Copper-catalyzed synthesis of substituted furans and pyrroles by heterocyclodehydration and tandem heterocyclodehydration-hydration of 3-yne-1,2-diols and 1-amino-3-yn-2-ol derivatives

Article abstract of DOI:10.1021/jo400533j

CuCl₂-catalyzed heterocyclodehydration of readily available 3-yne-1,2-diols and 1-amino-3-yn-2-ol derivatives afforded substituted furans and pyrroles, respectively, in good to high yields (53-99%) under mild conditions (MeOH as the solvent, 80-100 °C, 1-24 h). In the case of 2,2-dialkynyl-1,2-diols, bearing an additional alkynyl substituent at C-2, a cascade process, corresponding to copper-catalyzed heterocyclodehydration followed by acid-catalyzed hydration of the triple bond, was realized when the reaction was carried out in the presence of both CuCl₂ and TsOH, leading to 3-acylfurans in one step and high yields (75-84%). Under the same conditions, N-Boc-2-alkynyl-1-amino-3-yn-2-ols were converted into the corresponding N-unsubstituted 3-acylpyrroles in low to fair yields (19-59%). However, working in the presence of added water and a large excess of CO ₂ (40 atm), in addition to CuCl₂ and TsOH, caused a significant improvement of the yields of 3-acylpyrroles (68-87%), thus making the method of general synthetic applicability.

Full text of DOI:10.1021/jo400533j

Article
pubs.acs.org/joc
Copper-Catalyzed Synthesis of Substituted Furans and Pyrroles by
Heterocyclodehydration and Tandem Heterocyclodehydration−
Hydration of 3‑Yne-1,2-diols and 1‑Amino-3-yn-2-ol Derivatives
Bartolo Gabriele,* Lucia Veltri, Pierluigi Plastina, Raffaella Mancuso, Mabel V. Vetere, and Vito Maltese
Dipartimento di Chimica e Tecnologie Chimiche, Universita
Italy
̀
della Calabria, Via P. Bucci, 12/C, 87036 Arcavacata di Rende (CS),
S
* Supporting Information
ABSTRACT: CuCl2-catalyzed heterocyclodehydration of
readily available 3-yne-1,2-diols and 1-amino-3-yn-2-ol deriva-
tives afforded substituted furans and pyrroles, respectively, in
good to high yields (53−99%) under mild conditions (MeOH
as the solvent, 80−100 °C, 1−24 h). In the case of 2,2-
dialkynyl-1,2-diols, bearing an additional alkynyl substituent at
C-2, a cascade process, corresponding to copper-catalyzed
heterocyclodehydration followed by acid-catalyzed hydration of
the triple bond, was realized when the reaction was carried out
in the presence of both CuCl2 and TsOH, leading to 3-
acylfurans in one step and high yields (75−84%). Under the
same conditions, N-Boc-2-alkynyl-1-amino-3-yn-2-ols were
converted into the corresponding N-unsubstituted 3-acylpyr-
roles in low to fair yields (19−59%). However, working in the
presence of added water and a large excess of CO2 (40 atm), in addition to CuCl2 and TsOH, caused a significant improvement
of the yields of 3-acylpyrroles (68−87%), thus making the method of general synthetic applicability.
Scheme 1. Formation of Substituted Furans (2) and Pyrroles
(4) by Metal-Catalyzed Heterocyclodehydration of 3-Yne-
1,2-diols (1) and 1-Amino-3-yn-2-ol Derivatives (3),
Respectively
INTRODUCTION
■
Copper catalysis has recently acquired an increasing impor-
tance, in view of the availability, lower toxicity and higher
environmental compatibility of copper when compared with
other transition metal catalysts.1,2 The growing importance of
copper-based catalysts in organic synthesis is testified by the
increasing number of publications in this field during the past
years,2 including reviews.1
On the other hand, metal-catalyzed heterocyclodehydration
of suitably functionalized acyclic precursors is currently
established as a versatile and powerful method for the direct
synthesis of heterocyclic derivatives under mild reaction
conditions starting from readily available precursors.3,4
A
particularly attractive process consists of the heterocyclodehy-
dration of 3-yne-1,2-diols 1 and 1-amino-3-yn-2-ol derivatives 3
to give the corresponding furans 2 and pyrroles 4, respectively,
according to eq 1. The heterocyclodehydration occurs by 5-exo-
This reaction has been reported to occur under the catalysis
of various transition metals, including gold,3b,c ruthenium,3d
silver,3e,g molybdenum,3i,j and palladium.3k,l However, before
our short report,5 no general method based on the use of
copper catalysts had been disclosed. In this work, we report a
full account on CuCl2-catalyzed heterocyclodehydration of 1
and 3 to give furans 2 and pyrroles 4, respectively, which allows
an efficient, convenient, and economical synthesis of these
dig intramolecular nucleophilic attack of the hydroxyl group to
the triple bond coordinated to the metal center, followed by
protonolysis and aromatization or vice versa (Scheme 1).
Received: March 13, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
important classes of heterocycles6,7 under mild conditions using
a very simple and ligand-free catalyst.
directly obtain 3-acylfurans by tandem heterocyclodehydration/
water addition to the 3-alkynyl substituent. In order to realize
this process, we allowed 2,2-dialkynyl-1,2-diols 1f−i to react
under conditions similar to those reported in Table 1, entries
6−9 but in the presence of an organic acid such as TsOH (20
mol %). Gratifyingly, after 3−24 h at 80−100 °C, the
corresponding 3-acylfurans 5f−i were formed in high yields,
based on starting 1f−i (Table 2).8
RESULTS AND DISCUSSION
■
CuCl2-Catalyzed Heterocyclization of 3-Yne-1,2-diols
to Give Substituted Furans. The reactivity of 3-yne-1,2-diols
1, easily obtained by alkynyation of the suitable α-hydroxy
carbonyl compound, was investigated first. The reaction of 2-
methyl-4-phenylbut-3-yne-1,2-diol 1a, carried out in the
presence of 2 mol % of CuCl2, in MeOH as the solvent (0.2
mmol of 1a per mL of MeOH) at 80 °C for 1 h, led to the
formation of the desired 4-methyl-2-phenylfuran 2a in 37%
GLC yield at 47% substrate conversion (entry 1, Table S1,
Supporting Information). After a brief optimization study
(Table S1, Supporting Information), 2a could be obtained in
75% isolated yield at total conversion of 1a, working at 100 °C
for 2 h (Table 1, entry 1). Under the same conditions, 2,4-
Table 2. Synthesis of 3-Acylfurans 5 by Tandem CuCl2-
Catalyzed Heterocyclodehydration of 2,2-Dialkynyl-1,2-
a
diols/Acid-Catalyzed Water Addition to the Triple Bond
b
Table 1. Synthesis of Substituted Furans 2 by CuCl2-
Catalyzed Heterocyclodehydration of 3-Yne-1,2-diols 1
entry
1
R1
R2
T (°C) time (h)
5
yield of 5 (%)
a
c
1
1f
Me
Ph
Bu
80
80
3
24
3
5f
84
89
78
75
2
1g
1h
1i
Bu
5g
5h
5i
c
3
c
Me
Me
t-Bu
Ph
80
4
100
15
a
All reactions were carried out in MeOH in the presence of 2 mol % of
CuCl2 and 20 mol % of TsOH·H2O (0.20 mmol of 1 per mL of
MeOH, 1 mmol scale based on 1). Conversion of 1 was quantitative in
T
(°C)
time
(h)
yield of
b
entry
1
R1
R2
R3
2
2
(%)
b
c
all cases. Isolated yield based on starting 1. The substrate employed
was the S enantiomer [prepared from commercially available ethyl (S)-
α-hydroxypropionate].4b
1
2
3
4
5
1a
1b
1c
1d
1e
1f
H
Me
Ph
Ph
Ph
Ph
Ph
Bu
Bu
Bu
Bu
Bu
tBu
Ph
100
100
80
2
3
2
2
2
2
2
2
3
2a
2b
2c
2d
2e
2f
75
H
53
80
81
87
91
84
81
84
H
Ph
H
80
CuCl2-Catalyzed Heterocyclization of 1-Amino-3-yn-
2-ol Derivatives to Give Substituted Pyrroles. A variety of
N-Boc-1-amino-3-yn-2-ols 3 were allowed to react under
conditions similar to those successfully employed for 3-yne-
1,2-diols 1, in order to develop a general synthesis of
substituted pyrroles 4. The results obtained by varying the
nature of the substituent α to the amino group, α to the
hydroxyl group, and on the triple bond are reported in Table 3.
