Solid-phase synthesis of N-(buta-2,3-dien-1-yl)amides by the Crabbé reaction

Article abstract of DOI:10.1139/cjc-2012-0255

The Crabbé homologation of polymer-supported propargylamine with paraformaldehyde, CuI, and dicyclohexylamine in 1,4-dioxane at 100 C, followed by cleavage with dilute trifluoroacetic acid, furnishes N-(buta-2,3-dien-1-yl) amides as isolable products. The N-acyltriazene linker on Merrifield resin serves simultaneously as a protecting group for the nucleophilic primary amine. The product diversity is achieved by altering the acyl chloride in the acylation of the triazene linker. In addition to being a new route to nitrogen-containing allenes, our solid-phase method enables immobilization of these reactive cumulated dienes for further synthetic operations.

Full text of DOI:10.1139/cjc-2012-0255

38
Solid-phase synthesis of
N-(buta-2,3-dien-1-yl)amides by the
Crabbé reaction
Tuomo Leikoski, Pauli Wrigstedt, Jorma Matikainen, Jussi Sipilä,
and Jari Yli-Kauhaluoma
Abstract: The Crabbé homologation of polymer-supported propargylamine with paraformaldehyde, CuI, and
dicyclohexylamine in 1,4-dioxane at 100 °C, followed by cleavage with dilute trifluoroacetic acid, furnishes
N-(buta-2,3-dien-1-yl)amides as isolable products. The N-acyltriazene linker on Merrifield resin serves simultaneously as a
protecting group for the nucleophilic primary amine. The product diversity is achieved by altering the acyl chloride in the
acylation of the triazene linker. In addition to being a new route to nitrogen-containing allenes, our solid-phase method
enables immobilization of these reactive cumulated dienes for further synthetic operations.
Key words: allene, solid phase, Crabbé, homologation, propargylamine.
Résumé : La réaction d’homologation de Crabbé de la propargylamine fixée a un polymère, par du paraformaldéhyde, en
`
présence de CuI et de dicyclohexylamine, dans le 1,4-dioxane, a 100 °C, suivie par un clivage a l’aide d’acide trifluo-
`
`
roacétique dilué, conduit a la formation de N-(buta-2,3-dién-1-yl)amides comme produits isolables. Le N-acyltriazène utilisé
`
comme coupleur sur la résine de Merrifield agit simultanément comme groupe protecteur pour l’amine primaire
nucléophile. La diversion des produits est obtenue en modifiant la nature du chlorure d’acyle utilisé dans l’acylation du
coupleur triazène. En plus d’être une nouvelle voie vers des allènes contenant de l’azote, notre méthode en phase solide
permet d’immobiliser ces diènes cumulés réactifs en vue d’opérations de synthèse ultérieures.
Mots-clés : allène, phase solide, Crabbé, homologation, propargylamine.
[Traduit par la Rédaction]
To the best of our knowledge, there are no reports about the
solid-phase synthesis of allenes. Rafai Far and Tidwell7 pre-
pared allenecarboxylic esters for ␤-ketoester equivalents by
the Wittig reaction, starting from ␣-haloacetates, which were
attached on soluble poly(ethylene glycol). On the other hand,
Ma et al.8,9 used 1,2-allenyl carboxylic acids in solution in a
palladium(0)-catalyzed cyclization reaction with polymer-
bound aryl iodides to give butenolides. The ␣-allenyl amine
derivatives of our interest have previously been synthesized in
solution, e.g., Casara et al.10 prepared a series of ␣-allenyl
amines from N-tert-butoxycarbonyl-protected propargylamines
by the Crabbé reaction for inhibition studies of pyridoxal-
phosphate-dependent enzymes. There are, however, no exam-
ples of the synthesis of simple N-(buta-2,3-dien-1-yl)
amides in the literature.
Introduction
Allenes as cumulated dienes are useful and versatile synthetic
intermediates in numerous synthetic applications, e.g., in gold-
catalyzed intramolecular hydroamination reactions1 and in pho-
toinduced [2 ϩ 2] cycloadditions with olefins.2 Moreover,
nitrogen-containing, such as amidomethyl-substituted, allenes
are useful building blocks in organic synthesis.3 Certain ami-
noallenes, such as 1-amino-2,3-butadiene, have been associ-
ated with monoamine oxidase B inhibition.4 Our continuing
interest in immobilizing amines onto solid support and
modifying them by carbon–carbon bond-forming reactions5
was the starting point for the study of the one-carbon homol-
ogation of solid-supported propargylamine. Keeping in mind
the easy nucleophilic attack of primary amines at the central
carbon atom of allenes, to give enamines,6 the general reac-
tivity and potent lability of cumulated carbon–carbon double
bonds make the synthesis and use of allenes sometimes chal-
lenging.
