Copper(II)-Promoted, One-Pot Conversion of 1-Alkynes with Anhydrides or Primary Amines to the Respective 2,5-Disubstituted Furans or Pyrroles under Microwave Irradiation Conditions

Article abstract of DOI:10.1002/adsc.201500711

Furans and pyrroles are prepared from 1-alkynes by using a Cu(II)-promoted, one-pot, microwave irradiation method. Glaser coupling of 1-alkynes and cyclization of the resulting 1,3-diyne in the presence of an anhydride or a primary amine results in the formation of the respective 2,5-diaryl- or 2,5-dialkyl-substituted furans and pyrroles.

Full text of DOI:10.1002/adsc.201500711

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DOI: 10.1002/adsc.201500711
Copper(II)-Promoted, One-Pot Conversion of 1-Alkynes with
Anhydrides or Primary Amines to the Respective 2,5-Disubstitut-
ed Furans or Pyrroles under Microwave Irradiation Conditions
Hyejeong Lee,a Yeonhui Yi,a and Chul-Ho Juna,*
a
Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea
Fax: (+82)-2-3147-2644; phone: (+82)-2-2123-2627; e-mail: junch@yonsei.ac.kr
Received: July 27, 2015; Revised: August 21, 2015; Published online: November 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500711.
Abstract: Furans and pyrroles are prepared from 1-
alkynes by using a Cu(II)-promoted, one-pot, mi-
crowave irradiation method. Glaser coupling of 1-
alkynes and cyclization of the resulting 1,3-diyne in
the presence of an anhydride or a primary amine
results in the formation of the respective 2,5-diaryl-
or 2,5-dialkyl-substituted furans and pyrroles.
pyrroles in a highly concise and efficient manner. To
the best of our knowledge, there has been no report
on the one-pot direct synthesis of aliphatic disubsti-
tuted heterocyclic compounds from 1-alkylalkynes.
In a study aimed at optimizing the conditions for
the newly developed process, 1-octyne (1a) was
chosen as the prototypical 1-alkyne substrate. The re-
sults (Table 1) show that reaction of 1a with acetic an-
hydride (Ac2O, 2) and ammonium acetate (NH4OAc,
3) carried out in the presence of Cu(OAc)2·H2O (4,
1 equiv.) at 1508C for 10 min under microwave irradi-
ation conditions generates 2,5-dihexylfuran (5a) in
a 95% GC yield (entry 1). Ac2O (2) and NH4OAc (3)
are important reagents for this process because reac-
Keywords: copper; cyclization; heterocycles; micro-
wave heating
Five-membered heterocyclic compounds have attract- tions catalyzed by Cu(OAc)2·H2O (4, 1 equiv.) in the
ed much attention over many years because of their absence of either of these respective substances gen-
importance as building blocks for pharmaceuticals, erate 5a in only 44% and 24% yields (entries 2 and 3)
molecular sensors and semiconductors.[1] Numerous and when both of these reagents are not used a 4%
transition metal-catalyzed methods have been devised yield of 5a is obtained (entry 4). The reaction of 1-
for the preparation of these substances.[2] However, octyne (1a) utilizing benzoic anhydride (Bz2O) with
transition metal-promoted processes previously devel- NH4OAc (3) gives 5a in 19% yield (entry 5). In the
oped for this purpose have some drawbacks associat- case of using NH4Cl instead of NH4OAc (3), the reac-
ed with the use of 1,3-diyne as a starting material[3] tion of 1a with Ac2O (2) generates a trace amount of
and expensive transition metals, such as Au,[4] Ru[5] 5a (entry 6). Use of CuCl2 or CuI instead of
and Rh,[6] as catalysts. In addition, most of the proto- Cu(OAc)2·H2O (4) does not produce any observable
cols generate 2,5-diaryl-substituted five-membered amount of 5a (entries 7 and 8). Interestingly, use of
heterocycles.[7]
CuOAc leads to a 69% yield of 5a (entry 9) and em-
In this investigation described below, we have de- ploying 0.5 or 2 equiv. of Cu(OAc)2·H2O (4) does not
veloped a novel, one-pot, microwave irradiation-pro- improve the efficiency of the process (entries 10 and
moted, Cu(II)-catalyzed method for the synthesis of 11). Finally, lowering the temperature of the reaction
2,5-disubstituted furans and pyrroles from 1-alkynes to 130 and 1108C results in a decrease in the yield to
and the respective anhydrides and primary amines as 86% and 27%, respectively (entries 12 and 13). For
heteroatom source. The reactions proceed through comparison purposes, conventional heating at 1508C
a pathway involving intermolecular homocoupling of for 10 min was employed to promote the reaction.
the 1-alkyne and subsequent cyclization of the result- However, this process produces 5a in only 25% yield
ing 1,3-diyne with the heteroatom precursors. Com- (entry 14) whereas extension of the time of conven-
pared with previously reported methods, which have tional heating at 1508C to 24 h results in an 80%
focused on 2,5-diaryl-substitued targets, the new syn- yield of 5a (entry 15). The results demonstrate that
thetic protocol is unique in that it can be utilized to microwave irradiation enhances the efficiency of the
produce alkyl- as well as aryl-substituted furans and furan forming reaction.
