢀEmmons protocol
to give 58; subsequent DIBAL reduction delivered 5935 (Scheme 10).
The CadiotꢀChodkiewicz coupling of 59 with bromoalkyne 43
followed by deprotection gave the terminal diyne 61 in 57% from
59. A Swern oxidation/Wittig condensation sequence with phos-
phonate 57 afforded alkyl amides 12 (62%) and 62 (21%).
Alkyl amide 12 has previously been synthesized by Kraus29 from
alcohol precursor 53 was available in three operational steps from
50. THP cleavage to 51 was followed by Swern oxidation and cis-
selective HornerꢀWadsworthꢀEmmons methodology to yield
52. The 9:1 (Z:E) mixture of R,β-unsaturated esters 52 was
separated by flash chromatography to yield 73% of the pure cis-
isomer (Z)-52, which underwent DIBAL reduction to 53. TPAP-
mediated oxidation and Wittig condensation with the anion of 20
in a manner identical to that developed for the synthesis of 4 gave
3 in 60% yield (Scheme 7).
Prior to the success with the TPAP oxidation/Wittig proce-
dure for the preparation of the 4Z isomers 3 and 4, we also
investigated the previously unreported diphenylphosphonate
reagent 54 (Scheme 8).
It was expected that substitution of the ethoxy substituents in
the trans-selective diethylphosphonate reagent 27, by the phe-
noxy groups, would provide high Z-selectivity in the newly
formed double bond. This was based upon the same empirical
principles which account for the high Z-selectivity seen in the
(diphenylphosphono)acetate reagent developed by Ando.30
This reagent 54 offered the possibility of a one-step synthesis
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Scheme 10. Synthesis of Alkyl Amide 12a
Scheme 11. Reduction of Diynes to (Z,Z)-Dienesa
a Reagents and conditions: (a) (i) (ClCO)2, DMSO, CH2Cl2, ꢀ78 °C,
then Et3N, (ii) (EtO)2POCH2COOEt, NaH, Et2O, 0 °C, 89%; (b)
i
a Reagents and conditions: (A) (a) Ti(OiPr)4 (4 equiv), PrMgBr (11
equiv), Et2O, ꢀ70 °C to ꢀ30 °C, 50%. (B) Preparation of alkyl amides 5
and 67. Reagents and conditions: (b) (i) (ClCO)2, DMSO, CH2Cl2,
ꢀ78 °C, then Et3N; (ii) (EtO)2POCH2COOEt, NaH, Et2O, 0 °C, 84%;
(c) DIBAL, Et2O, 0 °C, 90%; (d) ZnCl2 (4 equiv), Li (6 equiv),
naphthalene (0.1 equiv), THF, MeOH, 60 °C, 91%; (e) (i) (ClCO)2,
DMSO, CH2Cl2, ꢀ78 °C, then Et3N, (ii) 20, KOtBu, THF, 55%.
DIBAL, Et2O, 0 °C, 85%; (c) 43, nPrNH2, H2O, CuCl, NH2OH HCl,
3
76%; (d) NaOH, PhMe, reflux, 75%; (e) (i) (COCl)2, DMSO, CH2Cl2,
ꢀ78 °C, then Et3N, (ii) 57, NaHDMS, THF, ꢀ20 °C, 83%.
pent-4-yn-1-ol in nine steps in 24% overall yield. The synthesis
reported here is comparable (seven steps in 27% yield) and can
easily be conducted on a multigram scale. Although alkyl amide
62, synthesized here for the first time, has not been reported from
the three medicinally preferred Echinacea sp., it has been
identified from the dried roots of E. atrorubens Nutt.36
THP group was incompatible with the reduction conditions, and
therefore, we opted to perform the reduction at a more advanced
stage of the synthesis to overcome any volatility issues associated
with the reduction product of 51 (Scheme 11B). Thus, the
desired diyne 65 was available in three steps from alcohol 51 via a
standard Swern, stabilized Wittig, DIBAL reduction sequence.
Pleasingly, we found that stereoselective reduction of 65 with 4
equiv of freshly prepared Reike zinc in THF/MeOH (4:1) at
60 °C for 8 h proceeded smoothly and resulted in >91% yield of
diene 66. 1H NMR analysis confirmed the Z,Z geometry of the
product and the isomeric purity was judged to be >95%, based on
integration of the signals corresponding to the methyl terminus.
In our hands, Reike zinc was superior for this reduction com-
pared to other zinc reagents such as Zn(Cu/Ag) couple42 and
zinc dust activated by (CH2Br)2,20 returning higher yields, and
requiring shorter reaction times. Completion of the synthesis of 5
by standard Swern oxidation/Wittig condensation gave the
desired alkyl amide 5 (51%) yield and new amide 67 (4%) in
55% overall yield. This constitutes the first reported synthesis of
tetraene amide 5, which was spectroscopically identical to the
natural material isolated by Bauer.9
Selective Reduction of the Methyl Diyne Unit to a (Z,Z)-
Diene. With a practical route to methyl-substituted diynes such
as 50 developed, we sought to utilize it as a precursor of alkyl
amide 5 via selective reduction to the conjugated (Z,Z)-diene.
There was literature precedent for partial cis-selective hydroge-
nation of conjugated enynes using Lindlar’s catalyst37 or P-2
nickel.38 However, we found that, despite much experimentation,
hydrogenation of the diyne 50 with either of these catalysts did
not cleanly yield the corresponding (Z,Z)-diene, but instead
resulted in a mixture of over and under reduced products with
mixed stereochemistry. Turning our attention to other metal-
mediated reductions, we obtained moderate yields (40ꢀ50%) of
the desired diene 63 albeit with excellent Z,Z-selectivity by
reduction of 50 using a TiII-based procedure developed by
Kitching39 (Scheme 11A). However, in our laboratory, we found
this reaction difficult to scale up due to both the very large
quantities of isopropylmagnesium bromide required and the
careful temperature control needed.
A number of other syntheses of key intermediate 65 were also
explored. It was envisioned that enyne 59 would be a valuable
intermediate for the preparation of not only 65 but also alkyl
amides 7 and 8. We investigated the conversion of the enyne 59
to the conjugated methyl diyne 65 via the KOt-Bu/DMSO
catalyzed isomerization of skipped diyne 69 (Scheme 12). How-
ever, deprotonation of precursor 68 (THP derivative of 59) with
EtMgBr followed by copper-catalyzed addition to propargyl
bromide in the usual manner returned approximately 20% of
unreacted starting material, which could not be separated from
the product. Attempts to circumvent this by the number of
increasing equivalents of EtMgBr or propargyl bromide used
were unsuccessful. Carrying the mixture forward through the
base-catalyzed isomerization protocol prior to separation was
We were intrigued by a report in which Rieke zinc was shown
to reduce some alkynes to the corresponding (Z)-alkenes.40
Chou et al. found that Rieke zinc successfully reduced conjugated
and nonconjugated propargylic alcohols in excellent yields with
as little as 2 equiv of zinc, whereas other zinc reductions require
upwards of 25 equiv. This highly activated zinc is prepared by
electrochemical reduction of anhydrous zinc chloride with
lithium metal in THF, with approximately 10 mol % of naphtha-
lene added as an electron transfer reagent.41 Rieke zinc reduction
of conjugated diynes that were not part of a propargylic alcohol
system had not been reported in the literature. Using an
analogous procedure, we found that the conjugated diyne moiety
was also sufficiently active toward Rieke zinc reduction and
produced the (Z,Z)-diene in excellent yields. Unfortunately, a
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Scheme 12. Attempted Synthesis of 65 from 59a
Scheme 14. Preparation of Alkyl Amides 7 and 8a
a Reagents and conditions: (a) DHP, TsOH, CH2Cl2, 78%; (b) (i)
EtMgBr, THF, 60 °C, (ii) propargyl bromide, CuCl, 50 °C, 65% (þ20%
of unreacted 59).
a Reagents and conditions: (a) trans-1-bromopropene, PdCl2(PhCN)2,
CuI, morpholine, 25 °C, 87%; (b) ZnCl2 (2 equiv), Li (3 equiv),
naphthalene (0.1 equiv), THF, MeOH, 60 °C, 92% or Zn/1,2-dibro-
moethane, MeOH, Δ, 4 days, 88%; (c) (i) (ClCO)2, DMSO, CH2Cl2,
ꢀ78 °C, then Et3N, (ii) 20, KOtBu, THF, 7 = 52%; 8 = 50%.; 73 = 4%.
Scheme 13. Preparation of Alkyl Amide 6a
Scheme 15. Synthesis of Alkyl Amides 9 and 80a
a Reagents and conditions: (a) cis-1-bromopropene, PdCl2(PhCN)2,
CuI, morpholine, 25 °C, 91%; (b) (i) TPAP, NMO, DCM, 3 Å mol
sieves, (ii) 20, KOtBu, THF, 56%.
similarly unsuccessful. Thus, the route developed previously
(Schemes 5 and 11) was employed for the synthesis of 65.
Preparation and Selective Reduction of Enynes. Several of
the alkyl amides found in Echinacea spp. such as 6 and 7 contain a
methyl-substituted enyne moiety. We wished to synthesize these
compounds and to use the (E)-enyne moiety as a precursor for a
conjugated (E,Z)-diene, which is present in the other major alkyl
amide 8 found in Echinacea sp. We proposed that selective Rieke
zinc reduction of the enyne 71 would yield the desired precursor
for alkyl amide 8. The requisite enynes are readily available from
coupling the appropriate alkyne and bromoalkene precursors.
Thus, the key enyne precursor 70 of alkyl amide 6 was synthe-
sized directly in 92% yield by coupling alkyne-ol 46 with (Z)-1-
bromopropene under modified Sonagashira conditions.43 Con-
version to the amide 6 was then accomplished in 56% overall
yield employing the TPAP oxidation/Wittig condensation se-
quence used for the synthesis of amide 4 (Scheme 13).
Synthesis of amide 7 (Scheme 14) was accomplished by a
similar strategy that utilized the (E)-alkenynol precursor 59 (see
Scheme 10). Sonagashira coupling of alkynol 59 with (E)-1-
bromopropene afforded the key enyne 71, which was subjected
to the Swern oxidation/Wittig reaction sequence employing
phosphonium salt 20, completing the synthesis of amide 7
(Scheme 14). The proton NMR data for our synthetic product
7 compare well with that reported by Bauer for the isolated
material.9
a Reagents and conditions: (a) catechol borane, 60 °C, 4 h, 92%; (b)
Pd(PPh3)4, cis-1-bromopropene, NaOEt, benzene, 60 °C, 2 h, 77%; (c)
MeOH, conc HCl, 25 °C, 91%; (d) (i) (COCl)2, DMSO, CH2Cl2, then
Et3N, ꢀ78 °C, (ii) (EtO)2P(O)CH2CO2Et, NaH, ether, 0 °C, 71%; (e)
DIBAL, ether, 0 °C, 96%; (f) (i) (COCl)2, DMSO, CH2Cl2, then Et3N,
ꢀ78 °C, (ii) 20, KOt-Bu, THF, 0 °C, 63%.
sequence, we secured 8 in 50% isolated yield (along with 4% of
the previously unknown 2Z-isomer 73). This constitutes the first
synthesis of 8 which has been previously isolated as a solid from
E. purpurea,9 E. angustifolia,10 and Asarum forbesii Maxim.44
Synthesis of Alkyl Amides 9 and 80. We recently identified 9
in E. purpurea and E. angustifolia extracts by stereospecific
synthesis of 9 and GCMS co-injection studies.6 Two different
routes were developed to 9, both of which started from pent-4-
yn-1-ol. The less specific proceeded via a 1:1 mixture of
(2E,6E,8Z)-deca-2,6,8-trien-1-ol 79 and its (2E,6E,8E)-isomer
to yield, after separation, 9 in 11% yield.6 To supply larger
quantities of 9, a stereospecific synthesis was developed
(Scheme 15) with the key step being a Suzuki coupling45 of
the boronate ester 75 with cis-1-bromopropene to provide
alcohol intermediate 77. This route also yielded the previously
unreported alkyl amide 80 in 11% yield.