Owing to the sensitivity of these nitrogen-containing allenes,
the linker on the polymer must be stable enough during the
preparation and storage to serve simultaneously as the crucial
protective group. In addition, the cleavage step should be
Received 29 June 2012. Accepted 27 September 2012. Published at www.nrcresearchpress.com/cjc on 19 December 2012.
T. Leikoski, P. Wrigstedt, J. Matikainen, and J. Sipilä. Department of Chemistry, Laboratory of Organic Chemistry, P.O. Box 55
(A. I. Virtasen aukio 1), FI-00014 University of Helsinki, Finland.
J. Yli-Kauhaluoma. Faculty of Pharmacy, Division of Pharmaceutical Chemistry, P.O. Box 56 (Viikinkaari 5 E), FI-00014 University
of Helsinki, Finland.
Corresponding author: Tuomo Leikoski (e-mail: tuomo.leikoski@helsinki.fi).
This article is part of a Special Issue dedicated to Professor Derrick Clive.
Can. J. Chem. 90: 38–42 (2012)
doi:10.1139/cjc-2012-0255
Published by NRC Research Press

Leikoski et al.
39
Scheme 1. Loading of propargylamine to polystyrene through a
triazene linker. rt, room temperature.
performed fast and simply, under as mild conditions as possible.
The drawbacks of many cleavage procedures of amines are long
reaction times under relatively harsh conditions, such as 60%
trifluoroacetic acid (TFA) in dichloromethane11 or oxidation
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).12
These procedures would not be among the first desirable options
to choose. It would also be preferable if the allenes could be
cleaved as some less reactive derivatives of amines.
We decided to test the triazene linkage13 for immobilization
of propargylamine to fit the requirements mentioned previ-
ously. This linker is prepared from Merrifield resin-bound
3-aminophenol by diazotization and adding a primary amine to
the polymer-bound diazonium salt. The triazene moiety can be
acylated with acyl chlorides and it is cleavable as an amide,
with 5% TFA in CH2Cl2 at room temperature, within a few
minutes. These immobilized triazenes are remarkably stable at
room temperature under dry conditions and they are safe to
handle when compared with triazenes in solution, which are
potent carcinogens.14
In our studies with seven various polymer-bound acyltria-
zenes, the yield of allene from propargyl triazene resin varied
between 10% and 63%, depending on the N substituent (Ta-
ble 1). It is very likely that the allene formation is strongly
controlled by steric factors, because the best yields were
obtained with simple small-sized aliphatic N substituents,
acetyl, and pivaloyl groups. Otherwise, a yield significantly
higher than 11% of the electronically very similar
N-octanoyl-substituted product would have been expected.
However, although sterically crowded, the pivaloyl group is
apparently too short to reach the vicinity of the terminal
acetylene unit to interfere with the reaction. On the other
hand, the reactivity of the acryloyl group apparently sup-
presses the yield, despite its small size.
It must be pointed out that the yield of the isolated product
does not necessarily solely illustrate the success of the Crabbé
reaction on resin. Decomposition after the cleavage cannot be
excluded, despite the fast procedure (2 ϫ 15 min) and the
immediate neutralization of additional TFA using NaHCO3,
after filtering the resin off. This was very evident with the
N-2-phenylacetyl-substituted triazene resin, which gave, ac-
cording to 1H NMR, an approximate 1:1 mixture of the desired
allene and phenylacetic acid as the cleavage product. Decom-
position, although in this particular case probably independent
of the allene moiety, is understandable considering the easy
acidolysis of 2-phenylacetamide to phenylacetic acid.20 Ac-
cording to thin-layer chromatography, this allene product also
decomposes on silica gel.
For the allene formation we used the Crabbé reaction,15
which is a powerful method for homologation of terminal
alkynes. In the updated procedure, alkyne is heated with
paraformaldehyde, dicyclohexylamine, and copper(I) iodide in
1,4-dioxane at 100 °C.16 Since the reaction involves a Man-
nich base derived from acetylene, formaldehyde, and amine as
an intermediate, which turns to the allene via the copper-
mediated 1,5-hydride transfer, the use of a secondary amine is
necessary.15,17 Anhydrous conditions are essential. In compar-
ison, in a study by Bieber and da Silva,18 a series of terminal
alkynes was subjected to the related Mannich conditions in
aqueous dimethyl sulfoxide at 30 °C to give tertiary propar-
gylamines as products instead of allenes.