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Table 1. Synthesis of 2,5-dihexylfuran (5a) from 1-octyne (1a) under various conditions.[a]
Entry
Oxygen source
Additive
Cu
Temp. [8C]
Yield[b] [%]
1
Ac2O
Ac2O
–
NH4OAc
–
NH4OAc
–
NH4OAc
NH4Cl
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
CuCl2 (1 equiv.)
150
150
150
150
150
150
150
150
150
150
150
130
110
150 (D)
150 (D)
95
44
24
4
19
trace
trace
0
69
22
64
86
27
25
80
2[c]
3
4[c]
5
6
7
8
–
Bz2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
CuI (1 equiv.)
CuOAc (1 equiv.)
9
10
11
12
13
14[d]
15[e]
Cu(OAc)2·H2O (0.5 equiv.)
Cu(OAc)2·H2O (2 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
Cu(OAc)2·H2O (1 equiv.)
[a]
Reaction conditions: 1-octyne (1a, 0.4 mmol), oxygen source (3 equiv.), additive (3 equiv.), Cu, MeOH (200 mg), micro-
wave 10 min at various temperatures.
GC yields.
Use of mixed solvent of MeOH (100 mg) and DMSO (100 mg) for heating up to 1508C.
Conventional heating at 1508C for 10 min.
Conventional heating at 1508C for 24 h.
[b]
[c]
[d]
[e]
1-Alkynes possessing a variety of alkyl and aryl
Table 2. Cu(II)-catalyzed synthesis of 2,5-disubstituted
groups can be used in this reaction to form symmetric
2,5-disubstituted furans (Table 2). For example, reac-
tions of 1-alkynes, such as 1-octyne (1a), 1-decyne
(1b) and 1-dodecyne (1c), with Ac2O (2) and
NH4OAc (3) in the presence of Cu(OAc)2·H2O (4) in
MeOH at 1508C for 10 min, under microwave irradia-
tion conditions, produce the corresponding furans 5a,
5b and 5c in high yields (87%, 75% and 83%). Even
1-alkyne 1d, bearing a sterically more demanding cy-
clohexyl group, reacts under these conditions to form
furan 5d in 73% yield. Reactions of 1-alkynes 5e–g
containing aryl groups give rise to 2,5-diarylfurans in
high yields (91%, 75% and 86%, respectively). These
results show that both alkyl- and aryl-substituted 1-al-
kynes are good substrates for the new furan produc-
ing process.
furans from 1-alkynes[a,b]
In order to gain insight into the mechanism of the
process, the progress of the furan forming reaction
was monitored as a function of time (Figure 1). Reac-
tion of 1a with 2 and 3 was carried out at 1308C in
the presence of catalyst 4 over a period of 30 min.
The results show that at 5 min, 1-octyne (1a) is com-
pletely converted to a mixture of furan 5a (36%), 1,3-
diyne 6a (47%) and acetoxyenyne 7a (14%, deter-
mined using GC). As the time increases, the propor-
tion of furan 5a continuously increases and those of
[a]
Reaction conditions: 1-alkyne (1, 0.4 mmol), 2 (3 equiv.),
3 (3 equiv.), 4 (1 equiv.), MeOH (200 mg), M.W. (micro-
wave) 1508C, 10 min.
Isolated yields.
Cy=cyclohexyl.
[b]
[c]
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Copper(II)-Promoted, One-Pot Conversion of 1-Alkynes with Anhydrides
Scheme 1. Homocoupling and furan formation from 1-
octyne (1a) and phenylacetylene (1e). Isolated yields report-
ed.
produces the symmetrically 2,5-disubstituted furans
5a (17%) and 5f (26%) along with the hetero-disub-
stituted furan 5h (36%). In addition, the Cu(OAc)2-
promoted coupling reaction 1-alkynes 1a and 1e in
Figure 1. Time dependent progress of the reaction.
diyne 6a and acetoxyenyne 7a gradually decrease, and the absence of 2 and 3 produces a mixture of 1,3-
at 30 min, furan 5a is the only product present. The
results of this experiment demonstrate that 6a and 7a
are important intermediates in the route for the for-
mation of furan 5a.
To obtain further evidence showing that 6a and 7a
are intermediates in this reaction, each of these sub-
stances was isolated in pure form. We observed that
reaction of 1,3-diyne 6a with 2 and 3 in the presence
of Cu(OAc)2 generates 2,5-dihexylfuran 5a in 86%
isolated yield [Eq. (1)] and that 7a reacts in the pres-
ence of NH4OAc (3) and the catalyst 4 to form 5a in
78% isolated yield [Eq. (2)].
In addition, we examined the utilization of the new
process in the preparation of furans containing two
different 2,5-disubstituents starting with two different
1-alkynes (Scheme 1). We found that reaction of a 1:1
mixture of 1-octyne (1a) and phenylacetylene (1e)
with 2 and 3 at 1508C for 10 min in the presence of 4 Scheme 2. Proposed mechanism for the formation of furans.
