Synthesis of allenes via CuBr-catalyzed homologation of alk-1-ynes accelerated by microwave

Article abstract of DOI:10.1016/j.tetlet.2008.10.019

CuBr-catalyzed homologation of alk-1-ynes 1 with paraformaldehyde and N,N-diisopropylamine (or N,N-dicyclohexylamine) was accelerated by microwave irradiation at 150 °C to afford the corresponding allenes 2 in good to high yields in 1-10 min. Bisalkynes 5

Full text of DOI:10.1016/j.tetlet.2008.10.019

Tetrahedron Letters 49 (2008) 7230–7233
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of allenes via CuBr-catalyzed homologation
of alk-1-ynes accelerated by microwave
*
Hiroyuki Nakamura , Tsuyuka Sugiishi, Yuko Tanaka
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
CuBr-catalyzed homologation of alk-1-ynes 1 with paraformaldehyde and N,N-diisopropylamine (or N,N-
dicyclohexylamine) was accelerated by microwave irradiation at 150 °C to afford the corresponding
allenes 2 in good to high yields in 1–10 min. Bisalkynes 5 and 7 were also converted to the corresponding
bisallenes 6 and 8 in 63% and 61% yields, respectively, under the current condition.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 September 2008
Accepted 6 October 2008
Available online 8 October 2008
Keywords:
Allenes
Homologation
Alk-1-ynes
Microwave
Microwaves have been recognized as an efficient heating source
for organic synthesis.1,2 Microwave-accelerated transformations
are considered as an environmentally friendly alternative to
standard heating methodologies in view of use of less volume of
solvents, milder reagents, and reduced energy consumption.3
Numerous protocols have been developed due to the advantages
of the convenience and special characteristics of microwave chem-
istry. In many cases, the surpassing heating performance by micro-
wave has affected in improvement of reaction rates and yields with
minimizing side reactions in the shorter intervals of reaction time.4
In this Letter, we developed the microwave-assisted CuBr-cata-
lyzed homologation of alk-1-ynes to allenes. Allenes have extraor-
dinary properties such as an axial chirality of the elongated
tetrahedron and a higher reactivity than alkenes, hence, these have
been paid attention not only as an attractive building block for
organic synthesis but also as a potent functional group for
improvement of the biological and pharmacological active com-
pounds.5–7 Therefore, development of simple protocols for the
introduction of an allenic moiety into the existing backbone of
the molecules is still an important requirement.8 Allenes can be
generally prepared from propargylic alcohol derivatives by SN20-
type displacement with organocopper species named Crabbé reac-
tion.9 Crabbé and co-workers also developed a simple method for
CuBr-catalyzed homologation of alk-1-ynes to terminal allenes
with peraformaldehyde and N,N-diisopropylamine in refluxing
dioxane.10 They proposed a two-step mechanism in this trans-
formation; the first step being a CuBr-catalyzed Mannich-type
CuBr
+
R
HCHO
+ HNi-Pr2
+
R
N
N
R
H
Scheme 1.
reaction and the second, a 1,5-sigmatropic rearrangement of
hydrogen (Scheme 1). We found that this Crabbé-type allene for-
mation was dramatically accelerated by microwave irradiation11
and various allenes were able to be synthesized from the corre-
sponding terminal alkynes.12
The reaction of propargyl benzyl ether 1a with formaldehyde
and various amines was examined in the presence of copper and
palladium catalysts under microwave conditions. The results are
summarized in Table 1. The reaction of 1a with paraformaldehyde
and N,N-diisopropylamine proceeded in the presence of CuBr
(50 mol %) at 110 °C under microwave irradiation condition to give
the corresponding allene 2a in 24% yield (entry 1). The reaction
was complete within 10 min at 150 °C and 2a was obtained quan-
titatively (entry 2). When the reaction was carried out without
microwave irradiation, it took 3 h to obtain 2a in 78% yield at
110 °C (entry 3), and the lower yield was observed at 150 °C (entry
4). Although the reaction was complete within 5 min using a
30 mol % of CuBr, 2a was generated only in 45% for 1 min (entries
5–7). N,N-Dicyclohexylamine was more effective for this transfor-
mation13 and 2a was obtained in 76% yield even for 1 min at
* Corresponding author. Tel.: +81 3 3986 0221; fax: +81 3 5992 1029.
E-mail address: hiroyuki.nakamura@gakushuin.ac.jp (H. Nakamura).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.019

