A direct synthesis of trisubstituted allenes from propargyl alcohols via oxaphosphetane intermediates

Article abstract of DOI:10.1246/bcsj.20170372

A direct synthetic method for trisubstituted allenes from propargyl alcohol is provided; the synthesis proceeds via an oxaphosphetane intermediate. Functional groups such as for-myl and pyridyl exhibited a degree of tolerance during reaction without any protection. The alcohol dimethylated at the propargyl position afforded two structural isomers, allene and 1,3-diene. The product ratio was considerably influenced by the solvent. Allene was predominantly obtained when the reaction was conducted in cyclohexane, and the ratio was inverted by changing the solvent to dichloromethane. The prepared (2-pyridyl)allene served as a substrate for the copper(I) catalyzed cyclization reaction to afford 3,3-dimethylindolizine-2-one.

Full text of DOI:10.1246/bcsj.20170372

Advance Publication Cover Page
A Direct Synthesis of Trisubstituted Allenes from Propargyl Alcohols
via Oxaphosphetane Intermediates
Kento Iwai, Soichi Yokoyama, Haruyasu Asahara, and Nagatoshi Nishiwaki*
Advance Publication on the web December 4, 2017
doi:10.1246/bcsj.20170372
© 2017 The Chemical Society of Japan

A Direct Synthesis of Trisubstituted Allenes from Propargyl Alcohols via
Oxaphosphetane Intermediates
Kento Iwai,1 Soichi Yokoyama,1,2 Haruyasu Asahara,1,2,3 and Nagatoshi Nishiwaki*1,2
1
School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
2
Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
3Department of Applied Chemistry, Faculty of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
Nagatoshi Nishiwaki
Nagatoshi Nishiwaki received his Ph. D. in 1991 from Osaka University. He worked at Professor Ariga’s group in
Department of Chemistry, Osaka Kyoiku University as assistant professor (1991-2000) and as associate professor
(2001-2008). From 2000 to 2001, he joined to Karl Anker Jørgensen’s group at Århus University in Denmark. He
worked at Center for Collaborative Research, Anan National College of Technology as associate professor from 2008
to 2009. Then, he moved to School of Environmental Science and Engineering, Kochi University of Technology in
2009, and he is a professor from 2011. His research interests comprise synthetic organic chemistry using nitro
compounds, heterocycles (synthesis, ring transformation, 1,3-dipolar cycloaddition, application as tools in organic synthesis),
pseudo-intramolecular reaction, and solid supported palladium catalysts.
Abstract
A direct synthetic method for trisubstituted allenes from
allenes. As an alternative approach, transition-metal-catalyzed
synthesis is also developed, however, the products are
sometimes contaminated with intrinsically toxic and expensive
transition metals (Eq. 5).2,7
propargyl alcohol is provided; the synthesis proceeds via an
oxaphosphetane intermediate. Functional groups such as formyl
and pyridyl exhibited a degree of tolerance during reaction
without any protection. The alcohol dimethylated at the
propargyl position afforded two structural isomers, allene and
1,3-diene. The product ratio was considerably influenced by the
solvent. Allene was predominantly obtained when the reaction
was conducted in cyclohexane, and the ratio was inverted by
changing the solvent to dichloromethane. The prepared
(2-pyridyl)allene served as a substrate for the copper(I)
Additionally, allenes are also prepared by the Wittig
reaction via the oxaphosphetane intermediate (Scheme 2).2,8 In
this reaction, unstable ketenes and reactive phosphine ylide
should be used under basic conditions, which prevents the
practical use of this method. In other words, allenes are
promisingly synthesized if oxaphosphetane is constructed by an
alternative method. From this viewpoint, we paid attention to
propargyl alcohol because the oxygen atom and an electrophilic
triple bond are considered to form an oxaphosphetane
framework upon treatment with an oxaphilic and nucleophilic
phosphine. Although there are numerous reports on the
preparation of allenes, this protocol has not been reported
except for only a few descriptions with a limited substrate
scope.8 These circumstances prompted us to study this reaction
in detail, and functionalized allenes could be successfully
prepared directly from propargyl alcohol under mild conditions
even in the absence of a transition metal.
catalyzed
cyclization
reaction
to
afford
3,3-dimethylindorizine-2-one.