As can be seen, good to excellent yields of the corresponding
N-Boc-pyrroles were obtained with all the substrates tested, at
80−100 °C and after 1−24 h reaction time. Monoalkynyl
substrates 3a−f turned out to be less reactive than monoalkynyl
3-yne-1,2-diols, and a higher catalyst loading (5 mol % instead
of 2 mol %) was necessary in order to achieve acceptable
reaction rates and product yields (Table 3, entries 1−7). As
already observed with 3-yne-1,2-diols, conjugation of the triple
bond with an aromatic ring caused a slight decrease of
reactivity, as can be seen by comparing entry 2 (3b, R1 = Bn, R2
= H, R3 = Bu) with entry 7 (3f, R1 = Bn, R2 = H, R3 = Ph). In
this latter case, the reaction of (S)-N-Boc-4-amino-1,5-
diphenylpent-1-yn-3-ol 3f led to the formation of a mixture
of N-Boc-2-benzyl-5-phenylpyrrole 4f (32%) and 2-benzyl-5-
phenyl-1H-pyrrole 6f (21%), deriving from in situ deprotection
of 4f. After treatment of the reaction crude with NaOMe (3
equiv with respect to starting 3f), 6f was selectively obtained in
53% yield, according to Scheme 2. On the other hand, dialkynyl
substrates 3g−k were significantly more reactive than
monoalkynyl substrates 3a−f, as shown by entries 8−12
(Table 3). The reaction could also be successfully applied to N-
tosyl derivatives, as shown by entry 13 (Table 3).
CCBu
CCBu
CCBu
CCtBu
CCPh
80
c
6
Me
Ph
Me
Me
80
7
1g
1h
1i
80
2g
2h
2i
c
8
c
80
9
100
a
All reactions were carried out in MeOH in the presence of 2 mol % of
CuCl2 (0.20 mmol of 1 per mL of MeOH, 1 mmol scale based on 1).
Conversion of 1 was quantitative in all cases. Isolated yield based on
b
c
starting 1. The substrate employed was the S enantiomer [prepared
from commercially available ethyl (S)-α-hydroxypropionate].4b
diphenylbut-3-yne-1,2-diol 1b led to the corresponding 2,4-
diphenylfuran 2b in 53% isolated yield after 3 h reaction time
(Table 1, entry 2). Quite interestingly, the reactivity of 3-yne-
1,2-diols bearing an alkyl group on the triple bond (R3 = alkyl)
was higher with respect to the analogous substrates substituted
with a phenyl group (R3 = phenyl). Thus, 2-phenyloct-3-yne-
1,2-diol 1c could be converted into 2-butyl-4-phenylfuran 2c in
80% yield by conducting the reaction at 80 °C for 2 h (Table 1,
entry 3), and under the same conditions, 1,2-diphenyloct-3-
yne-1,2-diol 1d afforded 5-butyl-2,3-diphenylfuran 2d in 81%
yield (Table 1, entry 4).
Of particular interest was the reaction of 2,2-dialkynyl-1,2-
diols 1e−i, bearing an additional alkynyl substituent at C-2.
These substrates, in fact, were smoothly converted into the
corresponding furans 2e−i in high yields (81−91%) without
affecting the additional alkynyl substituent (Table 1, entries 5−
9). The reaction worked nicely even in the presence of a bulky
substituent, such as tert-butyl, on the triple bond, as shown in
entry 8 of Table 1.
The influence of the substrate stereochemistry on the
reaction outcome was also investigated, by reacting the racemic
(3RS,4RS) syn diastereomer of N-Boc-3-amino-2-methyldec-5-
Having assessed the possibility to obtain 3-alkynylfurans
from 2,2-dialkynyl-1,2-diols, we then verified the possibility to
B
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Synthesis of Substituted Pyrroles 4 by CuCl2-Catalyzed Heterocyclodehydration of 1-Amino-3-yn-2-ol Derivatives 3
b
entry
3
R1
R2
R3
Y
mol % CuCl2
T (°C)
time (h)
4
yield of 4 (%)
c
1
3a
Me
Bn
i-Pr
i-Pr
Bn
H
H
Bu
Bu
Bu
Bu
Bu
Bu
Ph
Bu
Bu
Bu
Bu
Ph
Bu
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Ts
5
5
5
5
5
5
5
2
2
2
2
2
2
100
100
100
100
100
100
100
80
15
15
8
4a
4b
4c
4c
4d
4e
4f
56
70
76
71
75
97
c
2
3b
3c
H
c
3
H
d
4
syn-3c
3d
3e
3f
H
8
c
5
Me
H
15
18
24
1
6
c
e
7
f
Bn
Me
Bn
i-Bu
H
H
32
8
3g
3h
3i
CCBu
CCBu
CCBu
CCBu
CCPh
CCBu
4g
4h
4i
99
73
78
73
82
83
9
80
8
f
10
100
80
1
11
3j
2
4j
f
12
3k
3l
Me
Me
80
1
4k
4l
f
13
80
8
a
All reactions were carried out in MeOH in the presence of CuCl2 as the catalyst (0.20 mmol of 3 per mL of MeOH, 1 mmol scale based on 1).
b
c
Conversion of 3 was quantitative in all cases. Isolated yield based on starting 3. The substrate employed was a (S,S) + (S,R) diastereomeric mixture
(obtained starting from the corresponding commercially available methyl N-Boc-L-amino ester).4c The substrate employed was the racemic
d
(3RS,4RS) syn diastereomer (obtained starting from commercially available N-Boc-D/L-valine methyl ester).4c The reaction also led to the formation
e
f
of 2-benzyl-5-phenyl-1H-pyrrole 6f in 21% isolated yield. The substrate employed was the S enantiomer (obtained starting from the corresponding
commercially available methyl L-amino ester).4c
Scheme 2. Synthesis of 2-Benzyl-5-phenyl-1H-pyrrole 6f by
CuCl2-Catalyzed Heterocyclodehydration of (S)-N-Boc-4-
amino-1,5-diphenylpent-1-yn-3-ol 3f Followed by Base-
Promoted Deprotection
Table 4. Formation of 3-Acylpyrroles 7 by Tandem CuCl2-
Catalyzed Heterocyclodehydration of N-Boc-2-Alkynyl-1-
amino-3-yn-2-ols/Acid-Catalyzed Water Addition to the
a
Triple Bond
yn-4-ol, syn-3c, and comparing its reactivity with that of the
corresponding diastereomeric mixture (3S,4S) + (3S,4R), 3c.
As shown in Table 3, entries 3 and 4, the syn diastereomer
(Table 3, entry 4) gave practically the same results as those
obtained with the diastereomeric mixture (3S,4S) + (3S,4R)
(Table 3, entry 3), so it can be concluded that the
stereochemistry of the substrate does not significantly affect
the reaction outcome.
Also in the case of N-Boc-2-alkynyl-1-amino-3-yn-2-ols, we
verified the possibility to realize the one-pot sequential Cu-
catalyzed heterocyclodehydration/acid-catalyzed water addition
to the triple bond. The results obtained working in the
presence of 2 mol % of CuCl2 and 20 mol % of TsOH are
shown in Table 4. Under these conditions, triple bond
hydration was accompanied by acid-promoted N-deprotection,
with formation of the corresponding N-unsubstituted-3-
acylpyrrole 7. As can be seen from Table 4, moderate to fair
yields (48−59%) of 7 were obtained in almost all cases, with
the exception of 2-methyl-3-phenylacetyl-5-phenylpyrrole 7k,
which was formed in low yield (19%, Table 4, entry 4).
With the aim of improving these results, we carried out the
cascade reaction also in the presence of added water and of a
large excess of carbon dioxide, in addition to CuCl2 and TsOH.
In fact, it is known that CO2, under appropriate conditions, can
cause β-carboxylation of the pyrrole ring.9 Therefore, working
in the presence of CO2 and TsOH, the formation of the
b
entry
3
R1
R2
T (°C) time (h)
7
yield of 7 (%)
c
1
3g
3h
3i
Me
Bn
Bu
100
100
100
100
100
15
15
15
15
15
7g
7h
7i
54
59
48
19
56
2
Bu
c
3
i-Bu
Me
Me
Bu
c
4
c
3k
3m
Ph
7k
7m
5
t-Bu
a
All reactions were carried out in MeOH in the presence of 2 mol % of
CuCl2 and 20 mol % of TsOH·H2O (0.20 mmol of 3 per mL of
MeOH, 1 mmol scale based on 3). Conversion of 3 was quantitative in
all cases. Isolated yield based on starting 3. The substrate employed
was the S enantiomer (obtained starting from the corresponding
commercially available methyl N-Boc-L-amino ester).4c
b
c
cationic carboxylated intermediate I from the reaction between
the 3-alkynyl intermediate, CO2 and TsOH should take place.
This would favor triple bond protonation, thus promoting the
subsequent water attack to the triple bond with simultaneous
decarboxylation. In this way, CO2 would actually act as an
efficient cocatalyst for the triple bond hydration of the 3-alkynyl
intermediate (Scheme 3).
Indeed, working in the presence of added water and large
excess of CO2 (40 atm), in addition to CuCl2 and TsOH,
caused a significant improvement of the yields of acylpyrroles 7,
thus making the method of general synthetic applicability, as
shown by the results reported in Table 5. In particular,
C
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Possible Mechanism for the CO2/TsOH-
Promoted Hydration of 3-Alkynylpyrrole Intermediates
(Obtained by CuCl2-Catalyzed Heterocyclodehydration of
N-Boc-2-alkynyl-1-amino-3-yn-2-ols) Leading to 3-
a
Acylpyrroles
amino-3-yn-2-ol derivatives 3, respectively. The process is
catalyzed by a simple and inexpensive catalyst (CuCl2) and
takes place under mild conditions (MeOH as the solvent, 80−
100 °C, 1−24 h).