Treatment of enyne 71 with an excess of Zn dust (30 equiv) in
methanol in the presence of 1,2-dibromoethane afforded 72 in
88% yield. In this case, we also found that 2 equiv of Rieke zinc
smoothly reduced the triple bond, securing the required key (Z,
1
E)-diene precursor 72 in 92% yield. H NMR analysis of 72
indicated that isomeric impurities amounted to less than 1%
based on integration of the signals corresponding to the methyl
terminus. When 72 was subjected to the standard Swern/Wittig
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’ CONCLUSION
General Procedure D: Terminal-Skipped Diyne Prepara-
tion. In a 500 mL round-bottom flask equipped with reflux condenser
and pressure equalizing dropping funnel, a solution of ethyl magnesium
bromide was prepared in the usual manner from ethyl bromide (13.1 g,
120 mmol), Mg (3.14 g, 130 mmol), and a small crystal of iodine in a
total of 240 mL of THF. The mixture was warmed to 50 °C, and the
alkyne (100 mmol) was added dropwise (ethane evolution). After
complete addition, the reaction was stirred for a further 60 min at this
temperature before cooling to room temperature. Next, CuCl (320 mg,
3.2 mmol) was added, and the mixture was stirred at room temperature
for a further 15 min. Then the mixture was warmed to 50 °C again, and
propargyl bromide (11.9 g, 100 mmol) was added dropwise. After
complete addition, the reaction was stirred for a further 45 min, by which
time a heavy bright yellow precipitate had developed. The mixture was
then cooled using an external water/ice bath and quenched by the slow
addition of saturated NH4Cl solution (200 mL). The organic phase was
collected, and the aqueous layer was extracted with hexanes (2 ꢁ
100 mL). The combined organic layers were then washed with brine
(150 mL), dried (MgSO4), and stripped of solvent. The pure skipped
diynes were obtained by flash chromatographic purification.
General Procedure E: Isomerization of Skipped Diynes.
Skipped diyne (54.2 mmol) was dissolved in THF (200 mL) to which
DMSO (20 mL) had been added, and the solution was cooled to
ꢀ40 °C. With good stirring, KOt-Bu (1.21 g, 10.8 mmol) was then
added portionwise, and the resulting dark brown mixture was stirred for
20 min at this temperature before dilution with hexanes (200 mL) and
addition of water (100 mL). The organic layer was separated, washed
with brine (2 ꢁ 150 mL), dried (MgSO4), and stripped of solvent. Flash
chromatographic purification of the residue gave the pure methyl-
substituted diyne.
General Procedure F: CadiotꢀChodkiewicz Coupling.
CuCl (238 mg, 2.4 mmol) was added to 75 mL of a stirred solution
consisting of 30% w/v n-PrNH2 in H2O at 0 °C. After a few min of
stirring, hydroxylamine hydrochloride (100 mg, 1.4 mmol) was added
(this discharged the blue color). Terminal alkyne (55 mmol) was then
added neat, and the mixture was stirred at 0 °C for 10 min by which time
the formation of a bright yellow precipitate (probably the alkynyl
cuprate) was observed. 43 (10.6 g, 65 mmol) dissolved in THF
(12 mL) was then added dropwise, and the mixture was stirred at
0 °C for 1 h before addition of saturated NH4Cl (125 mL). The mixture
was extracted into ether (3 ꢁ 100 mL), and the combined ether layers
were then washed with brine (2 ꢁ 100 mL), dried (MgSO4), and
evaporated to give an oil which was purified by column chromatography
giving the pure coupling product.
In summary, 14 alkyl amides which occur naturally in Echina-
cea sp. and one from Achilla sp. have been synthesized by direct
and flexible routes as well as five previously unreported geometric
isomers of naturally occurring alkyl amides. The procedures offer
methodology for convenient and cost-effective multigram pro-
duction of these and analogous alkyl amides in research labora-
tories. Alkyl amides containing methyl diyne moieties were
prepared utilizing new methodology which involves the isomer-
ization of terminal-skipped diynes. Alkyl amides containing
terminal diyne moieties were prepared via CadiotꢀChodkiewicz
coupling of an appropriate alkyn-1-ol with a common protected
bromoacetylene precursor 43, followed by deprotection of the
coupled bisacetylene product. The two major alkyl amides
(containing conjugated methyl (Z,Z)- and (Z,E)-diene moieties)
5 and 8 have been successfully synthesized by selective cis-
reduction of the corresponding conjugated diyne or enyne
respectively utilizing Rieke zinc. The requisite enynes were
prepared by Sonagashira coupling of appropriate alkyn-1-ols
with either cis- or trans-1-bromopropene. Considering the ready
availability of alkyn-1-ols, these procedures are expected to be
valuable to researchers who require pure synthetic standards of
these and analogous alkyl amides from Echinacea sp.
’ EXPERIMENTAL SECTION
General Methods. NMR spectra were recorded on 300, 400, or
500 MHz spectrometers. 1H and 13C signals were recorded in parts per
million (ppm) on the δ scale, with the residual solvent peaks (CDCl3:
δH 7.24 and δC 77.0; C6D6: δH 7.15 and δC 128.0) as internal
references. Flash chromatography separations were performed with
silica gel. Melting points were performed on a melting-point apparatus
(Dr. Tottoli) and are uncorrected.
General Procedure A: THP protection. Alcohol (94 mmol) and
3,4-dihydro-2H-pyran (8.4 g, 100 mmol) were dissolved in dichloro-
methane (300 mL), and the mixture was cooled to 0ꢀ5 °C using
an external ice bath. p-Toluene sulfonic acid monohydrate (180 mg,
0.94 mmol) was then added, and the reaction was stirred for 30 min at
0 °C. Then, 1 M NaOH solution (50 mL) was added, and the mixture
was vigorously stirred for an additional 30 min. After separation of the
two layers, the dichloromethane solution was dried (MgSO4) and
stripped of solvent. The crude material was then purified by distillation
of flash chromatography.
General Procedure G: Diyne Deprotection. The protected
diyne (7.9 mmol) was dissolved in toluene (35 mL) to which freshly
ground sodium hydroxide (32 mmol) had been added. The mixture was
then refluxed with stirring for 25 min by which time TLC indicated the
reaction was complete. After cooling, the mixture was washed with water
(100 mL), then brine (100 mL), then stripped of toluene and purified
using flash chromatography yielding the corresponding deprotected
diyne.
General Procedure H: Sonagashira Coupling. PdCl2-
(PhCN)2 (76 mg, 0.2 mmol) and CuI (76 mg, 0.4 mmol) were
suspended in freshly distilled morpholine (10 mL) at 0 °C with stirring.
Then cis-1-bromopropene [or trans-1-bromopropene] (0.58 g, 4.8
mmol) was added in one portion followed by the slow addition of
alkyne (4.1 mmol) dissolved in THF (2 mL). After complete addition of
the alkyne, the ice bath was removed and the resulting pale green
solution was stirred at room temperature for 3 h over which time the
color had changed to a pale brown and a light precipitate had formed.
The mixture was quenched with saturated ammonium chloride solution
(40 mL) and extracted into ether (3 ꢁ 25 mL). The organic layers were
washed with 0.5 M HCl (50 mL) then brine (50 mL) and dried
General Procedure B: THP deprotection. THP-protected alcohol
(0.63 mmol) was dissolved in 5 mL of methanol to which p-toluene
sulfonic acid monohydrate (24 mg, 0.12 mmol) was added. The mixture
was stirred at room temperature for 2 h, then 5 mL of 1 M NaOH
solution was added followed by water (20 mL). The mixture was
extracted into ether (3 ꢁ 10 mL), and the combined organic layers
were washed with brine (10 mL) and dried (MgSO4). The crude oil
obtained after evaporation of the ether was sufficiently pure to carry on
to the next step. A small quantity was purified for analysis using column
chromatography (silica gel, 20% ethyl acetate in hexane).
General Procedure C: DIBAL Reduction. DIBAL (9.6 g, 66
mmol) was dissolved in ether (150 mL) and the solution cooled to 0 °C.
Next, the ester (30 mmol) dissolved in ether (15 mL) was added
dropwise. After stirring at 0 °C for 1 h, the mixture was carefully
quenched by the addition of water (20 mL), followed by 1 M HCl
(100 mL). The mixture was stirred for a further 90 min, then the organic
layer was separated and the aqueous phase extracted with ether
(100 mL). The combined ether layers were washed with brine, dried
(MgSO4), and evaporated, and the crude material was purified by flash
chromatography.
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(MgSO4). After removal of the solvent, the residue was purified by
column chromatography (20% EtOAc in hexanes, silica gel 60).
General Procedure I: Reike Zinc Reduction. Naphthalene
(1.92 g, 15 mmol) was dissolved in THF (30 mL), and lithium (3.1 g,
450 mmol) was cut with a pair of scissors into thin slithers (approx 1 mm
wide ꢁ 5 mm long) which fell directly into the THF solution. After
stirring for 30 min at 25 °C, the deep green color indicative of lithium
naphthalide was observed. Then, anhydrous zinc chloride (20.5 g, 150
mmol) dissolved in THF (150 mL) was added dropwise over 30 min,
and after complete addition, the gray/black mixture was stirred for a
further hour at 25 °C. Next, the mixture was heated to 50 °C, and the
alkyne (37 mmol) dissolved in methanol (40 mL) was added dropwise
with good stirring. Stirring was continued at 50 °C for 12 h, then the
mixture was cooled to room temperature and water (500 mL) was
added. The mixture was extracted into ether (3 ꢁ 100 mL), and the
combined organic layers were washed with brine (150 mL), dried
(MgSO4), and stripped of solvent. Flash chromatographic purification
gave the corresponding alkene.
General Procedure J: Consecutive Swern Oxidation/cis-
Selective HornerꢀWadsworthꢀEmmons Protocol. Oxalyl
chloride (3.81 g, 30 mmol) was added to CH2Cl2 (100 mL), and the
solution was cooled to ꢀ78 °C. Next, DMSO (3.9 g, 50 mmol) was
added dropwise, and after complete addition, the solution was stirred for
a further 2 min before the dropwise addition of the alcohol (23 mmol).