Results and discussion
We immobilized propargylamine on Merrifield resin
(Scheme 1) according to the known literature procedure for
primary amines,13 with minor modifications. In the attachment
of 3-aminophenol to the Merrifield resin, 5 mol % of cesium
iodide was added to increase the rate of the substitution
reaction. For the formation of diazonium salt from polymer-
bound 3-aminophenol, isopentyl nitrite was used instead of
tert-butyl nitrite. This three-step transformation was a reliable
method and easy to reproduce. The intermediate orange (deep
carmine-red with solvent) polymer-bound diazonium salt is
relatively stable to air and safe to handle. The air-stable
brown-orange (deep orange-red with solvent) propargyltria-
zene resin is formed by the addition of propargylamine to the
polymer-bound diazonium salt in dry tetrahydrofuran (THF) at
room temperature.
We studied the stability of the isolated and purified N-4-
nitrobenzoyl-substituted allene by dissolving a sample to 5%
TFA in CDCl3 and monitoring the content by 1H NMR for 24 h
(27 °C, 8 h; and 21 °C, 16 h). A little surprisingly, the product
was totally intact despite this prolonged acidic treatment, dem-
onstrating its stability in mild acidic conditions. Thus, we assume
that the cleavage with 5% TFA in CH2Cl2 is not the origin of
decomposition or suppression of the yields, except with the
previously mentioned N-2-phenylacetyl derivative.
To broaden the product diversity and to improve the stabil-
ity, the NH group of the triazene moiety was acylated with
various acyl chlorides13 prior to the Crabbé reaction and
cleavage (Scheme 2). At this stage, the order of introduction of
the reagents into the reaction medium is particularly impor-
tant. Triethylamine must be added before the acyl chloride to
maintain a basic solution phase throughout the reaction. Acyl
chlorides alone cleave the extremely acid-labile triazene,19
liberating propargylamine as an amide into the solution. In
fact, we observed that the triazene linker is cleaved by far
more dilute TFA concentrations than 5% in CH2Cl2, so acidic
contamination must be excluded in all operations.
The N-(buta-2,3-dien-1-yl)amides generally appeared to be
fairly stable when stored below –18 °C under argon and protected
from light. The compounds could be characterized unambigu-
ously with very distinct allenic traces at 1950–1960 cm–1 by
FT-IR, and 4.7–4.9 ppm (td) and 5.1–5.4 ppm (quint) by
1H NMR. The CH2, CH, and central carbon atom signals were
also distinct at 78, 87–88, and 208 ppm, respectively, by 13C
NMR. However, a small amount of aliphatic polymers appeared
in most products, according to signals in the 1H and 13C NMR, at
around 0.8–2.2 and 20–30 ppm, respectively, demonstrating
slow decomposition. Despite this, considering the treatment
of the previously mentioned N-phenylacetyl derivative,
Published by NRC Research Press

40
Can. J. Chem. Vol. 90, 2012
Scheme 2. N-Acylation and the allene formation from the propargyltriazene resin. rt, room temperature.
Table 1. Yields of isolated
N-(buta-2,3-dien-1-yl)amides obtained with
various acyl chlorides.
molecular sieves. Dicyclohexylamine was dried with activated
3 Å molecular sieves. Otherwise, commercial grade reagents
and solvents were used without further purification or drying.
Merck aluminium sheets coated with silica gel 60 F254 were
used for thin-layer chromatography and they were visualized
by UV light at 254 nm or by brief heating at 120 °C, after
wetting with 0.4 mol/L vanilline solution in H2SO4/ethanol
(1:100, v/v). Column chromatography was performed with
Fluka silica gel 60, 230–400 mesh. 1H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, on a Varian
Mercury 300 Plus spectrometer. Chemical shifts are relative to
the residual solvent signal 7.26 ppm of CDCl3 in the 1H
spectra and to the NMR solvent signal 77.2 ppm for CDCl3 in
the 13C spectra. FT-IR spectra were recorded on a PerkinElmer
Spectrum One FT-IR spectrometer equipped with a one re-
flection attenuated total reflection (ATR) unit. Melting points
were obtained with an Electrothermal melting point apparatus
(Cat. No. IA6301) and they are uncorrected. High-resolution
(HR) electron impact (EI) mass spectrometry (MS) analyses
were performed using a Jeol JMS-700 mass spectrometer at
700 eV.21 GC–MS analyses were performed using an Agilent
6890N gas chromatograph equipped with a DB-1MS capillary
column (34.0 m ϫ 250 ␮m ϫ 0.25 ␮m; calibrated) and
Agilent 5973 Network mass-selective detector.