1. Introduction
The allene framework is often found as an important
motif in natural products, and substituted allenes have been
recognized as useful building blocks for construction of both
carbo- and heterocyclic systems.1 Many synthetic protocols for
allenes have been developed, among which chemical
transformations from readily available propargyl alcohols are
commonly used methods (Scheme 1). The nucleophilic
substitution of the hydroxy group in SN2’ fashion is the most
common method for preparing substituted allenes, in which the
hydroxy group is converted to ester function for a better
elimination (Eq. 1).2,3 In the case of neutral nucleophiles, the
generation of a propargylic cation is effective upon treatment of
propargyl alcohol with a Lewis acid (Eq. 2).2,4 The migration of
the heteroatoms or hydrogen is also acceptable.
O-Phosphinylated- or O-sulfenylated propargyl alcohol
facilitates the introduction of a heteroatom into the allene
framework (Eq. 3).2,5 Moreover, sulfonylhydrazine prepared by
the Mitsunobu reaction furnished trisubstituted allenes as a
result of 1,5-hydrogen shift (Eq. 4).2,6 Although these protocols
are certainly useful methods, additional experimental
manipulations or the use of highly reactive regents are required,
which sometimes prevent the synthesis of functionalized
2. Results and Discussion
When propargyl alcohol 1a was allowed to react with
tributylphosphine in toluene at room temperature for 1 d, the
desired allene 2a was obtained in 48% yield (Table 1, Entry 1).
The structure of 2a was confirmed by observing the
characteristic signal for the cumulene carbon at 200 ppm in the
13C NMR spectrum. In this reaction, 1,3-diene 3a9 was also
isolated in 17% yield. Although products 2a and 3a are
structural isomers, interconversion between 2a and 3a did not
occur upon treatment with tributylphosphine under the same
conditions. Therefore, each product was formed through
different reaction paths.

Nu
Nu
Nu
NuH
YCl
R1
R1
R3
(1)
•
OY
R3
Y = RCO, RSO2
R2
R2
NuH
NuH
Lewis Acid
R1
R3
R1
R3
•
(2)
R2
R2
R1
P(O)R2 or S(O)R
R2PCl or RSCl
OH
R3
R1
PR2 or SR
(3)
R1
R3
•
O
R2
R2
R3
R2
ArSO2NHNH2
DEAD, PPh3
H
H
R1
NH
N
R1
R3
(4)
(5)
•
SO2Ar
R2
R3
R2
R
R1
R
R-Y
R3
M OH
R1
•
M = Mn, Cu, Zr
Pd, Au
Y = Bpin, MgCl, ZnR
R3
R2
R2
Scheme 1. Synthetic methods of allenes starting from propargyl alcohols
Wittig Reaction
R1
R3
R1
R2
R3
Oxygen
• O
Oxaphilic
PR'3
+
R2
•
R3
PR'3
O
R1
Nucleophilic
Electrophilic
O=PR'3
R2
Oxaphosphetane
This work
Ar
Oxygen
Ar
PR'3
OH
Ar
R
PR'3
+
R
O
Nucleophilic
Oxaphilic
Electrophilic
R
R
R
R
O=PR'3
Scheme 2. Synthetic strategy of allenes via an oxaphosphetane intermediate

yield decreased (Entry 3). This disadvantage was overcome by
conducting the reaction over a longer period of time, which
afforded allene 2a with 58% yield and 92% selectivity (Entry
4). However, triphenylphosphine caused no reaction even at
100 °C, which is presumably due to the steric hindrance (Entry
5).