Stirring was continued at ꢀ78 °C for 30 min, and then the reaction was
warmed to ꢀ10 °C for 5 min. The mixture was recooled to ꢀ78 °C, and
Et3N (14.1 g, 140 mmol) was added. The reaction was allowed to return
to room temperature and washed with water (100 mL), then 1 M HCl
(100 mL) and then once more with water (100 mL). The organic layer
was dried (MgSO4) and the dichloromethane removed to give the crude
aldehyde which was diluted with THF (10 mL) and used in the next step
without delay. (PhO)2POCH2CO2Et (8 g, 25 mmol)46 was added
dropwise to a suspension of NaH (1.0 g, 25 mmol, 60% dispersion in
mineral oil) in THF (100 mL) at 0 °C (H2 evolution). After stirring a
further 20 min, the mixture was cooled to ꢀ78 °C and the crude
aldehyde solution prepared above was added to the reaction dropwise.
After complete addition, the reaction was stirred for 30 min, then the dry
ice bath was removed and water (200 mL) was slowly added. The
mixture was extracted with petroleum spirit, bp 40ꢀ60 °C (2 ꢁ
150 mL), and the combined organic layers were washed with water
(4 ꢁ 150 mL) then with brine (150 mL), dried (MgSO4), and
evaporated to give the crude product which was purified by flash
chromatography.
washed with water (2 ꢁ 150 mL) then with brine (150 mL), dried
(MgSO4), and stripped of solvent and the crude material purified by
distillation or by flash chromatography.
General Procedure L: Consecutive Swern Oxidation/Wit-
tig Protocol Employing Phosphonium Salt 20. Oxalyl chloride
(3.8 g, 30 mmol) was added to CH2Cl2 (200 mL), and the solution was
cooled to ꢀ78 °C. Next, DMSO (5.49 g, 70 mmol) was added dropwise,
and after complete addition, the solution was stirred for a further 2 min
before the dropwise addition of alcohol (19.7 mmol). Stirring was
continued at ꢀ78 °C for 30 min, and then the reaction was warmed
to ꢀ10 °C for 5 min. The mixture was recooled to ꢀ78 °C, and Et3N
(15.1 g, 150 mmol) was added. The reaction was allowed to return to
room temperature and washed with water (100 mL) then 1 M HCl
(100 mL) and then once more with water (100 mL). The organic layer
was dried (MgSO4) and the dichloromethane removed to give the crude
aldehyde which was diluted with tetrahydrofuran (15 mL) and used in
the next step without delay. Meanwhile, KOt-Bu (2.24 g, 20 mmol) was
added in one portion to a stirred suspension of 20 (9.0 g, 22 mmol) in
tetrahydrofuran (100 mL) at room temperature. Stirring was continued
for a further 30 min, then the mixture was cooled to 0 °C and the crude
aldehyde solution prepared from the previous step was added in one
portion. Stirring was continued at 0 °C for 2 h, then saturated NH4Cl
solution (100 mL) was added and the organic phase was separated. The
aqueous phase was extracted into ether (2 ꢁ 100 mL), and the combined
organic phases were washed with brine (100 mL), dried (MgSO4), and
stripped of solvent. Flash chromatographic purification (20% EtOAc in
hexanes, silica) yielded the corresponding alkyl amide.
General Procedure M: Consecutive TPAP Oxidation/
Wittig Protocol Employing Phosphonium Salt 20. The 3 Å
powdered molecular sieves (300 mg) were added to a solution of cis-
allylic alcohol (0.72 mmol) and NMO (93 mg, 0.8 mmol) in CH2Cl2
(3 mL). The mixture was stirred for 15 min at room temperature, and
then tetrapropylammonium perruthenate (12 mg, 0.036 mmol) was
added. After stirring for 15 min, the reaction was added via syringe to a
stirred mixture of the ylide generated from 20 (411 mg, 1.0 mmol) and
KOtBu (112 mg, 1.0 mmol) in THF (5 mL) (see general procedure L for
details). After stirring for 30 min at room temperature, saturated NH4Cl
solution (6 mL) was added followed by ether (6 mL). The organic layer
was separated and the aqueous phase extracted once more with ether
(6 mL), then the combined organic layers were washed with brine (2 ꢁ
10 mL), dried (MgSO4), and stripped of solvent. Flash chromatographic
purification (20% EtOAc in hexanes, silica gel 60) yielded the corre-
sponding (4Z)-alkyl amide.
General Procedure K: Consecutive Swern Oxidation/
trans-Selective HornerꢀWadsworthꢀEmmons Protocol. Ox-
alyl chloride (11.4 g, 90 mmol) was added to CH2Cl2 (300 mL), and the
solution was cooled to ꢀ78 °C. Next, DMSO (12.5 g, 160 mmol) was
added dropwise, and after complete addition, the solution was stirred for
a further 2 min before the dropwise addition of alcohol (70 mmol).
Stirring was continued at ꢀ78 °C for 30 min, and then the reaction was
warmed to ꢀ10 °C for 5 min. The mixture was recooled to ꢀ78 °C, and
Et3N (34.8 g, 345 mmol) was added. The reaction was allowed to return
to room temperature and washed with water (150 mL), then 1 M HCl
(100 mL) and then once more with water (100 mL). The organic layer
was dried (MgSO4) and the dichloromethane removed to give the crude
aldehyde which was diluted with ether (25 mL) and used in the next step
without delay. Ethyl 2-(diethoxyphosphoryl)acetate (15.6 g, 69.6 mmol)
was added dropwise to a suspension of NaH (3.0 g, 75 mmol, 60%
dispersion in mineral oil) in ether (280 mL) at 0 °C (H2 evolution).
After stirring a further 15 min, the crude aldehyde solution prepared
above was added slowly to the reaction mixture. After complete addition,
the reaction was stirred for 10 min, then the ice bath was removed and
water (200 mL) was slowly added. The mixture was extracted with
petroleum spirit (200 mL), and the combined organic layers were
(2E,4E,8Z)-N-Isobutyldodeca-2,4,8-trienamide (10) and
(2Z,4E,8Z)-N-Isobutyldodeca-2,4,8-trienamide (23). The title
compounds were obtained in 31.4% (10, white solid) and 3% (23,
colorless oil) yields from (Z)-oct-4-enal (22)17 according to the general
procedure L. 10: Mp = 56ꢀ58 °C; 1H NMR (400 MHz, CDCl3) δ 0.87
(t, J = 7.4 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H), 1.29ꢀ1.40 (m, 2H),
1.72ꢀ1.80 (m, 2H), 1.92ꢀ2.00 (m, 2H), 2.12ꢀ2.18 (m, 3H), 3.13 (dd,
J = 6.7, 6.7 Hz, 2H), 5.28ꢀ5.40 (m, 2H), 5.55 (brs, 1H), 5.74 (d, J =
15.0 Hz, 1H), 6.00ꢀ6.15 (m, 2H), 7.15 (dd, J = 10.4, 15.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.8, 20.1, 22.7, 26.5, 28.6, 29.3, 33.0, 46.9,
122.0, 128.4, 128.5, 130.7, 141.1, 142.2, 166.3; GC-MS EI m/z (%) 249
(4.4) [Mþ], 234 (2), 206 (3), 177 (21), 166 (18), 152 (16), 110 (16),
66 (61), 57 (74), 55 (100), 41 (99); HR-MS m/z calcd [M þ Na]þ
for C16H27NONa 272.1990, found 272.1985. 23: 1H NMR (400 MHz,
CDCl3) δ 0.86 (t, J = 7.6 Hz, 3H), 0.89 (d, J = 6.5 Hz, 6H), 1.28ꢀ
1.37 (m, 2H), 1.72ꢀ1.82 (m, 2H), 1.92ꢀ2.00 (m, 2H), 2.10ꢀ2.22
(m, 3H), 3.10 (dd, J = 6.2, 6.8 Hz, 2H), 5.29ꢀ5.38 (m, 2H), 5.46 (d, J =
11.0 Hz, 1H), 5.63 (brs, 1H), 5.92 (dt, J = 6.5, 13.3 Hz, 1H), 6.34 (t, J =
11.3 Hz, 1H), 7.43 (ddq, J = 1.4, 11.3, 15.1 Hz, 1H);13C NMR (100 MHz,
CDCl3) δ 13.7, 20.1, 22.7, 26.6, 28.5, 29.2, 33.0, 46.7, 118.7, 127.2, 128.6,
130.5, 141.3, 142.8, 166.5; GC-MS EI m/z (%) 249 (Mþ 0.4), 220 (6),
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206 (10), 166 (15), 152 (54), 110 (14), 66 (50), 57 (54), 55 (70), 41
(100); HR-MS m/z calcd [M þ Na]þ for C16H27NONa 272.1990, found
272.1985.
with water (2 ꢁ 100 mL) then with brine (100 mL), dried (MgSO4),
and evaporated. Purification by flash chromatography (silica gel 60/5%
EtOAc in hexane) yielded 9.5 g (96%) of the title compound as a
colorless oil. Spectroscopic data were consistent with a literature
report:50 1HNMR (400 MHz, CDCl3) δ 0.86 (t, J = 7.1 Hz, 3H),
1.20ꢀ1.36 (m, 8H), 1.27 (t, J = 6.8 Hz), 3H, 1.39ꢀ1.47 (m, 2H), 2.16
(dtd, J = 7.1, 7.1, 1.5 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 5.78 (dt, J = 15.6,
1.6 Hz, 1H), 6.94 (dt, J = 15.6, 6.9 Hz, 1H); 13CNMR (100 MHz,
CDCl3) δ 14.0, 14.2, 22.6, 28.0, 29.0, 29.1, 31.7, 32.1, 60.0, 121.5, 149.4,
166.7; GC-MS EI m/z (%) 198 (Mþ, 0.5), 169 (1), 153 (19), 152 (11),
141 (2), 127 (7), 110 (15), 101 (29), 84 (24), 69 (32), 55 (92), 43
(100).
(E)-4-Bromobut-2-enoic acid (24). Crotonic acid (10 g, 116
mmol) was dissolved in benzene (150 mL), and then N-bromosuccini-
mide (31.4 g, 120 mmol) was added followed by benzoyl peroxide (0.2 g,
1.4 mmol). The mixture was refluxed with stirring for 4 h, and after that,
it was allowed to cool to room temperature, which resulted in precipita-
tion of large succinimide crystals. The crystals were filtered and the
filtrate was stripped of solvent. The crude product was recrystallized
from the minimum amount of hexane yielding 15.4 g (80%) of the title
compound as a white solid: mp = 69ꢀ70 °C; lit47 mp = 72ꢀ73 °C.
Spectroscopic data were consistent with a literature report:47 1H NMR
(300 MHz, CDCl3) δ 4.02 (dd, J = 1.2, 7.2 Hz, 2H), 6.04 (dt, J = 1.2, 15.0
Hz, 1H), 7.11 (dt, J = 7.2, 15.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 28.7, 123.8, 144.4, 171.1.