Entry
R in RCOCl
Yield (%)
1
2
3
4
5
6
7
CH3
CMe3
PhCH2
4-NO2–C6H4
(E)-Ph–CHϭCH
CH2ϭCH
CH3(CH2)6
63
53
10
13
20
18
11
upon isolation (see the Experimental section) it is evident
that these allenes can tolerate even water for short periods.
Conclusion
We have developed a solid-phase method that introduces
new possibilities in the syntheses of biologically active ni-
trogen-containing allenes. All reagents required in our reaction
sequence are inexpensive and the final products are afforded
by a cleavage reaction under very mild conditions. Although
the yields of the isolated products in this preliminary study are
moderate, our method enables access to N-(buta-2,
3-dien-1-yl)amides, demonstrated by seven new characterized
compounds. Owing to the versatility of allenes as synthetic
intermediates, the possibility of immobilizing potentially la-
bile cumulated carbon–carbon double bonds on solid support
for further reactions is even more interesting. Hence, our
solid-phase method introduces interesting possibilities for new
applications.
Loading of propargylamine to polystyrene through a
triazene linker
Dry DMF (13 mL/g resin) was added to a mixture of the
Merrifield resin (loading: 0.64 mmol/g), sodium hydride as a
dispersion with mineral oil (~50%, 5 equiv), and cesium
iodide (0.05 equiv) under argon. 3-Aminophenol (5 equiv) in
dry DMF (4 mL/g) was slowly added at 0 °C and the mixture
was stirred at room temperature for 23 h. The resin was
filtered, washed three times (3 ϫ 3 mL/g resin) with each of
THF, MeOH, and CH2Cl2, and dried fast in high vacuum. Dry
THF (9 mL/g resin) was added and the mixture was cooled
under argon to –22 °C by means of EtOH / dry ice. After that,
BF3·Et2O (8 equiv) was added, followed after 5 min by isopen-
tyl nitrite (8 equiv). The mixture was stirred for 30 min in an
EtOH / dry ice bath, filtered, and washed four times (4 ϫ
3 mL/g resin) with cold THF. Dry THF (9 mL/g resin) and
propargylamine (10 equiv) were added and the mixture was
stirred at room temperature for 20 h under argon. After the
addition of methanol/THF (1:1, v/v; 3 mL/g resin), the mixture
was filtered, washed three times (3 mL/g resin) with each of
THF, MeOH, and CH2Cl2, and dried in vacuo to constant
Experimental
General
Reagents were obtained from Sigma-Aldrich, Fluka, Acros,
Riedel-de Haën, and Merck. Merrifield resin (loading:
0.64 mmol/g, 200–400 mesh, cross-linked with 1% divinyl-
benzene) was commercially available from Novabiochem. The
yields are based on the actual loading of 0.59 mmol/g of the
propargyltriazene resin. N,N-Dimethylformamide (DMF) was
dried by distillation from anhydrous CaSO4 under reduced
pressure. THF and 1,4-dioxane were dried by distillation from
sodium or with activated 3 Å molecular sieves. Triethylamine
was dried by distillation from P2O5 or with activated 3 Å
Published by NRC Research Press

Leikoski et al.
41
weight, which is in agreement with the quantitative attachment
of propargylamine, with a new loading of 0.59 mmol/g. The
resin was stored in a desiccator at room temperature.
oil (48.0 mg, 53%). Rf ϭ 0.41 (EtOAc–n-hexane, 1:1/
vanilline–H2SO4). IR (ATR, cm–1): 705, 845, 1166, 1201,
1525, 1641, 1959, 2963, 3342. 1H NMR (300 MHz, CDCl3) ␦:
1.21 (s, 9H), 3.84 (m, 2H), 4.88 (td, J ϭ 3.5, 6.9 Hz, 2H), 5.24
(quint, J ϭ 6.0 Hz, 1H), 6.05 (br s, 1H). 13C NMR (75 MHz,
CDCl3) ␦: 27.6, 37.4, 38.9, 78.2, 88.2, 179.1, 207.9. HR-MS
calcd for C9H15NO: 153.11536; found: 153.1146.