The product ratio 2a/3a was considerably affected by the
solvent (Table 1). When the reaction was conducted in
non-polar solvents such as toluene, hexane, cyclohexane, and
diethyl ether, allene 2a was predominantly formed (Entries
1–4), and yield and selectivity of allene 2a increased up to 70%
and 83%, respectively, when cyclohexane was employed as a
solvent (Entry 3). Notably, the ratio was inverted when the
reaction was conducted in ethyl acetate or in a halogenated
solvent such as dichloroethane and dichloromethane (Entries
5–7).
Table 3. Synthesis of other allene derivatives 2
PBu3
(1.0 equiv.)
Ar
R2
Ar
OH
Table 1. Study on solvents
c-Hex
1 d
R1
R1
R2
Ar
PBu3
OH
Me
(1.0 equiv.)
1
2
Me
Solv.
rt, 1 d
Temp. Yield
(°C)
60
Entry
Ar
R1
R2
(%)
0
0
14
14
34
37
50b
cmc
cmc
1a Ar = 4-NO2C6H4
Ar
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-MeC6H4
4-CF3C6H4
4-HCOC6H4
4-HCOC6H4
2-Pyridyl
4-NO2C6H4
4-NO2C6H4 Ph(CH2)2
4-NO2C6H4
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Ph
b
b
c
d
d
e
f
g
h
100
100
60
Ar
Me
Me
100a
60
Me
60
rt
rt
2a
3a
H
H
Yield (%) Ratio
Recovery of
1a (%)
H
Entry
Solvent
2a
48
57
70
64
27
3a
17
18
14
22
47
43
69
2a/3a
74/26
76/24
83/17
75/25
36/64
26/74
20/80
a
b
For
4
h.
The yield was determined by 1H NMR using
1
2
3
4
5
6
7
PhMe
Hexane
c-Hexa
Et2O
18
6
6
c
1,1,2,2-tetrachloroethane as an internal standard. A complex mixture was
obtained.
9
EtOAc
ClCH2CH2Cl 15
14
20
11
Table 4. Synthesis of monosubstituted allenes
Ar
CH2Cl2 17
PPh3 (1.0 equiv.)
a Cyclohexane
OH
Solv.
H
H
Temp., 1 d
Table 2. Study on phosphines
1
O
PR3
(1.0 equiv.)
H
Ar
Ar
Ar
1a
2a
3a
H
c-Hex
60 °C
2
4
Yield (%)
Ratio
Time
Yield (%)
Temp.
(°C)
60
60
60
Entry
PR3
(h)
2a
PBu3
Entry
Ar
Solv.
2
4
3a
15
17
3
2a/3a
82/18
80/20
93/7
92/8
—
1
2
3
4
5
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-HCOC6H4
h
c-Hexa
PhMe
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0
42
1
2
3
4
5
5
5
5
24
5
69
68
40
58
0
h
h
h
i
trace 52
PEt2Ph
PEtPh2
PEtPh2
24
36
30
0
0
0
100
100
5
0
a
PPh3
a Cyclohexane
aAt 100 °C
Synthesis of other allene derivatives 2b–h was studied
The reaction time could be shortened by conducting the
reaction at 60 °C (Table 2, Entry 1). Thereafter, several kinds of
phosphines were surveyed. Diethylphenylphosphine showed
similar reactivity to tributylphosphine to afford allene 2a
(Entries 1 and 2). To our delight, ethyldiphenylphosphine
considerably increased the selectivity of allene 2a, although the
under the optimized conditions in hand (Table 3). In each
reaction, the formation of diene 3 was not observed. In the case
of electron-rich propargyl alcohol 1b, no reaction occurred due
to the low electrophilicity of the ethynyl group even at 100 °C,
which prevented the initial addition of a phosphine (Entries 1

and 2). However, electron-poor propargyl alcohols 1c–e
underwent a reaction to afford the corresponding allenes 2c–e
possessing a functional group such as 4-trifluoromethylphenyl,
4-formylphenyl, and 2-pyridyl group (Entries 2–6). It is
noteworthy that the highly reactive formyl group of 1d exhibits
a degree of tolerance during the reaction without any protection
in a single step. It was possible to modify the substituents at the
propargyl position, and triarylated allene 2f could be
synthesized when diphenyl substituted alcohol 1f was used
(Entry 7). However, propargyl alcohols 1g and 1h yielded only
a complicated mixture due to side reactions under the employed
conditions (Entries 8 and 9). Since the formed allenes 2g and
2h are highly reactive, they underwent the further reactions
with reactive tributylphosphine.