Of particular interest was the reaction of 2,2-dialkynyl-1,2-
diols and N-Boc-2-alkynyl-1-amino-3-yn-2-ols, bearing an
additional alkynyl substituent at C-2, which were converted
into the corresponding 3-alkynylfurans and 3-alkynylpyrroles in
high yields without affecting the additional alkynyl substituent.
Moreover, under appropriate conditions, these substrates could
be converted in one step into the corresponding 3-acylfurans 5
and N-unsubstituted 3-acylpyrroles 7 by a cascade process,
corresponding to copper-catalyzed heterocyclodehydration
followed by acid-catalyzed hydration of the triple bond. This
latter approach was also successfully applied to (S)-7-
(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8 to give a novel dihy-
dropyrrolizine derivative 9 in good yield.
a
The acid-promoted deprotection is shown to occur as the end of the
process, but it can also take place in an earlier stage.
Table 5. Synthesis of 3-Acylpyrroles 7 by Tandem CuCl2-
Catalyzed Heterocyclodehydration of N-Boc-2-Alkynyl-1-
amino-3-yn-2-ols/Acid- and CO2-Promoted Water Addition
a
to the Triple Bond
EXPERIMENTAL SECTION
■
General Experimental Methods. Melting points are uncorrected.
1H NMR and 13C NMR spectra were recorded at 25 °C in CDCl3 or
DMSO-d6 solutions at 300 or 500 MHz and 75 or 126 MHz,
respectively, with Me4Si as internal standard. Chemical shifts (δ) and
coupling constants (J) are given in ppm and in Hz, respectively. IR
spectra were taken with an FT-IR spectrometer. Mass spectra were
obtained using a GC−MS apparatus at 70 eV ionization voltage or a
mass spectrometer equipped with a turbo ion spray ionization source
in the positive mode [ion spray voltage (IS) 4500 V; curtain gas 10 psi;
temperature 25 °C; ion source gas (1) 20 psi; declustering and
focusing potentials 50 and 400 V, respectively]. Microanalyses were
carried out at our analytical laboratory. All reactions were analyzed by
TLC on silica gel 60 F254 or on neutral alumina and by GLC using a
gas chromatograph and capillary columns with polymethylsilicone
+5% phenylsilicone as the stationary phase. Column chromatography
was performed on silica gel 60 (70−230 mesh). Evaporation refers to
the removal of solvent under reduced pressure.
b
entry
3
R1
R2
7
yield of 7 (%)
c
1
3g
3h
3i
Me
Bn
Bu
Bu
Bu
Ph
7g
7h
7i
70
82
68
80
87
71
78
2
c
3
i-Bu
Me
Me
i-Pr
i-Bu
i-Bu
c
4
c
3k
3m
3n
3o
7k
7m
7n
7o
7p
5
t-Bu
Bu
t-Bu
H
6
c
7
c
d
e
8
3p
82
a
All reactions were carried out at 100 °C for 15 h in MeOH (0.20
mmol of 3 per mL of MeOH, 1 mmol scale based on 3), in the
presence of CuCl2 (2 mol %), TsOH·H2O (20 mol %), H2O (1 equiv)
and CO2 (40 atm). Conversion of 3 was quantitative in all cases.
Preparation of Substrates. 3-Yne-1,2-diols 1a−c, 1e,f,4b N-Boc-
1-amino-3-yn-2-ols 3a−i, 3k, 3m−o,4c and (S)-7-(pyrrolidin-2-yl)-
trideca-5,8-diyin-7-ol 84c were prepared as we previously described. 3-
Yne-1,2-diols 1d, 1g−i, N-Boc-1-amino-3-yn-2-ols 3j and 3p, N-Ts-7-
(1-aminoethyl)trideca-5,8-diyn-7-ol 3l were prepared as described
below. All other materials were commercially available and were used
without further purification.
b
c
Isolated yield based on starting 3. The substrate employed was the S
enantiomer (obtained starting from the corresponding commercially
available methyl N-Boc-L-amino ester).4c Crude substrate. Based on
the bis-(trimethylsilyl) precursor of 3p, that is, (S)-N-Boc-4-amino-6-
methyl-1-(trimethylsilyl)-3-[2-(trimethylsilyl)ethynyl]hept-1-yn-3-ol
3p′. (Substrate 3p, obtained by deprotection of 3p′, was used crude
without further purification. See the Experimental Section for details.)
d
e
Preparation of 1,2-Diphenyl-oct-3-yne-1,2-diol 1d. A solution
of 1-hexyne (4.55 g; 44.5 mmol) in anhydrous THF (6 mL) was added
dropwise under nitrogen to a stirred, cooled (−40 °C) mixture of BuLi
(28 mL of a 1.6 M solution in hexanes, 44.8 mmol) in anhydrous THF
(18 mL) and anhydrous hexane (28 mL). To the resulting mixture,
maintained at −40 °C, was added, with stirring, a solution of LiBr
(1.56 g, 18 mmol) in THF (6 mL). After 0.5 h, 2-hydroxy-1,2-
diphenylethanone (3.61 g, 17 mmol), diluted in anhydrous THF (5
mL), was slowly added under nitrogen at the same temperature. The
resulting mixture was stirred for additional 2 h and then allowed to
warm up to room temperature. After quenching with a saturated
solution of NH4Cl (20 mL), the mixture was extracted with Et2O (3 ×
50 mL). The combined organic layers were washed with water (40
mL) and then dried over Na2SO4. After filtration, the solvent was
evaporated, and the crude 1,2-diphenyl-oct-3-yne-1,2-diol 1d was
purified by column chromatography on silica gel using hexane−AcOEt
acylpyrrole 7k was now obtained in a yield as high as 80% (to
be compared with 19% obtained in Table 4, entry 4).10 The
method could also be successfully applied to a substrate bearing
terminal triple bonds, such as (S)-N-Boc-4-amino-3-ethynyl-6-
methylhept-1-yn-3-ol 3p (Table 5, entry 8), and to a substrate
bearing a secondary unprotected amino group, such as (S)-7-
(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8 (eq 2).
CONCLUSIONS
■
In conclusion, we have reported a general and convenient
method for the synthesis of furans 2 and pyrroles 4 by copper-
catalyzed heterocyclodehydration of 3-yne-1,2-diols 1 and 1-
D
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6:4 as eluent. Yield: 4.25 g, starting from 3.61 g of 2-hydroxy-1,2-
diphenylethanone (85%). Yellow amorphous solid: mp 94−95 °C,
lit.11 96 °C; IR (KBr) ν = 3489 (m, br), 3451 (m, br), 2219 (v w),
1450 (w), 1384 (m), 1181 (w), 1061 (m), 735 (w), 697 (m), 631 (w)
THF (3 mL), maintained under nitrogen and under reflux, was added
pure ethyl bromide (0.5 mL) to start the formation of the Grignard
reagent. The remaining bromide was added dropwise in THF solution
(1.3 mL of EtBr in 12 mL of THF; total amount of EtBr added: 2.63 g,
24.1 mmol). The mixture was then allowed to reflux for additional 20
min. After cooling, the resulting solution of EtMgBr was transferred
under nitrogen to a dropping funnel and added dropwise under
nitrogen to a solution of the 1-hexyne (1.98 g, 24.1 mmol) in
anhydrous THF (6 mL) at 0 °C with stirring. After additional stirring
at 0 °C for 15 min, the mixture was allowed to warm up to room
temperature and then was heated at 45 °C and stirred for 2 h. To the
hot solution of the 1-hexynylmagnesium bromide thus obtained was
added, dropwise and under nitrogen, a solution of N-Boc-glycine
methyl ester (1.17 g, 6.21 mmol) in anhydrous THF (7 mL). The
resulting mixture was allowed to stir at 35 °C overnight. After cooling
to room temperature, saturated NH4Cl (50 mL) and AcOEt (50 mL)
were sequentially added, phases were separated, and the aqueous phase
was extracted with AcOEt (3 × 50 mL). The collected organic layers
were washed with brine and dried over Na2SO4. After filtration and
evaporation of the solvent, product 3j was purified by column
chromatography on silica gel using 8:2 hexane−AcOEt as the eluent.
Yield: 0.80 g, starting from 1.17 g of N-Boc-glycine methyl ester
(40%). Yellow oil: IR (film) ν = 3413 (m, br), 2960 (m), 2932 (m),
2873 (w), 2240 (vw), 1701 (s), 1511 (m), 1457 (w), 1367 (m), 1251
1
cm−1; H NMR (300 MHz, CDCl3) δ = 7.44−7.35 (m, 2 H), 7.30−
7.04 (m, 8 H), 4.82 (s, 1 H), 2.87 (s, 1 H), 2.81 (d, J = 3.0, 1 H), 2.29
(t, J = 7.3, 2 H), 1.60−1.33 (m, 4 H), 0.92 (t, J = 7.3, 3 H); 13C NMR
(75 MHz, CDCl3) δ = 140.5, 137.7, 128.0, 127.93, 127.87, 127.3,
126.7, 88.8, 81.1, 76.3, 30.5, 22.0, 18.5, 13.6; MS (ESI+, direct
infusion) m/z = 317 [(M + Na)+]. Anal. calcd for C20H22O2 (294.39):
C, 81.60; H, 7.53. Found: C, 81.71; H, 7.52.