(E)-4-Bromo-N-isobutylbut-2-enamide (25). 24 (15.0 g, 90.5
mmol) and thionyl chloride (16.0 g, 135 mmol) were mixed together
and stirred at 25 °C overnight. The reaction was then setup for vacuum
distillation, and after removal of excess thionyl chloride, the acid chloride
was collected at 68ꢀ69 °C (3 mmHg), yielding 12.0 g of a colorless oil:
1H NMR (300 MHz, CDCl3) δ 4.05 (dd, J = 1.2, 7.2 Hz, 2H), 6.27 (dt,
J = 1.2, 15.0 Hz, 1H), 7.20 (dt, J = 7.2, 15.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 27.6, 128.9, 147.8, 165.2. The acid chloride prepared above
was then added to a solution of isobutylamine (12.5 g, 170 mmol) in
ether (300 mL). After complete addition, water (100 mL) was added and
the mixture was stirred vigorously for 2 min. The ether layer was washed
with brine (100 mL), dried (MgSO4), and evaporated to yield 12.1 g
(61%) of the title compound as a white solid: mp = 90ꢀ91 °C; lit48 mp =
94ꢀ95 °C; 1H NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.8 Hz, 6H), 1.80
(sept, J = 6.8 Hz, 1H), 3.15 (d, J = 6.4, 6.4 Hz, 2H), 4.0 (dd, J = 1.2, 7.2
Hz, 2H), 5.92 (brs, 1H), 6.03 (d, J = 14.8 Hz, 1H), 6.90 (dt, J = 7.2, 14.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.1, 28.5, 29.8, 47.0, 127.1,
137.7, 164.7.
(2E,4E)-N-Isobutyldodeca-2,4-dienamide (13) and (2E,4Z)-
N-Isobutyldodeca-2,4-dienamide (28). The title compounds
were obtained (after purification by column chromatography using
20% EtOAc in hexanes, silica gel 60) in 40% (13, white solid) and 8%
(28, colorless oil) yields from octanal according to a procedure adapted
from general procedure K [using (E)-diethyl 4-(isobutylamino)-4-
oxobut-2-enylphosphonate (27) instead of ethyl 2-(diethoxyphos-
phoryl)acetate (20)]. 13: Mp = 74ꢀ75 °C; lit15a mp = 76ꢀ77 °C.
Spectroscopic data were consistent with a literature report:8 1H NMR
(500 MHz, CDCl3) δ 0.85 (t, J = 7.0 Hz, 3H), 0.90 (d, J = 6.9 Hz, 6H),
1.22ꢀ1.30 (m, 8H), 1.34ꢀ1.42 (m, 2H), 1.77 (sept, J = 6.9 Hz, 1H), 2.11
(brq, J = 6.7 Hz, 2H), 3.13 (dd, J = 6.5, 6.5 Hz, 2H), 5.59 (brs, 1H), 5.74
(d, J = 15.1 Hz, 1H), 5.99ꢀ6.13 (m, 2H), 7.16 (dd, J = 9.9, 15.1 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 14.0, 20.1, 22.6, 28.6, 28.8, 29.0, 29.1,
31.7, 32.9, 46.9, 121.7, 128.2, 141.2, 143.1, 166.4; GC-MS EI m/z (%)
251 (17) [Mþ], 236 (10), 222 (1), 208 (4), 196 (3), 180 (16), 179 (65),
166 (9), 152 (39), 138 (7), 126 (9), 113 (21), 96 (100), 81 (93), 68
(42), 55 (86), 41 (96); HR-MS m/z calcd Mþ for C16H29NONa
1
274.2147, found 274.2149. 28: H NMR (500 MHz, CDCl3) δ 0.85
(t, J = 6.9 Hz, 3H), 0.90 (d, J = 66 Hz, 6H), 1.20ꢀ1.31 (m, 8H),
1.33ꢀ1.40 (m, 2H), 1.78 (sept, J = 6.7 Hz, 1H), 2.26 (dq, J = 1.5, 6.7 Hz,
2H), 3.15 (dd, J = 6.2, 6.9 Hz, 2H), 5.54 (brs, 1H), 5.73ꢀ5.78 (m, 1H),
5.80 (d, J = 14.9 Hz, 1H), 6.05 (brt, J = 11.3 Hz, 1H). 7.53 (ddd, J =
1.1, 11.6, 15.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.1, 20.1, 22.6,
28.2, 28.6, 29.1, 29.2, 29.5, 31.8, 46.9, 123.7, 126.3, 136.0, 140.3, 166.3;
GC-MS EI m/z (%) 251 (26) [Mþ], 236 (11), 208 (5), 179 (78), 152
(20), 113 (24), 81 (100), 55 (50), 41 (52); HR-MS m/z calcd Mþ for
C16H29NONa 274.2147, found 274.2141.
(E)-(4-(Isobutylamino)-4-oxobut-2-enyl)triphenylphos-
phonium bromide (26). 25 (1.8 g, 8.2 mmol) and Ph3P (2.62 g, 10.0
mmol) were dissolved in toluene (15 mL) and heated to 80 °C for 2 h
with stirring. After cooling to room temperature, large crystals of the
product had formed, which were collected by vacuum filtration giving
2.7 g (88%) of 26 that was used without further purification: mp =
198ꢀ200 °C; lit49 = 202ꢀ204 °C; 1H NMR (400 MHz, CDCl3) δ 0.91
(d, J = 6.4 Hz, 6H), 1.92 (sept, J = 6.4 Hz, 1H), 3.12 (dd, J = 6.8 Hz, 2H),
4.92 (dd, J = 7.5, 15.8 Hz, 2H), 6.48 (dd, J = 15.8, 4.8 Hz, 1H), 6.85 (m,
1H), 7.8ꢀ7.95 (m, 15H).
(2E,4E)-N-Isobutyldodeca-2,4-dienamide (13) and (2Z,4E)-
N-Isobutyldodeca-2,4-dienamide (21). The title compounds
were obtained in 66% (13, white solid) and 6.68% (21, colorless oil)
yields from (E)-dec-2-enal (19)51 according to the general procedure L.
21: 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 6.8 Hz, 3H), 0.91 (d, J =
6.4 Hz, 6H), 1.18ꢀ1.43 (m, 10H), 1.78 (sept, J = 6.4 Hz, 2H), 3.11 (dd,
6.8, 6.8 Hz, 2H), 5.46 (d, J = 11.2 Hz, 1H), 5.65 (m, 1H), 5.93 (dt, J =
15.2, 6.8 Hz, 1H), 6.35 (dd, J = 10.8, 11.2 Hz, 1H), 7.43 (dd, J = 10.8,
15.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 20.1, 22.6, 28.5,
28.9, 29.1, 29.2, 31.7, 32.9, 46.7, 118.4, 126.9, 141.5, 143.7, 166.6; HR-
MS m/z calcd Mþ for C16H29NONa 274.2147, found 274.2141.
2-Methyl-11-(tetrahydro-2H-pyran-2-yloxy)undeca-3,5-
diyn-2-ol (31). A quantity of 5.3 mL (7.4 mmol) of n-BuLi in hexanes
(1.4M) was slowly added to a well-stirred solution of 2918 (0.41 g, 3.7
mmol) in THF (10 mL) and HMPA (2.5 mL) at 0 °C. After complete
addition, a heavy white precipitate had formed and the mixture was
stirred for a further 5 min. 3052 (0.93 g, 3.7 mmol) was then added, and
the mixture was stirred at 0 °C for 5 h. Saturated LiCl solution (30 mL)
was then added, and the mixture was extracted into ether. The ether
layers were washed with brine (100 mL), dried (MgSO4), and stripped
of solvent. Purification of the residue by flash chromatography (silica,
30% EtOAc in hexane) yielded 0.86 g (65%) of the title compound as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.40ꢀ1.84 (m, 12H), 1.49
(s, 6H), 2.01 (s, 1H), 2.27 (t, J = 6.7 Hz, 2H), 3.35 (dt, J = 6.5, 9.6 Hz,
(E)-Diethyl 4-(isobutylamino)-4-oxobut-2-enylphospho-
nate (27). 25 (2.0 g, 9.05 mmol) and triethyl phosphite (1.66 g, 10.0
mmol) were mixed together and stirred at 100 °C for 2 h. After cooling
to room temperature, the mixture was purified by flash chromatography
(silica gel, 50% EtOAc in hexane) yielding 1.9 g (76%) of the title
compound 27 as a white solid: mp = 44ꢀ46 °C; 1H NMR (500 M Hz,
CDCl3) δ 0.91 (d, J = 7.0 Hz, 6H), 1.31 (t, J = 7.0 Hz, 6H), 1.79 (sept, J =
7.0 Hz, 1H), 2.70 (ddd, J = 1.5, 8.0, 22.5 Hz, 2H), 3.16 (dd, J = 6.5, 6.5
Hz, 2H), 4.05ꢀ4.15 (m, 4H), 5.68 (brs, 1H), 6.72 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 16.4 (d, J = 6.0 Hz), 20.1, 28.5, 30.1(d, J = 138.0
Hz), 46.9, 62.2 (d, J = 7.0 Hz), 128.4 (d, J = 1.0 Hz), 132.5 (d, J = 1.0 Hz),
164.9. Anal. Calcd for C12H24NO4P: C, 51.98; H, 8.72; N, 5.05. Found:
C, 51.45; H, 8.69; N, 5.20.
(E)-Ethyl dec-2-enoate (18). (Diethoxyphosphoryl)acetic acid
ethyl ester (13 g, 58 mmol) was added dropwise to a suspension of NaH
(2.79 g, 58 mmol, 50% dispersion in mineral oil) in ether (250 mL) at
0 °C. After hydrogen evolution was complete (5 min), octanal (6.4 g, 50
mmol) was added dropwise with good stirring. Fifteen minutes later, the
reaction was quenched by the addition of 100 mL of saturated
ammonium chloride solution. The ether layer was separated and washed
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The Journal of Organic Chemistry
ARTICLE
1H), 3.50 (m, 1H), 3.72 (dt, J = 6.7, 9.6 Hz, 1H), 3.85 (m, 1H), 4.56 (dd,
J = 3.1, 4.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 19.3, 19.7, 25.57,
25.60, 28.1, 29.3, 30.8, 31.3, 62.4, 64.6, 65.3, 67.38, 67.39, 80.1, 81.7,
98.9; HR-MS m/z calcd Mþ for C17H26O3 278.1882, found 278.1888.
2-(Nona-6,8-diynyloxy)tetrahydro-2H-pyran (32). The title
compound was obtained in 85% yield (1.42 g, colorless oil) from 31
(2.2 g, 7.9 mmol) according to the general procedure G. The crude
product was purified using flash chromatography (20% EtOAc in
(100). Anal. Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found: C,
78.44; H, 9.39; N, 5.94.