H. Nakamura et al. / Tetrahedron Letters 49 (2008) 7230–7233
7231
Table 1
CuBr-mediated homologation of propargyl benzyl ether 1a to allene 2aa
CuBr
+
+
HNR2
(2 eq)
O
(CH2O)n
(2.5 eq)
O
dioxane
1a (1 eq)
2a
Entry
R2NH
Catalyst (mol %)
Condition
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Et2NH
CuBr (50)
CuBr (50)
CuBr (50)
CuBr (50)
CuBr (30)
CuBr (30)
CuBr (30)
CuBr (30)
CuBr (30)
CuBr (30)
CuBr (20)
CuBr (10)
CuBr (5)
110 °C/MW
150 °C/MW
110 °C
10
10
180
30
10
5
1
10
5
1
5
5
5
5
5
5
5
5
5
5
5
24
>99
78
150 °C
49c
>99
>99
45
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
150 °C/MW
>99 (86)d
>99
76
54
49
29
47
48
7
47
NR
NR
70
CuCl (30)
CuI (30)
CuOAc (30)
CuCl2 (30)
PdCl2 (30)
PdCl2(PPh3)2 (30)
CuBr (30)
CuBr (30)
CuBr (30)
i-Bu2NH
Bn2NH
89
e
5
—
TM
a
All reactions were carried out in a sealed vial tube. The mixture was heated with stir using the microwave apparatus (Initiator , Biotage, Co. Ltd). The initial heating was
carried out with 380 W of microwave power, and then the reaction was irradiated with 75 W of microwave to maintain the reaction temperature at 110 or 150 °C for an
appropriate period.
b
GC yields based on 1a using hexadecane as an internal standard.
Longer reaction time resulted in decomposition of the products.
Isolated yield based on 1a was indicated in the parentheses.
Mannich-type three-component coupling product was observed instead of 2a.
c
d
e
150 oC (entries 8–10). The amounts of catalyst also affected the
reaction and use of less amounts of CuBr resulted in lower yields
of 2a (entries 11–13). Other cupper catalysts, such as CuCl, CuI,
CuOAc, and CuCl2 were not effective for this transformation (en-
tries 14–17) and the reaction did not proceed under palladium-
catalyzed conditions (entries 18 and 19). Effect of amines was also
examined. Although N,N-diethylamine and N,N-diisobutylamine
were effective (entries 20 and 21), the use of N,N-dibenzylamine
did not afford the corresponding allene 2a but afforded the Man-
nich-type three-component coupling product 3 (entry 22).14
was able to be applied for aliphatic alkyne 1k, aromatic alkyne
1l, and biologically active alkynes 1m–n (entries 11–14).16,17
Bn2N
NBn2
4 (dimer product)
Recently, bisallenes have been paid attention as important
building blocks in transition-metal catalyzed cyclization reac-
tions.19 We applied the current microwave-accelerated homologa-
tion reaction for bisallene synthesis. The symmetric bisalkyne 5,
which was prepared from catechol and propargylbromide, under-
went the homologation reaction with paraformaldehyde (5 equiv)
and N,N-dicyclohexylamine (4 equiv) in the presence of CuBr
(0.5 equiv) to give the corresponding bisallene 6 in 63% yield. In
a similar manner, the unsymmetric bisalkyne 7 was also converted
to the corresponding bisallene 8 in 61% yield.20
O
NBn
3 (Mannich-type product)
We next examined synthesis of various allenes from the corre-
sponding terminal alkynes under the microwave condition. The re-
sults are shown in Table 2. Propargylic ethers 1a and 1b underwent
the allene formation with paraformaldehyde and N,N-dicyclohex-
ylamine to give the corresponding allenes 2a and 2b in 86% and
77% isolated yields, respectively (entries 1 and 2). The phenoxy
ether 1c also gave 2c in 62% yield (entry 3). In this case, 2c was ob-
tained in 44% yield without microwave irradiation at 110 oC for 4 h.
Although the reaction of N-propargylphthalimide 1d gave 2d in
61% yield, N-propargyldibenzylamine 1e gave the corresponding
allene 2e in 37% yield along with the dimer product 4 (entries 4
and 5).15 Reaction of the propargylic alcohols 1f–i and the acetate
1j also proceeded without affecting OH and OAc groups8 to afford
the corresponding allenyl carbinols 2f-i and allenyl acetate 2j in
good to high yields (entries 6–10). The current transformation
(CH2O)n, HNCy2
CuBr (0.5 eq)
O
O
O
dioxane, 150 oC
microwave, 10 min
ð1Þ
ð2Þ
O
63%
5
6
(CH2O)n, HNCy2
CuBr (0.5 eq)
dioxane, 150 ºC
microwave, 10 min
O
O
61%
7
8