General Procedure for the Preparation of 2-Alkynyl-3-yne-
1,2-diols 1g−i. A solution of 1-alkyne (51.0 mmol) (1-hexyne: 4.19
g; 3,3-dimethyl-1-butyne: 4.19 g; phenylacetylene: 5.21 g) in
anhydrous THF (8 mL) was added dropwise under nitrogen to a
stirred, cooled (−78 °C) mixture of BuLi (34 mL of a 1.6 M solution
in hexanes, 54.4 mmol) in anhydrous THF (22 mL) and anhydrous
hexane (34 mL). To the resulting mixture, maintained at −78 °C, was
added, with stirring, a solution of LiBr (2.13 g, 24.5 mmol) in THF (7
mL). After 0.5 h, a solution of methyl DL-mandelate (2.82 g, 17 mmol)
or ethyl L-lactate (2.01 g, 17 mmol) in anhydrous THF (5 mL) was
slowly added under nitrogen at the same temperature. The resulting
mixture was stirred for additional 2 h and then allowed to warm up to
room temperature. After quenching with a saturated solution of
NH4Cl (20 mL), the mixture was extracted with Et2O (3 × 50 mL).
The combined organic layers were washed with water (40 mL) and
then dried over Na2SO4. After filtration and evaporation of the solvent,
the product was purified by column chromatography on silica gel using
as eluent 9:1 hexane−AcOEt (1h, 1g) or 8:2 hexane−AcOEt (1i).
2-Hex-1-ynyl-1-phenyl-oct-3-yne-1,2-diol (1g). Yield: 4.26 g,
starting from 2.82 g of methyl DL-mandelate (84%). Yellow solid:
mp 34−35 °C; IR (KBr) ν = 3372 (s, br), 2955 (s), 2929 (s), 2860
(m), 2237 (m), 1454 (m), 1378 (m), 1062 (m), 727 (s), 696 (m), 646
1
(m), 1173 (m), 1077 (w) cm−1; H NMR (300 MHz, CDCl3) δ =
5.12−5.03 (m, br, 1 H), 3.54−3.44 (m, 2 H), 3.32 (s, br, 1 H), 2.22 (t,
J = 6.9, 4 H), 1.56−1.33 (m, 8 H), 1.46 (s, 9 H), 0.91 (t, J = 7.2, 6 H);
13C NMR (75 MHz, CDCl3) δ = 156.5, 84.9, 79.8, 79.1, 63.9, 52.0,
30.4, 28.4, 21.9, 18.4, 13.6; MS (ESI+, direct infusion) m/z = 344 [(M
+ Na)+]. Anal. calcd for C19H31NO3 (321.45): C, 70.99; H, 9.72; N,
4.36. Found: C, 71.08; H, 9.75; N, 4.35.
Preparation of (S)-N-Boc-4-amino-6-methyl-1-trimethylsi-
lanyl-3-trimethylsilanylethynylhept-1-yn-3-ol (3p′). To a sus-
pension of Mg turnings (1.8 g, 74.1 mmol) in anhydrous THF (9 mL),
maintained under nitrogen and under reflux, was added pure ethyl
bromide (1.5 mL) to start the formation of the Grignard reagent. The
remaining bromide was added dropwise in THF solution (3.9 mL of
EtBr in 36 mL of THF; total amount of EtBr added: 7.89 g, 72.3
mmol). The mixture was then allowed to reflux for an additional 20
min. After cooling, the resulting solution of EtMgBr was transferred
under nitrogen to a dropping funnel and added dropwise under
nitrogen to a solution of trimethylsilylacetylene (7.10 g, 72.3 mmol) in
anhydrous THF (18 mL) at 0 °C with stirring. After additional stirring
at 0 °C for 15 min, the mixture was allowed to warm up to room
temperature and then was heated at 45 °C and stirred for 2 h. To the
hot solution of the 1-trimethylsilylethynylmagnesium bromide thus
obtained was added, dropwise and under nitrogen, a solution of N-
Boc-L-leucine methyl ester (4.56 g, 18.6 mmol) in anhydrous THF (21
mL). The resulting mixture was allowed to stir at 35 °C overnight.
After cooling to room temperature, saturated NH4Cl (100 mL) and
AcOEt (100 mL) were sequentially added, phases were separated, and
the aqueous phase was extracted with AcOEt (3 × 100 mL). The
collected organic layers were washed with brine and dried over
Na2SO4. After filtration and evaporation of the solvent, the crude
product was purified by column chromatography on silica gel using 8:2
hexane−AcOEt as the eluent to give pure (S)-N-Boc-4-amino-6-
methyl-1-trimethylsilanyl-3-trimethylsilanylethynyl-hept-1-yn-3-ol 3p.
Yield: 5.87 g, starting from 4.56 g of N-Boc-L-leucine methyl ester
1
(s) cm−1; H NMR (300 MHz, CDCl3) δ = 7.57−7.48 (m, 2 H),
7.36−7.29 (m, 3 H), 4.77 (s, 1 H), 3.10 (s, 1 H), 3.00 (s, 1 H), 2.20 (t,
J = 7.0, 4 H), 1.54−1.27 (m, 8 H), 0.89 (t, J = 7.0, 3 H); 13C NMR (75
MHz, CDCl3) δ = 137.5, 128.24, 128.18, 127.4, 87.0, 86.8, 80.0, 78.5,
77.8, 68.1, 30.3, 21.9, 18.4, 13.6; GC−MS m/z = 298 (M+, absent),
280 (54), 265 (5), 238 (23), 237 (100), 207 (6), 191 (12), 178 (9),
165 (27), 152 (14), 135 (5), 121 (13), 108 (21), 107 (19), 105 (34),
91 (19), 79 (33), 77 (66). Anal. calcd for C20H26O2 (298.42): C,
80.50; H, 8.78. Found: C, 80.44; H, 8.80.
(S)-3-(3,3-Dimethylbut-1-ynyl)-6,6-dimethylhept-4-yne-2,3-diol
(1h). Yield: 2.81 g, starting from 2.01 g of ethyl L-lactate (70%).
Colorless solid: mp 71−72 °C; [α]25 (MeOH, c = 1.04 × 10−2
g
D
mL−1) = −6°; IR (KBr) ν = 3333 (m, br), 2669 (s), 2238 (w), 1477
(m), 1340 (m), 1266 (m), 1205 (w), 1135 (m), 1098 (w), 1023 (m),
992 (m), 871 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 3.81 (q, J =
6.1, 1 H), 3.39 (s, 1 H), 2.67 (s, 1 H), 1.33 (d, J = 6.1, 3 H), 1.24 (s, 3
H), 1.23 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ = 93.7, 93.1, 77.9,
76.5, 74.4, 67.8, 30.8, 30.7, 27.4, 27.3, 17.5; GC−MS m/z = 236 (M+,
absent), 188 (28), 187 (28), 159 (5), 147 (11), 146 (100), 131 (21),
117 (14), 115 (31), 109 (13), 105 (35), 91 (16), 77 (44), 59 (64).
Anal. calcd for C15H24O2 (236.35): C, 76.23; H, 10.24. Found: C,
76.30; H, 10.21.
(S)-5-Phenyl-3-(2-phenylethynyl)pent-4-yne-2,3-diol (1i). Yield:
3.76 g, starting from 2.01 g of ethyl L-lactate (80%). Yellow solid:
mp 90−92 °C, lit.11 106−107 °C; [α]25 (MeOH, c = 1.04 × 10−2
g
D
mL−1) = −7°; IR (KBr) ν = 3395 (m, br), 2200 (w), 1489 (w), 1443
(77%). Colorless solid: mp 82−84 °C; [α]25 (MeOH, c = 1.04 ×
D
(m), 1384 (m), 1293 (w), 1132 (m), 1092 (m). 1048 (m), 986 (w),
10−2 g mL−1) = −38°; IR (KBr) ν = 3446 (m, br), 2956 (m), 2171
(w), 1701 (s), 1511 (s), 1386 (w), 1341 (m), 1250 (m), 1178 (m),
1123 (w), 1062 (m), 1011 (m), 886 (m), 842 (s), 761 (m) cm−1; 1H
NMR (300 MHz, CDCl3) δ = 4.63 (d, br, J = 10.3, 1 H), 4.00−3.88
(m, 1 H), 3.41 (s, br, 1 H), 1.75−1.63 (m, 2 H), 1.50−1.35 (m, 1 H),
1.46 (s, 9 H), 0.95 (d, J = 6.0, 6 H), 0.19 (s, 9 H), 0.18 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ = 156.9, 104.0, 102.9, 89.9, 89.7, 80.2, 68.4,
58.3, 40.5, 28.7, 25.3, 24.1, 21.9; MS (ESI+, direct infusion) m/z = 432
[(M + Na)+]. Anal. calcd for C21H39NO3Si2 (409.71): C, 61.56; H,
9.59; N, 3.42. Found: C, 61.61; H, 9.58; N, 3.43.