(E)-N-Isobutylundeca-2-en-8,10-diynamide (2). The title
compound was obtained in 55% yield from 34, according to the general
procedure L: white solid; mp = 74ꢀ75 °C; lit10 mp = 69 °C. Spectro-
scopic data were consistent with a literature report:17 1H NMR
(400 MHz, CDCl3) δ 0.91 (d, J = 6.8 Hz, 6H), 1.52ꢀ1.60 (m, 4H),
1.79 (sept, J = 6.8 Hz, 1H), 1.97 (t, J = 0.8 Hz, 1H), 2.15ꢀ2.30 (m, 4H),
3.14 (t, J = 6.5 Hz, 2H), 5.54 (br s, 1H), 5.77 (dt, J = 1.2, 15.2 Hz, 1H), 6.80
(dt, J = 6.8, 15.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.8, 20.1,
27.2, 27.3, 28.6, 31.3, 46.8, 64.7, 65.0, 68.4, 77.9, 124.1, 143.7, 165.9;
GC-MS EI m/z (%) 231 (2) [Mþ], 230 (3), 216 (3), 202 (8), 188 (7),
174 (6), 160 (8), 146 (10), 131 (20), 116 (28), 103 (26), 91 (100), 79
(13). Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C,
77.94; H, 9.59; N, 5.68.
1
hexanes, silica): H NMR (500 MHz, C6D6) δ 1.25ꢀ1.50 (m, 8H),
1.62ꢀ1.67 (m, 2H), 1.72 (t, J = 0.9 Hz, 1H), 1.76ꢀ1.85 (m, 2H), 1.92
(dt, J = 0.9, 6.7 Hz, 2H), 3.25 (dt, J = 6.5, 9.6 Hz, 1H), 3.44 (m, 1H), 3.73
(dt, J = 6.7, 9.6 Hz, 1H), 3.83 (m, 1H), 4.59 (dd, J = 3.1, 4.3 Hz, 1H); 13C
NMR (125 MHz, C6D6) δ 17.9, 18.7, 24.8, 24.9, 27.0, 28.4, 30.0, 60.5,
64.3, 64.7, 66.1, 68.0, 77.4, 97.5; GC-MS EI m/z (%) 191 (0.3), 177 (1),
149 (2), 131 (2), 117 (14), 103 (9), 91 (33), 85 (100), 76 (18), 55 (38).
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.05; H, 9.53.
2-(Deca-6,8-diynyloxy)tetrahydro-2H-pyran (33). Method
A: 1.1 mL (1.54 mmol) of n-BuLi in hexanes (1.4 M) was slowly added
to a solution of 32 (340 mg, 1.54 mmol) in THF (12 mL) at 0 °C. MeI
(310 mg, 2.2 mmol) was then added in one portion, and the mixture was
stirred at 0 °C for 3 h. Water (20 mL) was then added, and the mixture
was extracted into hexanes. The organic layers were washed with water
(50 mL) then brine (50 mL), dried (MgSO4), and stripped of solvent.
Purification of the residue by flash chromatography (silica, 5% EtOAc in
hexane) yielded 330 mg (91%) of the title compound as a colorless oil.
Method B: The title compound was obtained in 88% yield (11.8 g,
colorless oil) from 42 (12.7 g, 54.2 mmol) according to the general
procedure E. Purification: flash chromatography (10% ether in hexanes,
silica): 1H NMR (500 MHz, CDCl3) δ 1.36ꢀ1.66 (m, 12H), 1.72ꢀ1.80
(m, 1H), 1.82 (t, J = 1.2 Hz, 3H), 2.19 (dt, J = 1.2, 6.8 Hz, 2H), 3.31
(dt, J = 6.7, 9.7 Hz, 1H), 3.40ꢀ3.46 (m, 1H), 3.65 (dt, J = 6.7, 9.7 Hz,
1H), 3.76ꢀ3.82 (m, 1H), 4.50 (t, J = 3.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 3.9, 18.9, 19.5, 25.3(2), 28.0, 29.0, 30.6, 62.1, 64.4, 65.3, 67.1,
72.7, 76.4, 98.6. Anal. Calcd for C15H22O2: C, 76.88; H, 9.46. Found:
C, 77.17; H, 9.83.
2-(Deca-6,9-diynyloxy)-tetrahydro-2H-pyran (42). The title
compound was obtained in 75% yield from 4122,23,53 according to the
general procedure D: flash chromatographic purification with 10% Et2O
1
in hexanes, silica gel; H NMR (500 MHz, C6D6) δ 1.20ꢀ1.64 (m,
12H), 1.70ꢀ1.79 (m, 1H), 1.74 (t, J = 2.7 Hz, 1H), 1.91ꢀ1.97 (m, 2H),
2.81ꢀ2.84 (q, J = 2.5 Hz, 2H), 3.24 (dt, J = 6.4, 9.6 Hz, 1H), 3.35ꢀ3.50
(m, 1H), 3.70ꢀ3.81 (m, 2H), 4.54 (t, J = 3.4 Hz, 1H); 13C NMR (125
MHz, C6D6) δ 9.6, 18.8, 19.6, 25.8, 25.9, 28.8, 29.6, 31.9, 61.5, 67.3, 68.8,
73.7, 79.0, 81.2, 98.5; GC-MS EI m/z (%) 195 (0.2), 167 (0.4), 125 (1),
111 (1.8), 101 (17), 85 (100), 79 (10), 67 (49), 55 (47). 42 was
converted to the corresponding methyl-substituted diyne 33 (88% yield,
purification with 10% Et2O in hexanes, silica gel) according to the
general procedure E.
10-Methylundeca-6,8-diyne-1,10-diol (44). The title com-
pound was obtained in 90% yield from 4325 according to the general
procedure F. The crude product was purified by column chromatogra-
phy (silica gel, 30% ethyl acetate in hexane) to give 44 as a white solid:
mp = 55ꢀ56 °C; 1H NMR (400 MHz, CDCl3) δ 1.40ꢀ1.60 (m, 6H),
1.51 (s, 6H), 2.18 (s, 1H), 2.29 (t, J = 6.8 Hz, 2H), 3.64 (t, J = 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 19.2, 24.9, 27.9, 31.2, 32.1, 62.7,
64.5, 65.5, 67.3, 79.8, 81.5. Anal. Calcd: C, 74.19; H, 9.34. Found: C,
73.96; H, 9.42. 44 was converted to the corresponding 34 in 85% yield
according to the general procedure E.
(Z)-Ethyl hept-2-en-6-ynoate (45). The title compound was
obtained in 69% yield from pent-4-yn-1-ol, according to the general
procedure J. Spectroscopic data were consistent with a literature
report.54
(Z)-Hept-2-en-6-yn-1-ol (46). The title compound was obtained
in 92% yield from 45, according to the general procedure C. Spectro-
scopic data were consistent with a literature report.55
(Z)-10-Methylundeca-2-en-6,8-diyne-1,10-diol (47). The ti-
tle compound was obtained in 88% yield from 46 (silica gel, 25% ethyl
acetate in hexane), according to the general procedure F: 1H NMR (400
MHz, CDCl3) δ 1.52 (s, 6H), 2.08 (s, 1H), 2.28ꢀ2.39 (m, 4H),
4.18ꢀ4.26 (m, 2H), 5.52ꢀ5.60 (m, 1H), 5.68ꢀ5.76 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 19.6, 26.1, 31.1, 58.5, 64.9, 65.5, 67.0, 80.4,
80.8, 130.1, 130.5; GC-MS EI m/z (%) 173 (1), 159 (2), 131 (5), 115
(7), 91 (9), 77 (7), 43 (100). Anal. Calcd for C12H16O2: C, 74.97; H,
8.39. Found: C, 74.86; H, 8.68.
Nona-6,8-diyn-1-ol (34). The title compound was obtained in
89% yield (11.8 g, colorless oil) from 32 (140 mg, 0.12 mmol) according
to the general procedure B: purification by flash chromatography (20%
ether in hexanes, silica); 1H NMR (500 MHz, C6D6) δ 1.18ꢀ1.33 (m,
6H), 1.57 (s, 1H), 1.63 (s, 1H), 1.90 (t, J = 6.7 Hz, 2H), 3.36 (brt, J = 6.6
Hz, 2H); 13C NMR (125 MHz, C6D6) δ 18.9, 25.2, 27.9, 32.3, 62.2, 65.3,
65.8, 68.9, 78.4; GC-MS EI m/z (%) 136 (Mþ, 0.5), 135 (4), 117 (25),
103 (31), 91 (47), 76 (100), 63 (80), 51(42). Anal. Calcd for C9H12O:
C, 79.37; H, 8.88. Found: C, 79.27; H, 8.65.
Deca-6,8-diyn-1-ol (35). The title compound was obtained in
93% yield from 33, according to the general procedure B: 1H NMR (500
MHz, CDCl3) δ 1.38ꢀ1.45 (m, 2H), 1.47ꢀ1.56 (m, 4H), 1.65 (s, 1H),
1.85 (t, J = 1.2 Hz, 3H), 2.21 (dt, J = 1.2, 6.7 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 4.0, 19.9, 24.9, 28.0, 32.1, 62.6, 64.4, 65.5, 73.0, 76.5;
GC-MS EI m/z (%) 149 (2), 135 (9), 115 (25), 103 (11), 91 (65), 79
(36), 77 (65), 65 (29), 51(100). Anal. Calcd for C10H14O: C, 79.96; H,
9.39. Found: C, 79.97; H, 9.62.
(E)-N-Isobutyldodeca-2-en-8,10-diynamide (1). The title
compound was obtained in 58% yield from 34, according to the general
procedure L: white solid; mp = 102ꢀ104 °C; lit10 mp = 104 °C, which
gave spectroscopic data consistent with a literature report;17 1H NMR
(500 MHz, CDCl3) δ 0.88 (d, J = 6.7 Hz, 6H), 1.45ꢀ1.54 (m, 4H), 1.75
(sept, J = 6.7 Hz, 1H), 1.85 (s, 3H), 2.10ꢀ2.24 (m, 4H), 3.10 (t, J = 6.7
Hz, 2H), 5.80 (d, J = 15.2 Hz, 1H), 5.98 (brs, 1H), 6.74 (dt, J = 6.9, 15.2
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 4.0, 18.8, 20.0, 27.2, 27.6,
28.5, 31.2, 46.8, 64.4, 65.6, 73.1, 76.2, 124.1, 143.4, 166.0; GC-MS EI m/z
(%) 245 (3) [Mþ], 244 (4), 230 (3), 216 (11), 202 (9), 188 (7), 174 (9),
160 (13), 145 (30), 130 (27), 117 (48), 105 (26), 91 (33), 77 (39), 41
(Z)-Nona-2-en-6,8-diyn-1-ol (48). The title compound was
obtained in 83% yield from 47, according to the general procedure G
1
and was used in the next step without delay: H NMR (400 MHz,
CDCl3) δ 1.44 (s, 1H), 1.98 (s, 1H), 2.30ꢀ2.35 (m, 4H), 4.21 (brd, J =
4.4 Hz, 2H), 5.51ꢀ5.60 (m, 1H), 5.72 (dt, J = 6.8, 10.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 19.3, 25.9, 58.4, 65.0, 65.2, 68.1, 77.4, 129.8,
130.6; GC-MS EI m/z (%) 134 (0.2) [Mþ], 133 (6), 115 (70), 103 (16),
91 (32), 77 (24), 63 (68), 41 (100); HR-MS m/z calcd [M þ Na]þ for
C9H10ONa 134.1751, found 134.1751.