General procedure for the N-acylation and the allene
formation from the propargyltriazene resin
Propargyltriazene resin (1.0 g, 0.59 mmol/g) was swollen
in 10 mL of dry THF. A catalytic amount of 4-dimethyl-
aminopyridine (DMAP) and 1.0 mL of dry triethylamine were
added, followed by 5–7 equiv of the acyl chloride under
stirring. The mixture was stirred at room temperature for
21–24 h. The resin was filtered and washed twice (2 ϫ 10 mL)
with each of DMF, MeOH, THF, diethyl ether, and CH2Cl2,
and introduced directly into the allene formation reaction. The
resin, 5–6 equiv of paraformaldehyde, 0.5–0.6 equiv of CuI,
and 2 equiv of dicyclohexylamine, in 5.0–10 mL of dry
1,4-dioxane, were stirred under argon at 100 °C for 20–22 h.
The resin was filtered, washed twice (2 ϫ 10 mL) with each of
1,4-dioxane, n-hexane, THF, diethyl ether, and CH2Cl2, and
subjected to the cleavage step.
N-(Buta-2,3-dien-1-yl)-2-phenylacetamide (3)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
phenylacetyl chloride (0.50 mL, 580 mg, 3.8 mmol) for 24 h
according to the general procedure. The allene formation was
achieved by reaction with paraformaldehyde (106 mg,
3.53 mmol CH2O), CuI (64.3 mg, 0.338 mmol), and dicyclo-
hexylamine (213 mg, 1.17 mmol) for 23 h. The product was
cleaved (general procedure) and dried in vacuo. The oily
residue was dissolved in chloroform, ~1 mL of triethylamine
was added (removal of phenylacetic acid), the solution was
filtered through a small plug of NaHCO3, and the solvents
were evaporated. The residue was dissolved in chloroform and
ethyl acetate and washed twice with water. The organic phase
was evaporated twice with acetone, and the product was dried
in vacuo. Brown oil (11.4 mg, 10%). Rf ϭ 0.0 (dec.; EtOAc–
n-hexane, 1:1/UV). IR (ATR, cm–1): 696, 719, 847, 1539,
General procedure for the cleavage of the N-acylated
allene product
The polymer-bound N-acylated allene product was double-
cleaved by stirring the resin twice in 5% trifluoroacetic acid in
dichloromethane (10 mL) at room temperature for 15 min.
After both treatments, the resin was filtered and washed (1 ϫ
10 mL) with each of CH2Cl2, diethyl ether, and CH2Cl2. The
filtrates were immediately neutralized with solid NaHCO3
(2.0 g), and the solvents were evaporated. The allene product
was purified by flash chromatography if necessary or applica-
ble and stored in a freezer, under argon and protected from
light.
1
1647, 1957, 2929. H NMR (300 MHz, CDCl3) ␦: 3.59 (s,
2H), 3.80 (m, 2H), 4.73 (td, J ϭ 3.4, 6.8 Hz, 2H), 5.15 (quint,
J ϭ 6.1 Hz, 1H), 5.52 (br s, 1H), 7.22–7.39 (m, 5H). 13C NMR
(75 MHz, CDCl3) ␦: 37.4, 43.9, 78.1, 88.0, 127.6, 129.2,
129.8, 134.8, 171.1, 207.7. HR-MS calcd for C12H13NO:
187.09971; found: 187.0990.
N-(Buta-2,3-dien-1-yl)-4-nitrobenzamide (4)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
4-nitrobenzoyl chloride (659 mg, 3.55 mmol) for 24 h accord-
ing to the general procedure. The allene formation was
achieved by reaction with paraformaldehyde (89.5 mg,
2.98 mmol CH2O), CuI (60.2 mg, 0.316 mmol), and dicyclo-
hexylamine (218 mg, 1.20 mmol) for 21 h. The product was
cleaved (general procedure) and dried in vacuo. Column chro-
matography on SiO2 (acetone–CHCl3, 1:10) gave the product.
Yellow crystals (17.1 mg, 13%; CHCl3), mp 119–122 °C.