proceeded to afford allyl propargyl ether 4h (Entries 1 and 2).
This undesired dimerization was suppressed by conducting the
reaction in the polar solvent, 1,4-dioxane, to afford allene 2h,10
which resulted in an increase to the yield at higher temperatures
(Entries 3 and 4). This method was applicable to alcohol 1i,
leading to the formation of formyl substituted allene 2i10
without detectable dimer 4i (Entry 5).
To realize the role of the hydroxy group in this reaction,
O-methylated substrate 5 was employed (Scheme 3). When
propargyl ether 5 was heated with triphenylphosphine (x = 0),
no reaction was observed at all, which indicates that the
hydroxy group is crucial for the formation of allene 2.
Furthermore, ether 5 was quantitatively recovered even when
the reaction was conducted in the presence of propargyl alcohol
1j (x = 1), and the corresponding allyl propargyl ether 4j was
not detected. The hydroxy group was found to be also
necessary for the formation of ether 4.
In order to synthesize monosubstituted allene by this
protocol, reaction conditions were investigated using 1h as a
model substrate and by using less reactive triphenylphosphine
instead of tributylphosphine (Table 4). When the reaction was
conducted at 60 °C, dimerization of 1h predominantly
1j
OH
(x equiv)
O
OMe
H
PPh3 (1.0 equiv.)
PhMe
100 °C, 1 d
(X = 0 or 1)
O2N
H
O2N
O2N
5
2h (0%)
4j (0%)
Scheme 3. Study on the hydroxy group propargyl alcohols 1 by the reaction using O-methylated substrate 5
Ar
PBu3
O
Ar
R2
a
R1
R2
R1
R1
R2
H
O
Bu3P=O
H
O
Ar
Ar
Ar
7
2
b
PBu3
a
R2
R1
OPrg
OPrg
Bu3P
b
R1
O
PBu3
PBu3
O
R2
Ar
Ar
1 (PrgOH)
6
H
O
R1
R2
R1
R2
8
9
OPrg
Ar
O
R1, R2 = H
Ar
Ar
PBu3
PrgO
Ar
R1
O
R1 R2
R2
Bu3P=O
4
4
10
R1, R2 = Me
Ar
Ar
PrgO
Me
H
PrgOH 1
Me
3
Scheme 4. A plausible mechanism for formation of 2, 3 and 4

On the basis of these results, a plausible mechanism for
the formation of allene 2 and 1,3-diene 3 is proposed (Scheme
4). This reaction was initiated by nucleophilic attack of a
phosphine to the alkynyl moiety to afford betaine intermediate
6 (route a), which serves as a common intermediate for all
products. Adding anionic oxygen to phosphonium moiety
affords oxaphosphetane 7, from which phosphine oxide is
eliminated leading to allene 2. However, when alcohol 1
attacks 6, betaine 9 is formed via 8 (route b). After cyclization
of 9, elimination of phosphine oxide yields allyl propargyl ether
4 (R1, R2 = H) via oxaphosphetane 10. When substituents of 4
(R1 and R2) are methyl groups, deprotonation accompanied by
the elimination of alcohol 1, successively occurs to furnish
diene 3.