1
898 (w), 757 (m), 691 (m) cm−1; H NMR (300 MHz, CDCl3) δ =
7.52−7.44 (m, 4 H), 7.35−7.24 (m, 6 H), 4.11 (q, J = 6.1, 1 H), 3.74
(s, 1 H), 2.88 (s, 1 H), 1.52 (d, J = 6.1, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 132.0, 131.9, 128.9, 128.3, 121.84, 121.79, 87.1, 86.0, 85.5,
85.0, 74.5, 68.7, 17.8; GC−MS m/z = 276 (M+, absent), 232 (41), 231
(64), 214 (55), 203 (28), 187 (7), 150 (3), 129 (100), 102 (21), 75
(17). Anal. calcd for C19H16O2 (276.33): C, 82.58; H, 5.84. Found: C,
82.54; H, 5.83.
Preparation of N-Boc-7-aminomethyl-trideca-5,8-diyn-7-ol
(3j). To a suspension of Mg turnings (0.6 g, 24.7 mmol) in anhydrous
E
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Preparation of (S)-N-Tosyl-7-(1-aminoethyl)trideca-5,8-diyn-
7-ol 3l. Preparation of Crude N-Tosyl-L-alanine methyl ester. To a
cold (0 °C) solution of L-alanine methyl ester hydrochloride (8.0 g,
57.3 mmol) in anhydrous CH2Cl2 (80 mL) was added under nitrogen
tosyl chloride (2.02 g, 63.0 mmol). To the resulting mixture was added
dropwise Et3N (12.7 g, 126.1 mmol) under nitrogen at 0 °C. The
mixture was allowed to warm up to room temperature, stirred for 20 h,
and then diluted with water (50 mL). Phases were separated, and the
aqueous phase was extracted with CH2Cl2 (50 mL). The collected
organic layers were washed with brine and dried over Na2SO4. After
filtration, the solvent was evaporated to obtain crude N-tosyl-L-alanine
methyl ester as a colorless amorphous solid (13.1 g, 89% yield based
on starting L-alanine methyl ester hydrochloride), which was
sufficiently pure to be used as such in the next step.
AcOEt for 4e; 95:5 hexane−AcOEt for 4f, 6f (order of elution: 4f, 6f)
and 4j] or neutral alumina (99:1 hexane−acetone for 2f and 2i).
4-Methyl-2-phenylfuran (2a). Yield: 119 mg, starting from 176 mg
of 1a (75%) (Table 1, entry 1). Colorless solid: mp 37−39 °C, lit.12
38−40 °C; IR (KBr) ν = 2960 (m), 1601 (w), 1495 (w), 1449 (w),
1
1266 (m), 1116 (w), 739 (m), 702 (m) cm−1; H NMR (300 MHz,
CDCl3) δ = 7.65−7.57 (m, 2 H), 7.37−7.28 (m, 2 H), 7.23−7.15 (m,
2 H, 1 H), 6.48 (s, 1 H), 2.02 (d, J = 1.2, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 154.0, 138.9, 131.2, 128.6, 127.1, 123.7, 122.0, 107.8, 9.8;
GC−MS (EI, 70 eV) m/z = 158 (M+, 100), 129 (70), 128 (43), 127
(21), 115 (39), 102 (11), 89 (5), 77 (20). Anal. calcd for C11H10O
(158.20): C, 83.51; H, 6.37. Found: C, 83.74; H, 6.36.
2,4-Diphenylfuran (2b). Yield: 117 mg, starting from 238 mg of 1b
(53%) (Table 1, entry 2). Colorless solid: mp 108−110 °C, lit.12
109.5−110.5 °C; IR (KBr) ν = 3062 (m), 1610 (w), 1538 (w), 1492
(w), 1453 (m), 1200 (w), 914 (m), 809 (m), 749 (m), 691 (m) cm−1;
1H NMR (300 MHz, CDCl3) δ = 7.75−7.65 (m, 3 H, 2 H), 7.55−7.47
(m, 2 H), 7.43−7.32 (m, 4 H), 7.31−7.21 (m, 2 H), 6.94 (s, 1 H); 13C
NMR (75 MHz, CDCl3) δ = 154.8, 137.9, 132.3, 130.6, 128.8, 128.7,
128.4, 127.6, 127.1, 125.8, 123.8, 104.0; GC−MS (EI, 70 eV) m/z =
220 (M+, 100), 192 (29), 191 (85), 190 (10), 189 (32), 165 (26), 139
(5), 115 (12), 94 (11), 63 (10). Anal. calcd for C16H12O (220.27): C,
87.25; H, 5.49. Found: C, 87.16; H, 5.48.
Preparation of (S)-N-Tosyl-7-(1-aminoethyl)trideca-5,8-diyn-7-ol.
To a suspension of Mg turnings (0.6 g, 24.7 mmol) in anhydrous THF
(3 mL), maintained under nitrogen and under reflux, was added pure
ethyl bromide (0.5 mL) to start the formation of the Grignard reagent.
The remaining bromide was added dropwise in THF solution (1.3 mL
of EtBr in 12 mL of THF; total amount of EtBr added: 2.63 g, 24.1
mmol). The mixture was then allowed to reflux for additional 20 min.
After cooling, the resulting solution of EtMgBr was transferred under
nitrogen to a dropping funnel and added dropwise under nitrogen to a
solution of 1-hexyne (1.98 g, 24.1 mmol) in anhydrous THF (6 mL) at
0 °C with stirring. After additional stirring at 0 °C for 15 min, the
mixture was allowed to warm up to room temperature and then stirred
for additional 2 h. To the solution of 1-hexynylmagnesium bromide
thus obtained was then added, dropwise under nitrogen at room
temperature, a solution of crude N-tosyl-L-alanine methyl ester (1.60 g,
6.21 mmol) in anhydrous THF (7 mL). The resulting mixture was
allowed to stir at 35 °C overnight. After cooling, saturated NH4Cl (50
mL) and AcOEt (50 mL) were sequentially added, and the phases
were separated. The aqueous phase was extracted with AcOEt (3 × 50
mL). The collected organic layers were washed with brine and dried
over Na2SO4. After filtration and evaporation of the solvent, the
products were purified by column chromatography on silica gel using
7:3 hexane−AcOEt as the eluent to give N-tosyl-7-(1-aminoethyl)-
trideca-5,8-diyn-7-ol 3l as a colorless oil (1.72 g, 71% based on crude
2-Butyl-4-phenylfuran (2c). Yield: 160 mg, starting from 218 mg of
1c (80%) (Table 1, entry 3). Colorless solid: mp 32−34 °C; IR (KBr)
ν = 2957 (s), 2930 (s), 2871 (m), 1601 (m), 1449 (m), 1128 (m), 747
1
(s), 695 (s) cm−1; H NMR (300 MHz, CDCl3) δ = 7.55 (s, 1 H),
7.46−7.35 (m, 2 H), 7.34−7.24 (m, 2 H), 7.22−7.12 (m, 1 H) 6.27 (s,
1 H), 2.61 (t, J = 7.7, 2 H), 1.69−1.57 (m, 2 H), 1.44−1.30 (m, 2 H),
0.92 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 157.7, 136.6,
133.0, 128.7, 127.0, 126.7, 125.7, 104.0, 30.1, 27.8, 22.3, 13.8; GC−MS
(EI, 70 eV) m/z = 200 (M+, 55), 171 (7), 158 (29), 157 (100), 141
(6), 129 (53), 128 (61), 127 (24), 115 (15), 102 (7), 77 (9). Anal.
calcd for C14H16O (200.28): C, 83.96; H, 8.05. Found: C, 83.90; H,
8.06.
5-Butyl-2,3-diphenylfuran (2d). Yield: 224 mg, starting from 294
mg of 1d (81%) (Table 1, entry 4). Yellow oil: IR (film) ν = 3060 (m),
3030 (m), 2871 (m), 1558 (m), 1502 (m), 1448 (m), 1330 (m), 1130
N-tosyl-L-alanine methyl ester): [α]25 (MeOH, c = 1.04 × 10−2
g
(m), 1071 (m), 952 (m), 762 (m), 695 (m) cm−1; H NMR (300
D
1
mL−1) = −122°; IR (film) ν = 3479 (m, br), 2934 (m), 2240 (w),
MHz, CDCl3) δ = 7.54−7.47 (m, 2 H), 7.42−7.36 (m, 2 H), 7.34−
7.12 (m, 6 H), 6.14 (s, 1 H), 2.68 (t, J = 7.6, 2 H), 1.76−1.63 (m, 2
H), 1.43 (sextuplet, J = 7.3, 2 H), 0.95 (t, J = 7.3, 3 H); 13C NMR (75
MHz, CDCl3) δ = 155.7, 146.6, 134.8, 131.6, 128.60, 128.53, 128.3,
127.0, 126.9, 125.9, 123.0, 109.3, 30.1, 27.8, 22.4, 13.9; GC−MS m/z =
276 (M+, 70), 234 (21), 233 (100), 215 (2), 203 (9), 189 (8), 178 (3),
127 (6), 105 (26), 77 (20). Anal. calcd for C20H20O (276.37): C,
86.92; H, 7.29. Found: C, 86.94; H, 7.28.