Rf ϭ 0.36 (EtOAc–n-hexane, 1:1/UV). IR (ATR, cm–1): 686,
707, 861, 1349, 1510, 1598, 1638, 1955, 3287, 3329. 1H NMR
(300 MHz, CDCl3) ␦: 4.07 (m, 2H), 4.92 (td, J ϭ 3.4, 6.7 Hz,
2H), 5.35 (quint, J ϭ 6.2 Hz, 1H), 6.38 (br s, 1H), 7.93 (d,
J ϭ 8.9 Hz, 2H), 8.28 (d, J ϭ 8.9 Hz, 2H). 13C NMR (75 MHz,
CDCl3) ␦: 38.2, 78.4, 87.8, 124.0, 128.3, 140.2, 149.8, 165.4,
208.2. HR-MS calcd for C11H10N2O3: 218.06914; found:
218.0704.
Syntheses of N-(buta-2,3-dien-1-yl)amides (1–7)
1H NMR and 13C NMR spectra for compounds 1–7 are
available in the Supplementary data.
N-(Buta-2,3-dien-1-yl)acetamide (1)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
acetyl chloride (0.30 mL, 330 mg, 4.2 mmol) for 22 h accord-
ing to the general procedure (without DMAP). The allene
formation was achieved by reaction with paraformaldehyde
(95.0 mg, 3.16 mmol CH2O), CuI (59.2 mg, 0.311 mmol), and
dicyclohexylamine (226 mg, 1.25 mmol) for 20 h. The product
was cleaved (general procedure) and dried in vacuo. Yellow-
brown oil (41.0 mg, 63%). Rf ϭ 0.07 (EtOAc–n-hexane,
1:1/vanilline–H2SO4). IR (ATR, cm–1): 705, 798, 849, 1152,
1
1548, 1647, 1959. H NMR (300 MHz, CDCl3) ␦: 2.07 (s,
3H), 3.86 (m, 2H), 4.87 (td, J ϭ 3.3, 6.5 Hz, 2H), 5.21 (quint,
J ϭ 6.3 Hz, 1H), 6.05 (br s, 1H). 13C NMR (75 MHz, CDCl3)
␦: 22.8, 38.1, 78.2, 87.3, 172.2, 208.2. GC–MS (m/z): 111,
110, 72, 70, 69, 68, 43, 32, 30, 28 (100%), 18.
N-(Buta-2,3-dien-1-yl)cinnamamide (5)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
cinnamoyl chloride (predominantly E isomer; 605 mg,
3.63 mmol) for 24 h according to the general procedure. The
allene formation was achieved by reaction with paraformalde-
hyde (100 mg, 3.33 mmol CH2O), CuI (67.5 mg, 0.354 mmol),
and dicyclohexylamine (223 mg, 1.23 mmol) for 22 h. The
product was cleaved (general procedure) and dried in vacuo.
Column chromatography on SiO2 (n-hexane to EtOAc–n-
hexane, 2:3) gave the product. Pale yellow solid (23.0 mg,
20%; CHCl3), mp 70–71 °C. Rf ϭ 0.33 (EtOAc–n-hexane,
1:1/UV). IR (ATR, cm–1): 674, 727, 853, 971, 1222, 1343,
N-(Buta-2,3-dien-1-yl)pivalamide (2)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
pivaloyl chloride (0.50 mL, 490 mg, 4.1 mmol) for 21 h
according to the general procedure. The allene formation was
achieved by reaction with paraformaldehyde (99.2 mg,
3.30 mmol CH2O), CuI (56.4 mg, 0.296 mmol), and dicyclo-
hexylamine (221 mg, 1.22 mmol) for 20 h. The product was
cleaved (general procedure) and dried in vacuo. Yellow-brown
Published by NRC Research Press

42
Can. J. Chem. Vol. 90, 2012
1552, 1610, 1655, 1952, 3246. 1H NMR (300 MHz, CDCl3) ␦:
3.99 (m, 2H), 4.86 (td, J ϭ 3.3, 6.5 Hz, 2H), 5.28 (quint, J ϭ
6.3 Hz, 1H), 6.01 (br s, 1H), 6.43 (d, J ϭ 15.6 Hz, 1H),
7.29–7.39 (m, 3H), 7.44–7.53 (m, 2H), 7.63 (d, J ϭ 15.6 Hz,
1H). 13C NMR (75 MHz, CDCl3) ␦: 37.9, 77.8, 88.0, 120.6,
127.9, 128.9, 129.8, 134.9, 141.3, 165.9, 208.2. HR-MS calcd
for C13H13NO: 199.09971; found: 199.0994.
the Academy of Finland, Drug Discovery and Development
Technology Center (DDTC) research programme of the Uni-
versity of Helsinki, and the Finnish Work Environment Fund.