+
N
N
Me
Me
CuI
Me
CuI
Me
12
HO H
13
air
N
11
Me
Me
14
H
OH
In non-polar solvents, such as cyclohexane, betaine 6 is
not stabilized enough, which facilitates the intramolecular
cyclization prior to intermolecular addition of alcohol 1 to
afford allene 2 predominantly. When bulky phosphine is
employed, the approach of alcohol 1 to betaine 6’ was
prevented, which resulted in the predominant formation of
allene 2a via route a (Figure 1).
Scheme 6. A plausible mechanism for forming 11
3. Conclusion
We provided a direct synthesis of functionalized allenes 2
from easily available propargyl alcohols 1 upon treatment with
phosphine, which proceeded via oxaphosphetane intermediate.
This method does not require the use of any transition metal,
thereby avoiding the contamination of the products. Moreover,
functional groups such as trifluoromethyl, formyl and pyridyl
groups exhibited a degree of tolerance during the reaction
without any protection. These features are advantageous for
practical use.
In addition to allenes 2, electron-deficient diene 3a and
allyl propargyl ether 4h were also formed. These products
could be synthesized with high selectivity by changing the
solvents. Furthermore, indolizinone 11 was synthesized from
pyridylallene 2e by copper-catalyzed cyclization.
PrgO H 1
Ph
Ph
Et
Ar
Prg-OH:
P
OH
R2
Ar
Me
R1
O
Me
1
6'
Figure 1. Effect by the substituents of the phosphine
This method facilitates the synthesis of functionalized
allenes 2, among which pyridylallene 2e served as a precursor
of indolizinone 11.11 When a solution of 2e in acetonitrile was
stirred at room temperature for 1 day in the presence of
copper(I) iodide, copper–catalyzed cyclization readily
proceeded to afford indolizinone 11 with a moderate yield
(Scheme 5). Although other mechanism including radical
species is also possible, a plausible mechanism is shown in
Scheme 6. The activated allene moiety by copper is attacked by
the ring nitrogen to form a five-membered ring 13. After
protonation and hydroxylation by a water, the resultant 14 is
oxidized by air to afford indolizinone 11.
4. Experimental
General
The melting points were determined on SRS-Optimelt
Automated Melting Point System, and are uncorrected. All the
reagents and solvents were commercially available and used as
1
received. The H NMR spectra were measured on a Bruker
Ascend-400 at 400 MHz with tetramethylsilane as an internal
standard. The 13C NMR spectra were measured on a Bruker
Ascend-400 at 100 MHz, and assignments of 13C NMR spectra
were performed by DEPT experiments. The high-resolution
mass spectra were measured on an AB SCIEX Triple TOF 4600.
The IR spectra were recorded on a JASCO FT/IR-4200
spectrometer.
CuI
General method for preparation of allenes 2
(10 mol%)
N
N
To the suspension of propargyl alcohol 1a (41.0 mg, 0.2
mmol) in cyclohexane (2 mL), tributylphosphine (50 µL, 0.2
mmol) was added. A resultant mixture was stirred for 1 d at
room temperature, and the solvent was removed in vacuo. The
residue was subjected to silica gel column chromatography
(hexane/ethyl acetate = 95/5) to afford allene 2a (26.5 mg, 0.14
mmol 70%) as a pale-yellow oil.
MeCN,
rt, 20 h
Me
Me
O
Me
2e
Me
11 32%
Scheme 5. Synthesis of indolidinone 11 from
pyridylallene 2e
When other propargyl alcohols were used, the reaction
was conducted in a same way.
3-Methyl-1-(4-nitrophenyl)-1,2-butadiene (2a)
1
IR (ATR, cm-1) 1952, 1517, 1340; H NMR (CDCl3, 400

MHz) d 8.13 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 6.05
(sep, J = 2.8 Hz, 1H), 1.85 (d, J = 2.8 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 205.4 (C), 146.1 (C), 143.4 (C), 126.9
(CH), 123.9 (CH), 100.4 (C), 91.7 (CH), 19.9 (CH3); HRMS
(ESI-TOF) m/z [M+Na]+ Calcd for C11H11NNaO2 212.0682;
found 212.0675.