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ARTICLE
(2E,4Z)-N-Isobutylundeca-2,4-dien-8,10-diynamide (4).
The title compound was obtained in 56% yield from 48, according to
the general procedure L: white solid; mp = 58ꢀ60 °C; lit9 mp = 61 °C.
Spectroscopic data were consistent with a literature report:9 1H NMR
(400 MHz, CDCl3) δ 0.91 (d, J = 6.4 Hz, 6H), 1.78 (sept, J = 6.4 Hz,
1H), 1.95 (t, J = 1.2 Hz, 1H), 2.32ꢀ2.38 (m, 2H), 2.50ꢀ2.56 (m,
2H), 3.15 (t, J = 6.4 Hz, 2H), 5.54 (brs, 1H), 5.79 (dt, J = 7.2, 10.8 Hz,
1H), 5.85 (d, J = 14.8 Hz, 1H), 6.15 (t, J = 10.8 Hz, 1H), 7.46 (ddd, J =
1.2, 11.6, 14.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.2, 20.1, 26.5,
28.6, 46.9, 64.9, 65.5, 68.2, 76.9, 124.9, 128.0, 135.1, 136.2, 166.0; GC-
MS EI m/z (%) 229 (3), 228 (4), 214 (4), 128 (100), 115 (32), 96 (27),
66 (60), 57 (74), 41 (50). Anal. Calcd for C15H19NO: C, 78.56; H, 8.35;
N, 6.11. Found: C, 78.15; H, 8.41; N, 6.09.
J = 0.8, 11.6, 14.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 4.2, 19.4,
20.1, 26.8, 28.6, 46.7, 64.4, 66.2, 73.5, 75.3, 124.8, 127.8, 135.3, 136.8,
166.1; GC-MS EI m/z (%): 148 (6) [Mþ], 242 (9), 215 (3), 186 (5),
171 (19), 152 (4), 143 (22), 128 (62), 115 (20), 77 (54), 57 (100). Anal.
Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 78.46; H,
8.70; N, 5.61. 55: 1H NMR (400 MHz, C6D6) δ 0.81 (d, J = 6.7 Hz, 6H),
1.35 (s, 3H), 1.71 (sept, J = 6.7 Hz, 1 H), 1.90ꢀ1.94 (m, 4H), 3.13 (dd,
J = 6.5, 6.5 Hz, 2H), 5.60 (dt, J = 15.2, 6.5 Hz, 1H), 5.78 (d, J = 15.0 Hz,
1H), 5.98 (dd, J = 11.0, 15.1 Hz, 1H), 6.04 (t, J = 5.8 Hz, 1H), 7.41 (dd,
J = 11.0, 15.0 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 3.2, 18.6, 19.9,
28.7, 31.5, 46.8, 65.3, 66.9, 73.4, 75.4, 123.9, 138.7, 138.9, 165.7; HR-MS
m/z calcd Mþ for C16H21NO 243.1623, found 243.1620.
(Z)-N-Isobutylundeca-2-en-8,10-diynamide (11). Oxalyl
chloride (0.99 g, 0.78 mmol) was added to CH2Cl2 (10 mL), and the
solution was cooled to ꢀ78 °C. Next, DMSO (0.80 g, 10.2 mmol) was
added dropwise, and after complete addition, the solution was stirred for
a further 2 min before the dropwise addition of alcohol (0.35 g, 2.6
mmol) in CH2Cl2 (5 mL). Stirring was continued at ꢀ78 °C for 30 min,
and then the reaction was warmed to ꢀ10 °C for 5 min. The mixture was
recooled to ꢀ78 °C, and Et3N (4.96 g, 49 mmol) was added. The
reaction was allowed to return to room temperature and washed with
water (20 mL), then 1 M HCl (20 mL), and then once more with water
(20 mL). The organic layer was dried (MgSO4), and the dichloro-
methane removed to give the crude aldehyde which was diluted with
tetrahydrofuran (5 mL) and used in the next step without delay.
Meanwhile, a 1 M solution of NaHMDS in tetrahydrofuran (2.77 mL,
2.77 mmol) was slowly added to a stirred suspension of (diphenylphos-
phonato)acetamide reagent 57 (0.98 g, 2.8 mmol) in tetrahydrofuran
(25 mL) at ꢀ78 °C. Stirring was continued for a further 20 min, and then
the crude aldehyde solution prepared from the previous step was slowly
added. Stirring was continued at ꢀ78 °C for 1 h, then saturated NH4Cl
solution (20 mL) was added and the organic phase was separated. The
aqueous phase was extracted into ethyl acetate (2 ꢁ 50 mL), and the
combined organic phases were washed with brine (30 mL), dried
(MgSO4), and stripped of solvent. Flash chromatographic purification
(20% EtOAc in hexanes, silica) yielded alkyl amides 11 (230 mg, 39%)
and 2 (20 mg, 25%). Spectroscopic data were consistent with a literature
report.17 11: 1H NMR (400 MHz, CDCl3) δ 0.90 (d, J = 6.8 Hz, 6H),
1.48ꢀ1.60 (m, 4H), 1.77 (sept, J = 6.8 Hz, 1H), 1.93 (t, J = 1.3 Hz, 1H),
2.26 (dt, J = 1.3, 6.8 Hz, 2H), 2.66 (dt, J = 1.9, 7.6 Hz, 2H), 3.10 (ddt, J =
6.2, 6.4 Hz, 2H), 5.47 (brs, 1H), 5.67 (dt, J = 1.6, 11.5 Hz, 1H), 5.94 (dt,
J = 7.6, 11.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.8, 20.1, 27.5,
27.9, 28.3, 28.5, 46.6, 64.5, 64.8, 68.5, 78.2, 122.7, 144.6, 166.5; GC-MS
EI m/z (%) 231 (0.6) [Mþ], 202 (6), 131 (58), 117 (73), 104 (24),
91 (85), 68 (35), 63 (55), 57 (72), 55 (60), 41 (100); HR-MS m/z calcd
[M þ Na]þ for C15H21NONa 254.1521, found 254.1515.
2-(Octa-4,6-diynyloxy)-tetrahydro-2H-pyran (50). 49 was
obtained in 77% yield from THP-protected pent-4-yn-1-ol,56 according
to the general procedure D: colorless oil; 1H NMR (500 MHz, CDCl3)
δ 1.47ꢀ1.84 (m, 8H), 2.04 (t, J = 2.5 Hz, 1H), 2.26ꢀ2.31 (m, 2H), 3.13
(q, J = 2.5 Hz, 2H), 3.43ꢀ3.53 (m, 2H), 3.77ꢀ3.89 (m, 2H), 4.59 (dd,
J = 3.0, 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 9.5, 15.6, 19.5,
25.5, 28.8, 30.7, 62.1, 65.9, 68.4, 73.3, 78.9, 80.5, 98.8; GC-MS EI m/z
(%) 205 (0.5), 167 (12), 135 (5), 122 (7), 103 (11), 85 (100), 77 (26).
The title compound 50 was obtained in 89% yield from 49, according to
1
the general procedure E: colorless oil; H NMR (500 MHz, CDCl3)
δ 1.48ꢀ1.60 (m, 4H), 1.66ꢀ1.73 (m, 1H), 1.77ꢀ1.83 (m, 3H), 1.89
(t, J = 1.0 Hz, 3H), 2.37 (tq, J = 1.0, 6.5 Hz, 2H), 3.43ꢀ3.53 (m, 2H),
3.77ꢀ3.87 (m, 2H), 4.58 (dd, J = 3.0, 4.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 4.1, 16.1, 19.5, 25.5, 28.6, 30.6, 62.2, 64.5, 65.6, 65.8, 73.0,
76.1, 98.8; GC-MS EI m/z (%) 206 (0.2) [Mþ], 191 (5), 161 (6), 149
(8), 135 (12), 122 (20), 103 (31), 85 (100). Anal. Calcd for C13H18O2:
C, 75.69; H, 8.80. Found: C, 75.81; H, 8.99.
Octa-4,6-diyn-1-ol (51). The title compound was obtained in 90%
1
yield from 50, according to the general procedure B: colorless oil; H
NMR (400 MHz, CDCl3) δ 1.75 (quint, J = 1.2 Hz, 2H), 1.89 (t, J = 1.2
Hz, 3H), 2.36 (tq, J = 1.2, 6.7 Hz, 2H), 3.72 (m, 2H). 13C NMR (125
MHz, CDCl3) δ 4.0, 15.5, 30.8, 61.2, 64.2, 65.6, 73.2, 75.8. Anal. Calcd
for C8H10O: C, 78.65; H, 8.25. Found: C, 78.85; H, 4.49.
(Z)-Ethyl deca-2-en-6,8-diynoate (52). The title compound
was obtained in 90% yield from 51, according to the general procedure J:
colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H),
1.88 (s, 3H), 2.38 (t, J = 7.0 Hz, 2H), 2.85 (dq, J = 1.7, 7.1 Hz, 2H), 4.15
(q, J = 7.1 Hz, 2H), 5.82 (dt, J = 1.7, 11.5 Hz, 1H), 6.27 (dt, J = 7.2, 14.5
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 4.2, 14.3, 18.9, 27.6, 60.0,
64.4, 66.2, 73.5, 75.4, 121.2, 147.2, 166.2; GC-MS EI m/z (%) 190 (0.2)
[Mþ], 189 (1), 175 (0.2), 162 (8), 161 (17), 145 (25), 133 (9), 117
(60), 115 (79), 105 (9), 91 (36), 77 (54), 51 (100). Anal. Calcd for
C12H14O2: C, 75.76; H, 7.42. Found: C, 75.06; H, 7.41.
(E)-Ethyl hept-2-en-6-ynoate (58). The title compound was
obtained in 89% yield from pent-4-yn-1-ol, according to the general
procedure K: purification by distillation (95ꢀ97 °C, 10 mmHg),
colorless oil. Spectroscopic data were consistent with a literature
report.51 (E)-hept-2-en-6-yn-1-ol (59): The title compound was ob-
tained in 91% yield from 58, according to the general procedure C.
Spectroscopic data were consistent with a literature report.33
(E)-10-Methylundeca-2-en-6,8-diyne-1,10-diol (60). The ti-
tle compound was obtained in 76% yield from 59, according to the
general procedure F: 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 6H), 1.94
(brs, 1H), 2.22ꢀ2.28 (m, 2H), 2.32ꢀ2.37 (m, 2H), 4.07ꢀ4.10 (m, 2H),
5.67ꢀ5.71 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.3, 30.7, 31.1,
63.3, 64.9, 65.4, 67.1, 80.2, 80.7, 130.1, 130.7; GC-MS EI m/z (%) 173
(1), 159 (2), 131 (5), 115 (7), 91 (9), 77 (7), 43 (100); HR-MS m/z
calcd [M þ Na]þ for C12H16O2Na 215.1048, found 215.1043. Anal.