7232
H. Nakamura et al. / Tetrahedron Letters 49 (2008) 7230–7233
Table 2
microwave irradiation. We believe that the current finding is sig-
nificantly important in aspects of widely applicable methodology
and reduction of energy consumption for organic synthesis.
Synthesis of allenes
2
from various terminal alkynes
1
under the microwave
condition18
CuBr (0.3 eq)
R
R
+ (CH2O)n + HNCy2
dioxane, 150 oC
microwave
Acknowledgment
1
2
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformations of
Carbon Resources’ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Entry
1
1
Time (min)
Yielda (%)
86
O
1a
1b
1c
5
5
5
O
2
3
77
62
References and notes
O
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4
5
6
1d
1e
1f
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61
37
74
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10
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Bn2N
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H3C OH
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Org. Biomol. Chem. 2008, 6, 1471.
11
12
1k
1l
10
10
62
60
7
H3CO
F
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HN
Cl
13
1m
5
63
52
O
OH
CH3
H
18. A representative procedure for the microwave-assisted allene formation from
terminal alkynes is as follows: To a mixture of alkyne 1a (73.3 mg, 0.50 mmol)
and CuBr (22 mg, 30 mol %) in dioxane (2.0 mL) were added paraformaldehyde
(37.5 mg, 1.25 mmol) and N,N-dicyclohexylamine (0.20 mL, 1.0 mmol) in a
sealed vial tube. The mixture was heated to 150 °C with stir using the
14
1n
10
H
H
HO
TM
microwave apparatus (Initiator , Biotage, Co. Ltd). When the reaction
a
Isolated yield based on 1a.
The reaction was carried out using 0.5 equiv of CuBr.
temperature was set at 150 °C on the apparatus, it took 3 min to reach this
temperature with 380 W of microwave power, and then reaction temperature
was maintained at 150 °C for 10 min with 75 W of microwave irradiation.
During the reaction course, the pressure in the sealed vial was less than 2 bar.
The mixture was filtered with a short column chromatography on silica gel
eluted with ether and concentrated. The residue was purified by column
chromatography on silica gel to give 2a in 86% yield (69.0 mg, 0.43 mmol) as a
b
In conclusion, we found that CuBr-catalyzed homologation of
alk-1-ynes to terminal allenes was dramatically accelerated by

H. Nakamura et al. / Tetrahedron Letters 49 (2008) 7230–7233
7233
colorless liquid: IR (neat) 3030, 2858, 1956, 1722, 1497, 1454, 1360,
4H), 4.61 (dt, J = 6.8, 2.4 Hz, 4H); 13C NMR (75 MHz, CDCl3) d 209.5, 148.3,
121.4, 114.6, 87.3, 66.9; MS(EI) m/z 214 (M+); Anal. Calcd for C14H14O2: C,
78.48; H, 6.59. Found: C, 78.46; H, 6.64.
1074 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.33 (m, 5H), 5.28 (q, J = 6.8 Hz, 1H),
;
4.80 (dt, J = 6.8, 2.4 Hz, 2H), 4.54 (s, 1H), 4.07 (dt, J = 6.8, 2.4 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 209.3, 138.1, 128.4, 127.8, 127.6, 87.7, 75.7, 71.8, 67.8; Anal.
Calcd for C11H12O: C, 82.46; H, 7.55. Found: C, 82.49; H, 7.70.
1-(Buta-2,3-dienyloxy)-2-(propa-1,2-dienyl)benzene 8: Colorless liquid: IR (neat)
3398, 2926, 2854, 2332, 1956, 1596, 1456, 1242, 1011 cmꢀ1
;
1H NMR
19. (a) Jiang, X.; Cheng, X.; Ma, S. Angew. Chem., Int. Ed. 2006, 45, 8009; (b)
Kang, S.-K.; Ha, Y.-H.; Kim, D.-H.; Lim, Y.; Jung, J. Chem. Commun. 2001, 1306;
(c) Pasto, D. J.; Yang, S-H.; Muellerleile, J. A. J. Org. Chem. 1992, 57, 2976.
20. Spectral data for 1,2-Bis(buta-2,3-dienyloxy)benzene 6: Colorless liquid: IR (neat)
(400 MHz, CDCl3) d 7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.15 (dt, J = 8.4, 2.0 Hz, 1H),
6.93 (dt, J = 7.6, 1.2 Hz, 1H), 6.87 (dd, J = 9.2, 1.2 Hz, 1H), 6.60 (t, J = 6.8 Hz, 1H),
5.41 (q, J = 6.8 Hz, 1H), 5.11 (d, J = 6.8 Hz, 1H), 4.86 (dt, J = 6.8, 2.8 Hz, 2H), 4.58
(dt, J = 6.8, 2.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 210.2, 209.3, 154..7, 127.8
(d), 122.9, 121.1, 112.7, 87.9, 87.2, 78.0, 76.6, 66.4; MS(EI) m/z 184 (M+); Anal.
Calcd for C13H13O: C, 84.75; H, 6.57. Found: C, 84.55; H, 6.78.
3065, 2928, 2868, 2359, 1956, 1717, 1506, 1456, 1375, 1043 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 6.88 (m, 4H), 5.39 (q, J = 6.8 Hz, 2H), 4.80 (dt, J = 6.8, 2.4 Hz,