1430 (m), 1333 (s), 1165 (s), 1093 (m), 916 (w), 816 (w), 662 (m)
1
cm−1; H NMR (300 MHz, CDCl3) δ = 7.82−7.77 (m, 2 H), 7.33−
7.28 (m, 2 H), 4.92 (d, br, J = 8.9, 1 H), 3.54−3.43 (m, 1 H), 2.99 (s,
br, 1 H), 2.42 (s, 3 H), 2.18 (t, J = 7.1, 2 H), 2.16 (t, J = 7.1, 2 H),
1.53−1.29 (m, 8 H), 1.22 (d, J = 6.5, 3 H), 0.90 (t, J = 7.1, 3 H), 0.88
(t, J = 7.1, 3 H); 13C NMR (75 MHz, CDCl3) δ = 143.5, 137.7, 129.7,
127.2, 86.3, 85.9, 78.3, 77.6, 66.8, 58.9, 30.4, 30.3, 22.00, 21.97, 21.6,
18.3, 17.8, 15.3, 13.6; MS (ESI+, direct infusion) m/z = 412 [(M +
Na)+, 100], 394 (21), 216 (21). Anal. calcd for C22H31NO3S (389.55):
C, 67.83; H, 8.02; N, 3.60; S, 8.23. Found: C, 67.63; H, 8.02; N, 3.62;
S, 8.24.
2-Butyl-4-hex-1-ynylfuran (2e). Yield: 178 mg, starting from 321
mg of 1e (87%) (Table 1, entry 5). Yellow oil: IR (film) ν = 2958 (m),
2933 (m), 2863 (m), 2230 (w), 1603 (m), 1466 (m), 1333 (m), 1133
1
(m), 944 (w), cm−1; H NMR (300 MHz, CDCl3) δ = 7.39 (s, 1 H),
General Procedure for the CuCl2-Catalyzed Heterocyclode-
hydration of 3-Yne-1,2-diols 1a−i and N-1-Amino-3-yn-2-ol
Derivatives 3a−l To Give Furans 2a−i and Pyrroles 4a−l. A
solution of pure 1 [1a (176 mg), 1b (238 mg), 1c (218 mg), 1d (294
mg), 1e (321 mg), 1f (236 mg), 1g (298 mg), 1h (236 mg), 1i (276
mg), 3a (255 mg), 3b (331 mg), 3c (283 mg), 3d (345 mg), 3e (241
mg), 3f (351 mg), 3g (335 mg), 3h (412 mg), 3i (378 mg), 3j (321
mg), 3k (375 mg), 3l (390 mg); 1.0 mmol] in anyhydrous MeOH (5.0
mL) was added to CuCl2 (2.7 mg, 2.0 × 10−2 mmol, for 1a−i and 3g−
l; 6.8 mg, 5 × 10−2 mmol, for 3a−f) under nitrogen in a Schlenk flask.
The resulting mixture was stirred under nitrogen at 100 °C (for 1a, 1b,
1i, 3a−f) or 80 °C (for 1c−h, 3g−l) and was monitored in TLC until
complete conversion of the substrate (1 h for 3g, 3i, and 3k; 2 h for
1a, 1c−h and 3j; 3 h for 1b and 1i; 8 h for 3c, 3h and 3l; 15 h for 3a,
3b and 3d; 18 h for 3e; 24 h for 3f). Solvent was evaporated, and the
crude products were purified by column chromatography on silica gel
[99:1 hexane−acetone for 2a−c; hexane−AcOEt from 9:1 to 8:2 for
2d, 2e, and 2h; pure hexane for 2g; 8:2 hexane−AcOEt for 4a, 4b, 4d,
4g, and 4l; 9:1 hexane−AcOEt for 4c, 4h, 4i, and 4k; 6:4 hexane−
5.98 (s, 1 H) 2.56 (t, J = 7.5, 2 H), 2.36 (t, J = 6.9, 2 H), 1.65−1.24
(m, 8 H), 0.92 (t, J = 7.0, 3 H), 0.91 (t, J = 7.0, 3 H); 13C NMR (75
MHz, CDCl3) δ = 156.7, 143.2, 108.4, 107.8, 91.4, 71.9, 30.9, 29.9,
27.5, 22.2, 22.0, 19.2, 13.8, 13.6; GC−MS m/z = 204 (M+, 63), 189
(11), 175 (5), 161 (100), 147 (14), 133 (11), 119 (32), 105 (30), 91
(54), 77 (23). Anal. calcd for C14H20O (204.31): C, 82.30; H, 9.87.
Found: C, 82.24; H, 9.88.
5-Butyl-3-hex-1-ynyl-2-methylfuran (2f). Yield: 199 mg, starting
from 236 mg of 1f (91%) (Table 1, entry 6). Pale yellow oil: IR (film)
ν = 2958 (m), 2932 (m), 2862 (m), 2230 (w), 1580 (m), 1465 (m),
1232 (m), 1124 (w), 951 (w), 799 (m), 734 (m) cm−1; 1H NMR (300
MHz, CDCl3) δ = 5.87 (s, 1 H), 2.51 (t, J = 7.7, 2 H), 2.37 (t, J = 6.9,
2 H), 2.28 (s, 3 H), 1.63−1.24 (m, 8 H), 0.93 (t, J = 7.4, 3 H), 0.91 (t,
J = 7.4, 3 H); 13C NMR (75 MHz, CDCl3) δ = 154.0, 153.5, 107.6,
103.7, 92.0, 72.9, 31.1, 30.1, 27.5, 22.2, 22.0, 19.2, 13.8, 13.7, 12.5;
GC−MS (EI, 70 eV) m/z = 218 (M+, 28), 203 (1), 175 (100), 161
(2), 145 (4), 133 (11), 115 (4), 105 (5), 91 (8), 77 (6). Anal. calcd for
C15H22O (218.33): C, 82.52; H, 10.16. Found: C, 82.32; H 10.19.
F
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5-Butyl-3-hex-1-ynyl-2-phenylfuran (2g). Yield: 235 mg, starting
from 298 mg of 1g (84%) (Table 1, entry 7). Colorless oil: IR (film) ν
= 2957 (m), 2927 (m), 2872 (m), 2232 (vw), 1600 (m), 1533 (w),
1493 (m), 1466 (m), 1254 (m), 1134 (m), 804 (m), 763 (m) cm−1;
1H NMR (300 MHz, CDCl3) δ = 8.07−7.99 (m, 2 H), 7.41−7.33 (m,
2 H), 7.28−7.19 (m, 1 H), 6.06 (t, J = 0.9, 1 H), 2.62 (td, J = 7.1, 0.9,
2 H), 2.47 (t, J = 6.9, 2 H), 1.70−1.32 (m, 8 H), 0.96 (t, J = 7.3, 3 H),
0.93 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 155.1, 152.3,
131.0, 128.3, 127.1, 124.1, 110.4, 103.9, 94.7, 74.1, 30.8, 30.0, 27.6,
22.2, 22.1, 19.5, 13.8, 13.6; GC−MS m/z = 280 (M+, 55), 265 (2), 237
(100), 207 (4), 195 (9), 178 (8), 165 (22), 152 (11), 115 (5), 105
(22), 77 (28). Anal. calcd for C20H24O (280.40): C, 85.67; H, 8.63.
Found: C, 85.79; H, 8.62.
5-tert-Butyl-3-(3,3-dimethyl-but-1-ynyl)-2-methylfuran-5-butyl-
2,3-diphenylfuran (2h). Yield: 177 mg, starting from 236 mg of 1h
(81%) (Table 1, entry 8). Yellow oil: IR (film) ν = 2968 (m), 2869
(w), 2217 (vw), 1575 (w), 1462 (m), 1362 (m), 1293 (m), 1232 (w),
1184 (w), 943 (m), 802 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ =
5.86 (s, 1 H), 2.28 (s, 3 H), 1.28 (s, 9 H), 1.21 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ = 161.8, 153.2, 104.9, 103.4, 100.3, 71.4, 32.4, 31.3,
28.9, 28.1, 12.4; GC−MS m/z = 218 (M+, 30), 203 (100), 188 (6),
173 (4), 145 (2), 115 (4), 105 (4), 91 (6). Anal. calcd for C15H22O
(218.33): C, 82.52; H, 10.16. Found: C, 82.59; H, 10.16.