Calcd for C12H16O2: C, 80.56; H, 7.51. Found: C, 80.45; H, 7.35.
(E)-Nona-2-en-6,8-diyn-1-ol (61). The title compound was
obtained in 75% yield from 60, according to the general procedure F,
(Z)-Deca-2-en-6,8-diyn-1-ol (53). The title compound was
obtained in 91% yield from 52, according to the general procedure C:
colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.88 (s, 3H), 2.22ꢀ2.40
(m, 4H), 4.13ꢀ4.18 (m, 2H), 5.50ꢀ5.59 (m, 1H), 5.66ꢀ5.73 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 4.1, 19.4, 26.2, 58.3, 64.2, 65.9, 73.6,
75.8, 130.0, 130.4; GC-MS EI m/z (%) 148 (1) [Mþ], 147 (7), 129 (21),
128 (17), 115 (41), 105 (18), 91 (25), 77 (45), 63 (15), 5 1(100). Anal.
Calcd for C10H12O: C, 81.04; H, 8.16. Found: C, 81.02; H, 8.18.
(2E,4Z)-N-Isobutyldodeca-2,4-dien-8,10-diynamide (3).
Method A: The title compound was obtained in 60% yield from 53,
according to the general procedure M: white solid; mp = 74ꢀ76 °C; lit9
mp = 74 °C. Method B: 3 was obtained in 18% yield (and 5% of 55) from
51 according to a procedure adapted from general procedure J using (E)-
1
diphenyl 4-(isobutylamino)-4-oxobut-2-enylphosphonate (54). 3: H
NMR (400 MHz, CDCl3) δ 0.93 (d, J = 6.8 Hz, 6H), 1.80 (sept, J = 6.8
Hz, 1H), 1.89 (t, J = 1.2 Hz, 3H), 2.32ꢀ2.38 (m, 2H), 2.48ꢀ2.55 (m,
2H), 3.17 (t, J = 6.4 Hz, 2H), 5.56 (brs, 1H), 5.81 (dt, J = 7.6, 10.8 Hz,
1H), 5.83 (d, J = 14.8 Hz, 1H), 6.15 (t, J = 11.6 Hz, 1H), 7.49 (ddd,
4478
dx.doi.org/10.1021/jo200289f |J. Org. Chem. 2011, 76, 4467–4481

The Journal of Organic Chemistry
ARTICLE
1
and was used in the next step without delay: H NMR (400 MHz,
CDCl3) δ 1.98 (brt, J = 1.1 Hz, 1H), 2.28ꢀ2.35 (m, 4H), 4.11 (brs, 2H),
5.71ꢀ5.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 19.0, 20.9,
30.5, 60.3, 63.3, 64.7, 129.8, 130.8; GC-MS EI m/z (%) 134 (Mþ 3), 133
(30), 115 (51), 103 (37), 91 (60), 77 (56), 63 (100).
2.20ꢀ2.33 (m, 4H), 3.16 (t, J = 6.8 Hz, 2H), 5.42 (dt, J = 6.8, 11.4 Hz, 1H),
5.50ꢀ5.60 (m, 2H), 5.77 (d, J = 15.2 Hz, 1H), 6.06 (dt, J = 6.9, 15.2 Hz,
1H), 6.15 (dd, J = 10.4, 15.2 Hz, 1H), 6.24 (ddq, J = 1.6, 11.0, 11.0 Hz, 1H),
6.30 (dd, J = 11.0, 11.0 Hz, 1H), 7.18 (dd, J = 10.8, 15.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.1, 20.1, 26.7, 28.6, 32.8, 46.9, 122.2, 124.1, 124.2,
126.7, 128.7, 130.0, 141.0, 141.8, 166.3. Anal. Calcd for C16H25NO: C,
77.68; H, 10.19; N, 5.66. Found: C, 77.66; H, 10.31; N, 5.58. The minor
(2Z,4E,8Z,10Z)-isomer 67 was also obtained in 4% yield: 1H NMR (400
MHz, CDCl3) δ0.91 (d, J=6.4Hz, 6H), 1.72(dd, J= 1.6, 7.2 Hz, 3H), 1.78
(sept, J = 6.4 Hz, 1H), 2.20ꢀ2.30 (m, 4H), 3.10 (dd, J = 6.4, 6.4 Hz, 2H),
5.38ꢀ5.56 (m, 2H), 5.49 (d, J = 10.8 Hz, 1H), 5.69 (brs, 1H), 5.93 (dt, J =
6.0, 15.2 Hz, 1H), 6.18ꢀ6.30 (m, 2H), 6.34 (dd, J= 11.0, 11.0 Hz, 1H), 7.48
(ddd, J = 1.2, 10.8, 15.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.1,
20.1, 26.9, 28.5, 32.8, 46.7, 118.8, 123.9, 124.3, 126.4, 127.4, 130.3, 141.2,
142.3, 166.5; HR-MS m/z calcd [M þ Na]þ for C16H25NONa 270.1834,
found 270.1828.
(2Z,8Z)-Deca-2,8-dien-6-yn-1-ol (70). The title compound was
obtained in 91% yield from 45, according to the general procedure H: 1H
NMR (300 MHz, C6D6) δ 0.8 (s, 1H), 1.79 (dd, J = 0.6, 6.4 Hz, 3H),
1.98ꢀ2.18 (m, 4H), 3.91 (brd, J = 6.0 Hz, 2H), 5.32ꢀ5.70 (m, 4H); 13C
NMR (75 MHz, C6D6) δ 15.8, 20.0, 27.0, 58.4, 78.3, 94.5, 110.9, 130.0,
131.0, 137.0. Anal. Calcd for C10H14O: C, 79.96; H, 9.39. Found: C,
79.45; H, 9.00.
(2Z,4E)-N-Isobutylundeca-2,4-dien-8,10-diynamide (12)
and (2E,4E)-N-Isobutylundeca-2,4-dien-8,10-diynamide (62).
Following a procedure similar to that for 11, the title compounds were
1
obtained in 83% yield from 61 (12, 62% and 62, 21%). 12: H NMR
(400 MHz, CDCl3) δ 0.90 (d, J = 6.8 Hz, 6H), 1.78 (sept, J = 6.8 Hz, 1H),
1.95 (brs, 1H), 2.34ꢀ2.41 (m, 4H), 3.10 (dd, J = 6.8, 6.8 Hz, 2H), 5.51 (d,
J = 11.3 Hz, 1H), 5.61 (brs, 1H), 5.94 (dt, J = 6.3, 15.4 Hz, 1H), 6.35 (t, J =
11.4 Hz, 1H), 7.49 (dd, J = 11.2, 15.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 18.9, 20.1, 28.5, 29.7, 31.2, 46.7, 64.9, 65.3, 68.3, 77.2, 119.7,
128.3, 139.5, 140.6, 166.3; 1H NMR (400 MHz, C6D6) δ 0.72 (d, J = 6.7
Hz, 6H), 1.46 (t, J = 1.2 Hz, 1H), 1.54 (sept, J = 6.7 Hz, 1H), 1.74ꢀ1.78
(m, 2H), 1.84ꢀ1.90 (m, 2H), 2.96 (dd, J = 6.3, 6.8 Hz, 2H), 4.61 (brs,
1H), 5.06 (brd, J = 11.3 Hz, 1H), 5.69 (ddt, J = 0.8, 7.0, 15.4 Hz, 1H), 6.12
(dt, J = 0.8, 11.3 Hz, 1H), 8.00 (ddq, J = 1.4, 11.3, 15.4 Hz, 1H); 13C NMR
(100 MHz, C6D6) δ 18.8, 20.1, 28.9, 31.1, 46.6, 65.3, 66.1, 68.9, 77.6,
120.2, 129.3, 139.2, 140.7, 165.4; GC-MS EI m/z (%) 229 (1) [Mþ], 214
(3), 186 (5), 172 (6), 166 (40), 152 (59), 128 (100), 115 (30), 96 (24),
66 (93), 57 (60), 41 (58); HR-MS m/z calcd [M þ Na]þ for
C15H19NONa 252.1364, found 252.1359. 62: 1H NMR (400 MHz,
CDCl3) δ 0.90 (d, J = 6.7 Hz, 6H), 1.78 (sept, J = 6.7 Hz, 1H), 1.96
(brs, 1H), 2.36ꢀ2.38 (m, 4H), 3.14 (dd, J = 6.7, 6.7 Hz, 2H), 5.54 (brs,
1H), 5.79 (d, J =15.1Hz, 1H), 5.99ꢀ6.06 (m, 2H), 6.17 (dd, J = 10.8, 15.1
Hz, 1H), 7.15 (dd, J = 10.8, 15.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 18.8, 20.1, 28.6, 31.2, 47.0, 65.0, 65.5, 68.2, 77.3, 123.1, 128.8, 139.1,
140.4, 166.2;GC-MS EIm/z (%) 229 (4), 228 (7), 214(5), 157(55), 128
(83), 110 (13), 66 (100), 41 (58); HR-MS m/z calcd [M þ Na]þ for
C15H19NONa 252.1364, found 252.1359.
(E)-Ethyl deca-2-en-6,8-diynoate (64). The title compound
was obtained in 78% yield from 51, according to the general procedure
K: colorless oil; 1H NMR (400 MHz, C6D6) δ 1.05 (t, J = 7.0 Hz, 3H),
1.41 (s, 3H), 1.82ꢀ1.97 (m, 4H), 4.10 (q, J = 7.0 Hz, 2H), 5.84 (d, J =
15.4 Hz, 1H), 6.93 (dt, J = 6.2, 15.4 Hz, 1H); 13C NMR (100 MHz,
C6D6) δ 3.2, 13.9, 17.7, 30.5, 59.7, 65.1, 67.1, 73.6, 74.7, 122.6, 145.6,
166.4; GC-MS EI m/z (%) 190 (0.8) [Mþ], 161 (39), 145 (20), 133
(10), 115 (41), 105 (8), 91 (26), 77 (77), 51 (100). Anal. Calcd for
C12H14O2: C, 75.76; H, 7.42. Found: C, 75.40; H, 6.97.
(E)-Deca-2-en-6,8-diyn-1-ol (65). The title compound was
obtained in 90% yield from 64, according to the general procedure C:
colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.70 (s, 1H), 1.88 (t, J = 2.3
Hz, 3H), 2.22ꢀ2.33 (m, 4H), 4.09 (d, J = 5.0 Hz, 2H), 5.67ꢀ5.71 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 4.1, 19.1, 30.9, 63.3, 64.3, 65,8,
73.3, 75.7, 130.2, 130.6; GC-MS EI m/z (%) 148 (1.5) [Mþ], 147 (12),
133 (16), 115 (29), 105 (29), 91 (41), 77 (65), 51 (100). Anal. Calcd for
C10H12O: C, 81.04; H, 8.16. Found: C, 80.94; H, 8.26.
(2E,4Z,10Z)-N-Isobutyldodeca-2,4,10-trien-8-ynamide (6).