162.0913; found 162.0908.
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(2c)
Colorless oil. IR (ATR, cm-1) 1955; 1H NMR (CDCl3, 400
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(CH), 125.3 (CH), 124.2 (q, JC-F = 269.8 Hz), 99.8 (C), 91.8
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C12H11F3K 251.0444; found 251.0447.
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3.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d 205.0 (C), 191.6
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3-Methyl-1-(2-pyridyl)-1,2-butadiene (2e)
1
Pale-yellow oil. IR (ATR, cm-1) 1958; H NMR (CDCl3,
400 MHz) d 8.43 (br d, J = 4.8 Hz, 1H), 7.50 (ddd, J = 8.0,
8.0, 1.2 Hz, 1H), 7.57 (d, J = 8.0, 1.2 Hz, 1H), 7.57 (d, J = 8.0,
4.8 Hz, 1H), 6.10 (sep, J = 3.2 Hz, 1H), 1.77 (d, J = 3.2 Hz,
6H); 13C NMR (CDCl3, 100 MHz) d 205.1 (C), 156.0 (C),
149.3 (CH), 136.0 (CH), 121.2 (CH), 120.8 (CH), 99.7 (C),
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for C10H11N 146.0964; found 146.0964.
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Takeuchi, T. Hashimoto J. Org. Chem. 1980, 45, 5100.
Yellow oil. IR (ATR, cm-1) 1518, 1345; 1H NMR (CDCl3,
400 MHz) d 8.22 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 8.4 Hz, 2H),
7.57 (d, J = 8.4 Hz, 4H), 5.89 (ddd, J = 17.2, 10.0, 7.2 Hz, 1H),
5.43 (d, J = 17.2 Hz, 1H), 5.40 (d, J = 10.0 Hz, 1H), 5.13 (d, J
= 7.2 Hz, 1H), 4.46 (s, 2H); 13C NMR (CDCl3, 100 MHz) d
147.6 (C), 147.4 (C), 147.3 (C), 136.4 (CH), 132.5 (CH), 129.2
(C), 127.6 (CH), 123.7 (CH), 123.5 (CH), 119.2 (CH2), 89.9
(C), 84.7 (C), 80.9 (CH), 56.4 (CH2); HRMS (ESI-TOF) m/z
[M+Na]+ Calcd for C18H14N2NaO5 361.0794; found 361.0804.
Synthesis of indolizinone 11
To the suspension of allene 2e (43.6 mg, 0.3 mmol) and
copper(I) iodide (5.7 mg, 0.03 mmol) in acetonitrile (3 mL)
was stirred at room temperature for 20 h. The reaction mixture
was washed with saturated sodium hydrogen carbonate aqueous
solution (5 mL), extracted with ethyl acetate (5 mL × 3).
Combined organic layer was dried over magnesium sulfate and
evaporated in vacuo. The residue was washed with hexane (5
mL × 2) to afford 3,3-dimethylindolizin-2(3H)-one 1111 (15.2
mg, 0.094 mmol, 32%) as a brown oil. Further purification was
performed with silica gel column chromatography
1
(hexane/ethyl acetate = 95/5). IR (ATR, cm-1) 1593, 1491; H
NMR (CDCl3, 400 MHz) d 7.41 (d, J = 6.8 Hz, 1H), 7.19 (dd,
J = 8.0, 8.0, Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0,
6.8 Hz, 1H), 4.94 (s, 1H), 1.44 (s, 6H); 13C NMR (CDCl3, 100
MHz) d 196.0 (C), 163.1 (C), 137.4 (CH), 133.3 (CH), 116.4
(CH), 108.98 (C), 108.94 (CH), 86.4 (CH), 68.7 (C), 24.5
(CH3); HRMS (ESI-TOF) m/z [M+H]+ Calcd for C10H12NO