N-Boc-2-benzyl-5-butyl-3-methylpyrrole (4d). Yield: 246 mg,
starting from 345 mg of 3d (75%) (Table 3, entry 5). Yellow oil: IR
(film) ν = 2962 (m), 2931 (m), 2877 (w), 1733 (s), 1373 (m), 1328
1
(m), 1252 (m), 1135 (m), 851 (m), 702 (m) cm−1; H NMR (300
MHz, CDCl3) δ = 7.25−7.17 (m, 2 H), 7.15−7.07 (m, 1 H), 7.02−
6.95 (m, 2 H), 5.82 (s, 1 H), 4.18 (s, 2 H), 2.77 (t, J = 7.6, 2 H), 1.98
(s, 3 H), 1.64−1.50 (m, 2 H), 1.47−1.32 (m, 2 H), 1.30 (s, 9 H), 0.93
(t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 150.2, 141.0, 135.6,
128.1, 127.6, 127.3, 125.5, 119.4, 111.8, 82.9, 31.7, 31.4, 29.0, 27.5,
22.6, 14.1, 11.2; MS (ESI+, direct infusion) m/z = 328 [(M + H)+].
Anal. calcd for C21H29NO2 (327.46): C, 77.02; H, 8.93; N, 4.28.
Found: C, 77.09; H, 8.91; N, 4.28.
N-Boc-2-butylpyrrole (4e). Yield: 217 mg, starting from 241 mg of
3e (97%) (Table 3, entry 6). Yellow oil: IR (film) ν = 2958 (m), 2932
(m), 1747 (s), 1405 (m), 1371 (m), 1330 (s), 1254 (w), 1171 (m),
1
1132 (m), 1064 (w), 852 (w), 717 (m) cm−1; H NMR (300 MHz,
CDCl3) δ = 7.18 (dd, J = 3.2, 1.6, 1 H), 6.06 (t, J = 3.2, 1 H), 5.97−
5.92 (m, 1 H), 2.83 (t, J = 7.6, 2 H), 1.66−1.50 (m, 2 H), 1.47−1.33
(m, 2 H), 1.59 (s, 9 H), 0.94 (t, J = 7.3, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 149.6, 136.5, 120.8, 110.7, 109.9, 83.1, 31.1, 28.6, 28.0,
22.5, 14.0; MS (ESI+, direct infusion) m/z = 246 [(M + Na)+]. Anal.
calcd for C13H21NO2 (223.31): C, 69.92; H, 9.48; N, 6.27. Found: C,
69.85; H, 9.50; N, 6.28.
2-Methyl-5-phenyl-3-phenylethynylfuran (2i). Yield: 217 mg,
starting from 276 mg of 1i (84%) (Table 1, entry 9). Colorless
solid: mp 72−73 °C; IR (KBr) ν = 2213 (w), 1600 (m), 1556 (m),
1489 (m), 1439 (m), 1235 (w), 1154 (m), 1113 (w), 1048 (w), 1023
N-Boc-2-benzyl-5-phenylpyrrole (4f). Yield: 106 mg, starting from
351 mg of 3f (32%) (Table 3, entry 7). Colorless solid: mp 89−90 °C,
lit.13 93−94 °C; IR (KBr) ν = 1736 (s), 1602 (w), 1527 (w), 1453
(w), 1369 (m), 1308 (s), 1213 (w), 1146 (m), 1066 (m), 790 (m),
1
1
(w), 928 (m), 816 (m), 753 (s), 689 (s) cm−1; H NMR (300 MHz,
763 (s), 698 (m) cm−1; H NMR (300 MHz, CDCl3) δ = 7.36−7.15
CDCl3) δ = 7.64−7.58 (m, 2 H), 7.53−7.45 (m, 2 H), 7.38−7.16 (m,
6 H), 6.64 (s, 1 H) 2.48 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ =
155.9, 151.9, 131.4, 130.3, 128.7, 128.3, 128.0, 127.4, 123.6, 107.6,
105.4, 92.1, 81.6, 12.9; GC−MS m/z = 258 (M+, 100), 229 (9), 216
(9), 215 (46), 213 (20), 189 (6), 163 (3), 152 (4), 129 (6), 105 (4),
77 (8). Anal. calcd for C19H14O (258.31): C, 88.34; H, 5.56. Found: C,
88.59; H, 5.57.
(m, 10 H), 6.10 (d, J = 3.2, 1 H), 5.84 (dt, J = 3.2, 0.9, 1 H), 4.22 (s,
br, 2 H), 1.12 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ = 150.1, 139.5,
135.6, 135.3, 135.1, 128.8, 128.2, 127.7, 126.7, 126.1, 111.8, 111.4,
83.5, 34.8, 27.1; MS (ESI+, direct infusion) m/z = 356 [(M + Na)+].
Anal. calcd for C22H23NO2 (331.17): C, 79.25; H, 6.95; N, 4.20.
Found: C, 79.19; H, 6.97; N, 4.19.
N-Boc-5-butyl-3-hex-1-ynyl-2-methylpyrrole (4g). Yield: 314 mg,
starting from 335 mg of 3g (99%) (Table 3, entry 8). Pale yellow oil:
IR (film) ν = 2968 (m), 2878 (m), 2229 (w), 1752 (s), 1548 (w),
N-Boc-2-butyl-5-methylpyrrole (4a). Yield: 134 mg, starting from
255 mg of 3a (56%) (Table 3, entry 1). Yellow oil: IR (film) ν = 2958
(s), 2930 (s), 1737 (s), 1626 (w), 1539 (m), 1480 (w), 1388 (m),
1369 (m), 1314 (s), 1256 (m), 1219 (s), 1015 (w), 852 (m), 783 (m)
1
1459 (w), 1338 (s), 1171 (m), 1108 (m), 856 (w) cm−1; H NMR
(300 MHz, CDCl3) δ = 5.87 (t, J = 0.9, 1 H), 2.77−2.69 (m, 2 H),
2.43 (s, 3 H), 2.39 (t, J = 7.0, 2 H), 1.62−1.30 (m, 8 H), 1.58 (s, 9 H),
0.93 (t, J = 7.1, 3 H), 0.92 (t, J = 7.1, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 150.1, 135.3, 134.4, 111.8, 106.4, 91.6, 83.7, 74.9, 31.3,
29.0, 28.1, 22.5, 22.0, 19.3, 14.8, 14.0, 13.6; MS (ESI+, direct infusion)
m/z = 340 [(M + Na)+]. Anal. calcd for C20H31NO2 (317.47): C,
75.67; H, 9.84; N, 4.41. Found: C, 75.75; H, 9.81; N, 4.43.
N-Boc-2-benzyl-5-butyl-3-hex-1-ynylpyrrole (4h). Yield: 287 mg,
starting from 412 mg of 3h (73%) (Table 3, entry 9). Colorless oil: IR
(film) ν = 2958 (m), 2932 (m), 2872 (w), 2231 (vw), 1743 (s), 1455
(w), 1335 (s), 1167 (m), 1131 (m), 850 (w), 703 (w) cm−1; 1H NMR
(300 MHz, CDCl3) δ = 7.26−7.18 (m, 2 H), 7.17−7.03 (m, 3 H), 5.96
(s, 1 H), 4.32 (s, 2 H), 2.72 (t, J = 7.5, 2 H), 2.35 (t, J = 6.9, 2 H),
1.60−1.46 (m, 4 H), 1.46−1.32 (m, 4 H), 1.31 (s, 9 H), 0.92 (t, J =
7.3, 3 H); 0.88 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ =
149.6, 140.5, 135.9, 135.6, 128.2, 127.9, 125.7, 111.4, 107.9, 91.7, 83.8,
74.7, 33.1, 31.1, 28.8, 27.5, 22.5, 22.0, 19.3, 14.0, 13.6; MS (ESI+, direct
infusion) m/z = 416 [(M + Na)+]. Anal. calcd for C26H35NO2
(393.56): C, 79.35; H, 8.96; N, 3.56. Found: C, 79.56; H, 8.95; N,
3.57.
1
cm−1; H NMR (300 MHz, CDCl3) δ = 5.82−5.78 (m, 2 H), 2.82−
2.72 (m, 2 H), 2.37 (s, 2 H), 1.60−1.50 (m, 2 H), 1.59 (s, 9 H), 1.46−
1.31 (m, 2 H), 0.93 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ =
150.5, 136.1, 131.2, 110.1, 109.0, 83.2, 31.4, 29.4, 28.1, 22.6, 16.5, 14.1;
MS (ESI+, direct infusion) m/z = 260 [(M + Na)+]. Anal. calcd for
C14H23NO2 (237.34): C, 70.85; H, 9.77; N, 5.90. Found: C, 70.80; H,
9.75; N, 5.91.
N-Boc-2-benzyl-5-butylpyrrole (4b). Yield: 219 mg, starting from
331 mg of 3b (70%) (Table 3, entry 2). Yellow oil: IR (film) ν = 3019
(m), 2928 (w), 1734 (s), 1496 (m), 1371 (w), 1335 (m), 1216 (s),
1160 (m), 1126 (w), 755 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ =
7.30−7.08 (m, 5 H), 5.84 (d, br, J = 3.2, 1 H), 5.68 (d, br, J = 3.2, 1
H), 4.16 (s, 2 H), 2.83−2.74 (m, 2 H), 1.65−1.50 (m, 2 H), 1.48−1.33
(m, 2 H), 1.42 (s, 9 H), 0.93 (t, J = 7.3, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 150.3, 140.2, 136.8, 133.4, 128.5, 128.2, 125.9, 111.5,
108.9, 83.4, 35.7, 31.3, 29.2, 27.7, 22.6, 14.0; MS (ESI+, direct
infusion) m/z = 336 [(M + Na)+]. Anal. calcd for C20H27NO2
(313.43): C, 76.64; H, 8.68; N, 4.47. Found: C, 76.49; H, 8.70; N,
4.46.