The title compound was obtained as a colorless oil in 54% yield from 70,
according to the general procedure L. Spectroscopic data were consis-
tent with a literature report:10 1H NMR (400 MHz, CDCl3) δ 0.92 (d,
6H, J = 6.8 Hz), 1.80 (sept, J = 6.8 Hz, 1H), 1.83 (dd, J = 1.5, 7.2 Hz, 3H),
2.43ꢀ2.59 (m, 4H), 3.16 (t, J = 6.5 Hz, 2H), 5.43 (dq, J = 1.6, 10.8 Hz,
1H), 5.56 (br s, 1H), 5.84 (d, J = 15.0 Hz, 1H), 5.84ꢀ5.91 (m, 2H), 6.16
(dd, J = 10.5, 10.5 Hz, 1H), 7.53 (ddd, J = 1.2, 14.8, 11.6 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 15.8, 19.7, 20.1, 27.5, 28.6, 46.9, 78.0, 93.4,
110.1, 124.5, 127.5, 135.6, 137.4, 137.6, 166.1. 1H NMR in C6D6 enabled
complete resolution of all alkene protons: 1H NMR (400 MHz, C6D6) δ
0.73 (d, J = 6.8 Hz, 6H), 1.58 (sept, J = 6.8 Hz, 1H), 1.79 (dd, J = 1.6, 6.8
Hz, 3H), 2.07ꢀ2.20 (m, 4H), 3.02 (dd, J = 6.4, 6.8 Hz, 2H), 4.84 (brs,
1H), 5.45 (d, J = 15.0 Hz, 1H), 5.51 (dq, J = 1.6, 10.8 Hz, 1H), 5.64 (dq,
J = 6.8, 10.8 Hz, 1H), 5.73 (dt, J = 7.2, 10.8 Hz, 1H), 6.07 (dd, J = 11.0,
11.0 Hz, 1H), 7.85 (ddd, J = 1.2, 11.6, 14.8 Hz, 1H); HR-MS m/z calcd
[M þ Na]þ for C16H23NONa 268.1677, found 268.1677.
(2E,8E)-Deca-2,8-dien-6-yn-1-ol (71). The title compound was
obtained as a colorless oil in 87% yield from 59, according to the general
procedure H: 1H NMR (500 MHz, C6D6) δ 0.89 (s, 1H), 1.51 (dd, J =
1.7, 6.8 Hz, 3H), 2.14ꢀ2.20 (m, 2H), 2.26ꢀ2.32 (m, 2H), 3.89 (d, J =
5.0 Hz, 2H), 5.52ꢀ5.66 (m, 3H), 6.14 (dq, J = 6.4, 15.7 Hz, 1H); 13C
NMR (125 MHz, C6D6) δ 17.2, 18.7, 30.9, 62.3, 79.3, 86.9, 110.9, 128.8,
130.2, 136.9. Anal. Calcd for C10H14O: C, 79.96; H, 9.39. Found: C,
80.09; H, 9.61.
(2E,6Z,8E)-Deca-2,6,8-trien-1-ol (72). The title compound was
obtained in 92% yield from 71, according to the general procedure I:
colorless oil; 1H NMR (500 MHz, C6D6) δ 0.84 (s, 1H), 1.70 (ddd, J =
0.54, 1.0, 6.7 Hz, 3H), 2.06ꢀ2.11 (m, 2H), 2.22ꢀ2.30 (m, 2H), 3.92 (d,
J = 4.1 Hz, 2H), 5.36 (dt, J = 6.9, 10.9 Hz, 1H), 5.57ꢀ5.60 (m, 2H), 5.65
(dq, J = 6.7, 14.1 Hz, 1H), 6.13 (t, J = 10.9 Hz, 1H), 6.42ꢀ6.49 (m, 1H);
13C NMR (125 MHz, C6D6) δ 18.1, 27.5, 32.4, 63.3, 127.4, 128.6, 129.2,
129.4, 130.4, 130.9; GC-MS EI m/z (%) 152 (1.0) [Mþ], 134 (1), 121
(3), 105 (2), 81 (100), 79 (47), 55 (11), 53 (37); HR-MS m/z calcd
[M þ Na]þ for C10H16O 152.1201, found 152.1204.
(2E,6Z,8Z)-Deca-2,6,8-trien-1-ol (66). The title compound was
obtained in 91% yield from 65, according to the general procedure I:
colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 1H), 1.75 (d, J =
8.4 Hz, 3H), 2.12ꢀ2.19 (m, 2H), 2.24ꢀ2.32 (m, 2H), 4.08 (d, J = 4.3
Hz, 2H), 5.45 (dt, 1H, J = 7.1, 10.4 Hz), 5.55 (dq, 1H, J = 7.0, 10.4 Hz),
5.63ꢀ5.74 (m, 2H), 6.22ꢀ6.34 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 13.1, 27.0, 32.1, 63.5, 123.8, 124.4, 126.4, 129.4, 130.5, 132.3; GC-MS
EI m/z (%) 152 (1) [Mþ], 134 (1), 119 (4), 105 (2), 81 (100), 80 (63),
53 (48), 41 (94). Anal. Calcd for C10H16O: C, 78.90; H, 10.59. Found:
C, 78.70; H, 10.87.
(2E,4E,8Z,10Z)-N-Isobutyldodeca-2,4,8,10-tetraenamide (5).
The title compound was obtained in 51% yield from 66, according to the
general procedure L: white solid; mp = 74ꢀ76 °C. Spectroscopic data were
consistent with a literature report:9 1H NMR (400 MHz, CDCl3) δ 0.92 (d,
J = 6.8 Hz, 6H), 1.74 (dd, J = 1.6, 7.2 Hz, 3H), 1.78 (sept, J = 6.8 Hz, 1H),
(2E,4E,10E)-N-Isobutyldodeca-2,4,10-trien-8-ynamide (7).
The title compound was obtained in 52% yield from 71, according to the
general procedure L: 1H NMR (400 MHz, CDCl3) δ 0.93 (d, J = 6.8 Hz,
6H), 1.75 (dd, J = 1.5, 7.2 Hz, 3H), 1.85 (sept, J = 6.8 Hz, 1H),
2.30ꢀ2.50 (m, 4H), 3.18 (t, J = 6.8 Hz, 2H), 5.45 (dq, J = 2.0, 15.0 Hz,
1H), 5.49 (brs, 1H), 5.78 (d, J = 15.2 Hz, 1H), 6.05 (dq, J = 6.4, 15.0 Hz,
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ARTICLE
1H), 6.10 (dt, J = 6.0, 15.2 Hz, 1H), 6.19 (dd, J = 10.4, 15.2 Hz, 1H), 7.18
(dd, J = 10.4, 15.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.5, 19.1,
20.1, 28.6, 32.2, 46.9, 80.0, 86.9, 110.8, 122.6, 129.2, 138.5, 140.4, 140.8,
166.2; GC-MS EI m/z (%) 245 (4) [Mþ], 244 (5), 230 (2), 173 (6), 167
(11), 145 (22), 117 (22), 91 (18), 77 (79), 57 (100). Anal. Calcd for
C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found: C, 77.94; H, 9.59;
N, 5.68.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: þ61 (7) 33653825. Fax: þ 61 (7) 3365 4299. E-mail:
j.devoss@uq.edu.au.
’ ACKNOWLEDGMENT
(2E,4E,8Z,10E)-N-Isobutyldodeca-2,4,8,10-tetraenamide (8).
The title compound was obtained in 50% yield from 72, according to the
general procedure L: white solid; mp = 66ꢀ68 °C. Spectroscopic data were
consistent with a literature report:9 1H NMR (400 MHz, CDCl3) δ0.92 (d,
J = 6.8 Hz, 6H), 1.78 (dd, J = 2.0, 6.8 Hz, 3H), 1.79 (sept, J = 6.8 Hz, 1H),
2.22ꢀ2.31 (m, 4H), 3.17 (t, J = 6.8 Hz, 2H), 5.25 (dt, J = 7.6, 10.8 Hz, 1H),
5.45 (brs, 1H), 5.70 (dq, J = 6.8, 15.2 Hz, 1H), 5.75 (d, J = 14.8 Hz, 1H),
5.97 (dd, J= 10.8, 10.8 Hz, 1H), 6.07 (dt, J= 6.4, 15.2 Hz, 1H), 6.16 (dd, J=
10.4, 15.2 Hz, 1H), 6.29 (ddt, J = 1.2, 11.2, 15.2 Hz, 1H), 7.19 (dd, J = 10.4,
14.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.3, 20.1, 26.9, 28.6, 33.0,
46.9, 122.1, 126.7, 127.9, 128.7, 129.3, 129.8, 141.1, 142.0, 166.3; GC-MS
EI m/z (%) 247 (1) [Mþ], 167 (16), 152 (5), 147 (2), 128 (8), 115 (12),
81 (100), 79 (43), 66 (45), 57 (36), 53 (29), 41 (55). Anal. Calcd: C,
77.68; H, 10.19; N, 5.66. Found: C, 77.62; H, 10.44; N, 5.56. The minor
(2Z,4E,8Z,10E)-isomer 76 was also obtained in 15% yield: 1H NMR (400
MHz, CDCl3) δ 0.91 (d, J = 6.6 Hz, 6H), 1.74 (dd, J = 1.2, 6.7 Hz, 3H),
1.78 (sept, J = 6.6 Hz, 1H), 2.20ꢀ2.31 (m, 4H), 3.11 (dd, J = 6.2, 6.8 Hz,
2H), 5.25 (dt, J = 6.6, 10.6 Hz, 1H), 5.45 (d, J = 11.3 Hz, 1H), 5.51 (brs,
1H), 5.65 (dq, J = 7.0, 15.0 Hz, 1H), 5.90ꢀ5.98 (m, 2H), 6.23 ꢀ6.31 (m,
1H), 6.35 (t, J = 11.1 Hz, 1H), 7.19 (ddq, J = 1.4, 11.3, 15.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 18.2, 20.1, 27.1, 28.6, 33.0, 46.7, 118.7, 126.9,
127.4, 128.2, 129.2, 129.5, 141.3, 142.5, 166.5; GC-MS EI m/z (%) 247 (2)
[Mþ], 232 (2) 167 (11), 152 (24), 115 (18), 81 (100), 66 (55), 57 (54),
41 (64); HR-MS m/z calcd [M þ Na]þ for C16H25NONa 270.1834,
found 270.1828.
The authors are grateful for funding from Australian Research
Council for funding (LP0453473) and for Australian Postgrad-
uate Research Award to N.J.M.
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The title compound was obtained in 63% yield from 79,6 according to the
general procedure L: white solid; mp =78ꢀ79 °C; 1H NMR (400 MHz,
CDCl3) δ0.92 (d, J= 6.8 Hz, 6H), 1.73 (dd, J= 2.0, 6.8 Hz, 3H), 1.78 (sept,
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1
(2Z,4E,8E,10Z)-isomer 80 was also obtained in 11% yield: H NMR
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3H), 1.78 (sept, J= 6 0.8 Hz, 1H), 2.19ꢀ2.30 (m, 4H), 3.11 (dd, J = 6.3, 6.8
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’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
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