We thank Dr. A.W.T. King for reviewing the language.
References
(1) Morita, N.; Krause, N. Org. Lett. 2004, 6 (22), 4121. doi:
10.1021/ol0481838.
N-(Buta-2,3-dien-1-yl)acrylamide (6)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
acryloyl chloride (0.30 mL, 330 mg, 3.6 mmol) for 23 h
according to the general procedure. The allene formation was
achieved by reaction with paraformaldehyde (112 mg,
3.73 mmol CH2O), CuI (57.8 mg, 0.303 mmol), and dicyclo-
hexylamine (222 mg, 1.22 mmol) for 21 h. The product was
cleaved (general procedure) and dried in vacuo. Column chro-
matography on SiO2 (n-pentane to acetone–n-pentane, 1:4)
gave the product. Pale yellow oil (13.0 mg, 18%). Rf ϭ 0.20
(EtOAc–n-hexane, 1:1/vanilline–H2SO4). IR (ATR, cm–1):
720, 730, 1240, 1463, 1660, 1739, 1958, 2849, 2917. 1H NMR
(300 MHz, CDCl3) ␦: 3.94 (m, 2H), 4.86 (td, J ϭ 3.4, 6.7 Hz,
2H), 5.26 (quint, J ϭ 6.3 Hz, 1H), 5.65 (dd, J ϭ 1.4, 10.2 Hz,
1H), 5.66 (br s, 1H), 6.09 (dd, J ϭ 10.1, 17.1 Hz, 1H), 6.29
(dd, J ϭ 1.4, 16.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) ␦:
37.9, 78.1, 87.5, 127.5, 130.4, 166.4, 208.2. GC–MS (m/z):
123, 122, 94, 84, 70, 69, 55 (100%), 32, 28, 18.
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N-(Buta-2,3-dien-1-yl)octanamide (7)
Propargyltriazene resin (1.0 g, 0.59 mmol) was treated with
n-octanoyl chloride (0.50 mL, 480 mg, 3.0 mmol) for 17 h
according to the general procedure. The allene formation was
achieved by reaction with paraformaldehyde (95.0 mg,
3.16 mmol CH2O), CuI (56.9 mg, 0.299 mmol), and dicyclo-
hexylamine (216 mg, 1.19 mmol) for 22 h. The product was
cleaved (general procedure) and dried in vacuo. Column chro-
matography on SiO2 (n-hexane to EtOAc–n-hexane, 1:1) gave
the product. Yellow oil (13.0 mg, 11%). Rf ϭ 0.33 (EtOAc–
n-hexane, 1:1/vanilline–H2SO4). IR (ATR, cm–1): 843, 1544,
1644, 1959, 2925, 3286. 1H NMR (300 MHz, CDCl3) ␦: 0.87
(t, J ϭ 6.9 Hz, 3H), 1.15–1.39 (m, 8H), 1.52–1.72 (m, 2H),
2.17 (t, J ϭ 7.6 Hz, 2H), 3.85 (m, 2H), 4.84 (td, J ϭ 3.4,
6.7 Hz, 2H), 5.22 (quint, J ϭ 6.3 Hz, 1H), 5.57 (br s, 1H).
13C NMR (75 MHz, CDCl3) ␦: 14.2, 22.7, 25.9, 29.2, 29.4,
31.8, 36.9, 37.5, 77.8, 88.3, 173.1, 208.1. HR-MS calcd for
C12H21NO: 195.16231; found: 195.1628.
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Supplementary data
Supplementary data (1H NMR and 13C NMR spectra for
compounds 1–7) are available with this article through the
journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2012-0255.
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(21) HR-MS analysis was preferred over elemental analysis for
these relatively labile allenes. Our attempts to obtain HR-MS
spectra of the acetyl- and acryloyl-substituted products (Ta-
ble 1, entries 1 and 6) failed because of their high volatility
in the prevacuum of the mass spectrometer. However,
GC–MS and 1H and 13C NMR data are fully unambiguous
with the structures shown.
Acknowledgement
This research has been financially supported by TEKES (the
Finnish Funding Agency for Technology and Innovation),
Juvantia Pharma Ltd., Orion Corporation, Hormos Medical,
Published by NRC Research Press