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Table 3. Cu(II)-catalyzed reactions for the formation of
N,2,5-trisubstituted pyrroles from 1-alkynes and primary
amines.[a]
diynes 6a, 6b and 6c in 19%, 38%, and 27% yields, re-
spectively. The ratios of the 1,3-diynes formed in this
process are similar to those of the furans generated
when 2 and 3 are present, suggesting that the furan
distribution depends on the rates of coupling of the 1-
alkynes. In addition, the results show that the homo-
coupling reactivity of the phenyl-substituted 1-alkyne
is slightly higher than that of alkyl-substituted ana-
logues.
Based on the above results, it is possible to propose
the plausible mechanism outlined in Scheme 2 for the
2,5-disubstituted furan forming reaction. In the route,
the 1-alkyne 1 is initially transformed into 1,3-diyne
A through Cu(OAc)2-promoted Glaser coupling.[8]
Next, diyne A is transformed to intermediate B by
addition of acetate ion, generated by reaction be-
tween Ac2O and NH4OAc. Ammonia-promoted de-
acetylation of the copper complex 11 followed by cyc-
lization of the yne-enolate 12 and loss of CuOAc af-
fords the 2,5-disubstituted furan 5. Cyclization of A in
the presence of 2 and 3 is possibly promoted by
CuOAc, which is generated from the homocoupling
of 1-alkyne with Cu(OAc)2. This proposal was con-
firmed by showing that CuOAc serves as a catalyst
under oxygen-free conditions for the reaction of 6a
with 2 and 3 to form 5a [70%, Eq. (3)].[9]
We also found that 1-alkynes 1 react with primary
amines 8 under the catalytic conditions to form N,2,5-
trisubstituted pyrroles 9 along with lesser amounts of
furans 5, which might be a consequence of the pres-
ence of acetate ion in Cu(OAc)2·H2O (Table 3). For
example, the reaction of 1-octyne (1a) with aniline
(8a) in the presence of Cu(OAc)2·H2O (4) under mi-
crowave irradiation conditions at 1508C for 10 min
generates N-phenyl-2,5-dihexylpyrrole (9a) in 80%
yield along with 8% of furan 5a (entry 1). Similarly,
pyrroles 9b, 9c, and 9d are produced in good to mod-
erate yields in the reactions of 1a with amines 8b, 8c,
and 8d (entries 2–4). Reactions of phenylacetylene
(1e) with various amines (8a–8d) also give the corre-
sponding pyrroles 9e, 9f, 9g and 9h in moderate yields
(entries 5–8).
[a]
Reaction conditions: 1-alkyne (1, 0.4 mmol), primary
amine (8, 3 equiv.), 4 (1 equiv.), MeOH (200 mg), M.W.
(microwave) 1508C, 10 min.
Isolated yields.
Reaction time: 30 min.
[b]
[c]
[d]
Reaction time: 60 min.
The proposed mechanism for the production of
N,2,5-trisubstituted pyrroles, depicted in Scheme 3,
begins with Cu(OAc)2-promoted Glaser coupling of
the 1-alkyne to yield diyne intermediate A. This is
followed by CuOAc-promoted hydroamination to
form the yne-enamine 13. Pyrrole 9 is then generated
Scheme 3. Proposed mechanism for the synthesis of pyr-
through cyclization followed by CuOAc elimination.[9] roles.
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phenyl-2,5-di(thiophen-2-yl)pyrrole (9i).
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Experimental Section
General Procedure
To a 10-mL microwave vessel were added 1-octyne (1a,
45.4 mg, 0.4 mmol), acetic anhydride (2, 122.5 mg,
1.2 mmol), NH4OAc (3, 92.4 mg, 1.2 mmol), Cu(OAc)2·H2O
(4, 80.0 mg, 0.4 mmol) and MeOH (200 mg, 6.25 mmol). The
mixture was stirred at 1508C for 10 min under microwave ir-
radiation. The crude mixture was subjected to column chro-
matography (n-hexane=100) on silica gel to give 2,5-dihex-
ylfuran (5a) as a pale yellow powder; yield: 82.1 mg (87%).
1H NMR (400 MHz, CDCl3): d=5.82 (s, 2H), 2.55 (t, J=
7.2 Hz, 4H), 1.64–1.57 (m, 4H), 1.37–1.30 (m, 12H), 0.88 (t,
J=6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=154.8,
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Acknowledgements
This work was supported by a grant from the National Re-
search Foundation of Korea (NRF) (2011-0016830).
Adv. Synth. Catal. 2015, 357, 3485 – 3490
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line (8a) gives pyrrole 9a in 54% isolated yield under
microwave heating of 1508C for 10 min.
[9] The reaction was carried out under an argon atmos-
phere to retard air-oxidation of Cu(I)OAc.
[10] The result was confirmed by the observation that the
CuOAc-promoted reaction of 1,3-diyne (6a) with ani-
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