N-Boc-2-butyl-5-isopropylpyrrole (4c). Yield: 202 mg, starting
from 283 mg of 3c (76%) (Table 3, entry 3). Yellow oil: IR (film) ν =
2966 (m), 2933 (m), 2873 (w), 1739 (s), 1458 (w), 1393 (w), 1369
N-Boc-5-butyl-3-hex-1-ynyl-2-isobutylpyrrole (4i). Yield: 280 mg,
starting from 378 mg of 3i (78%) (Table 3, entry 10). Colorless oil: IR
(film) ν = 2957 (m), 2925 (m), 2879 (w), 2231 (vw), 1741 (s), 1469
1
1
(m), 1321 (m), 1159 (m), 1115 (m), 757 (m) cm−1; H NMR (300
(w), 1372 (w), 1322 (s), 1167 (m), 1123 (m), 759 (m) cm−1; H
MHz, CDCl3) δ = 5.87 (dd, J = 3.2, 0.8, 1 H); 5.83 (dt, J = 3.2, 0.8, 1
H), 3.50−3.35 (m, 1 H), 2.77−2.69 (m, 2 H), 1.63−1.50 (m, 2 H),
1.60 (s, 9 H), 1.46−1.32 (m, 2 H), 1.20 (d, J = 6.5, 6 H), 0.93 (t, J =
3.6, 3 H); 13C NMR (75 MHz, CDCl3) δ = 150.6, 142.4, 135.9, 108.6,
106.3, 83.3, 31.4, 29.3, 27.9, 27.1, 23.2, 22.6, 14.0; MS (ESI+, direct
infusion) m/z = 266 [(M + H)+]. Anal. calcd for C16H27NO2
(265.39): C, 72.41; H, 10.25; N, 5.28. Found: C, 72.30; H, 10.26;
N, 5.27.
NMR (300 MHz, CDCl3) δ = 5.87 (s, br), 2.79 (d, J = 7.3, 2 H), 2.71
(t, J = 7.7, 2 H), 2.38 (t, J = 6.7, 2 H), 1.94−1.73 (m, 1 H), 1.60−1.29
(m, 8 H), 1.59 (s, 9 H), 0.98−0.81 (m, 12 H); 13C NMR (75 MHz,
CDCl3) δ = 150.1, 138.0, 135.3, 111.6, 107.4, 91.3, 83.6, 75.6, 36.4,
31.32, 31.26, 29.5, 29.0, 28.0, 27.9, 22.5, 22.4, 22.0, 19.3, 13.9, 13.6;
MS (ESI+, direct infusion) m/z = 382 [(M + Na)+]. Anal. calcd for
C23H37NO2 (359.55): C, 76.83; H, 10.37; N, 3.90. Found: C, 76.70;
H, 10.38; N, 3.89.
G
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
N-Boc-2-butyl-4-hex-1-ynylpyrrole (4j). Yield: 222 mg, starting
from 321 mg of 3j (73%) (Table 3, entry 11). Yellow oil: IR (film) ν =
2958 (m), 2933 (m), 2872 (w), 2226 (w), 1749 (s), 1458 (w), 1370
157 (8), 141 (3), 128 (12), 115 (8), 105 (51), 77 (26). Anal. calcd for
C20H26O2 (298.42): C, 80.50; H, 8.78. Found: C, 80.45; H, 8.76.
1-(5-tert-Butyl-2-methylfuran-3-yl)-3,3-dimethylbutan-1-one
(5h). Yield: 184 mg, starting from 236 mg of 1h (78%) (Table 2, entry
3). Colorless oil: IR (film) ν = 2957 (m), 2869 (w), 1668 (s), 1565
(m), 1464 (m), 1393 (m), 1364 (m), 1230 (m), 1108 (w), 1000 (w),
1
(s), 1342 (s), 1272 (m), 1156 (m), 1109 (w), 1088 (w) cm−1; H
NMR (300 MHz, CDCl3) δ = 7.26 (d, J = 2.0, 1 H), 5.97−5.94 (m, 1
H), 2.83−2.74 (m, 2 H), 2.36 (t, J = 6.9, 2 H), 1.63−1.32 (m, 8 H),
1.58 (s, 9 H), 0.93 (t, J = 7.2, 6 H); 13C NMR (75 MHz, CDCl3) δ =
148.9, 136.5, 123.6, 113.5, 106.8, 89.9, 83.6, 74.4, 31.0, 30.8, 28.3, 28.0,
22.4, 22.0, 19.2, 14.0, 13.7; MS (ESI+, direct infusion) m/z = 326 [(M
+ Na)+]. Anal. calcd for C19H29NO2 (303.44): C, 75.21; H, 9.63; N,
4.62. Found: C, 75.34; H, 9.65; N, 4.61.
N-Boc-2-methyl-5-phenyl-3-phenylethynylpyrrole (4k). Yield: 293
mg, starting from 375 mg of 3k (82%) (Table 3, entry 12). Colorless
oil: IR (film) ν = 2983 (w), 2922 (w), 2210 (m), 1744 (s), 1489 (m),
1370 (m), 1327 (s), 1291 (m), 1250 (m), 1152 (m), 1133 (m), 1067
(w), 850 (m), 775 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.52−
7.47 (m, 2 H), 7.38−7.24 (m, 8 H), 6.24 (s, 1 H), 2.61 (s, 3 H), 1.25
(s, 9 H); 13C NMR (75 MHz, CDCl3) δ = 149.6, 137.0, 134.5, 134.3,
131.3, 128.5, 128.3, 127.8, 127.7, 127.1, 123.9, 114.1, 106.0, 91.4, 84.1,
83.8, 27.3, 14.1; MS (ESI+, direct infusion) m/z = 380 [(M + Na)+].
Anal. calcd for C24H23NO2 (357.44): C, 80.64; H, 6.49; N, 3.92.
Found: C, 80.51; H, 6.50; N, 3.91.
1
902 (m), 799 (m) cm−1; H NMR (300 MHz, CDCl3) δ = 6.13 (s, 1
H), 2.56 (s, 2 H), 2.55 (s, 3 H), 1.26 (s, 9 H), 1.06 (s, 9 H); 13C NMR
(75 MHz, CDCl3) δ = 196.3, 161.0, 156.1, 122.0, 102.0, 52.2, 31.7,
30.7, 29.3, 28.2, 13.9; GC−MS m/z = 236 (M+, 35), 221 (80), 180
(61), 165 (100), 137 (7), 122 (5), 79 (9). Anal. calcd for C15H24O2
(236.35): C, 76.23; H, 10.24. Found: C, 76.31; H, 10.26.
1-(2-Methyl-5-phenylfuran-3-yl)-2-phenyl-ethanone (5i). Yield:
207 mg, starting from 276 mg of 1i (75%) (Table 2, entry 4). Yellow
solid: mp 60−62 °C; IR (KBr) ν = 1680 (s), 1385 (m), 1360 (m),
1
1308 (m), 1198 (w), 1053 (w), 958 (m), 737 (m) cm−1; H NMR
(300 MHz, CDCl3) δ = 7.65−7.59 (m, 2 H), 7.40−7.19 (m, 8 H), 6.86
(s, 1 H), 4.03 (s, 2 H), 2.63 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ =
193.8, 158.9, 151.7, 134.3, 129.9, 129.5, 128.7, 128.6, 127.8, 126.9,
123.7, 122.4, 104.8, 48.0, 14.5; GC−MS m/z = 276 (M+, 21), 185
(100), 157 (22), 129 (8), 115 (26), 105 (6), 91 (6), 77 (11). Anal.
calcd for C19H16O2 (276.33): C, 82.58; H, 5.84. Found: C, 82.51; H,
5.83.
N-Tosyl-5-butyl-3-hex-1-ynyl-2-methylpyrrole (4l). Yield: 308 mg,
starting from 390 mg of 3l (83%) (Table 3, entry 13). Brown oil: IR
(film) ν = 2931 (m), 2872 (m), 2232 (w), 1739 (s), 1597 (w), 1457
Synthesis of 2-Benzyl-5-phenylpyrrole 6f by CuCl2-Cata-
lyzed Heterocyclodehydration of N-Boc-4-amino-1,5-diphe-
nylpent-1-yn-3-ol 3f, Followed by Basic Treatment (Scheme 2).
A solution of N-Boc-4-amino-1,5-diphenylpent-1-yn-3-ol 3f (351 mg,
1 mmol) in anyhydrous MeOH (5.0 mL) was added to CuCl2 (2.7 mg,
6.8 mg, 5 × 10−2 mmol) under nitrogen in a Schlenk flask. The
resulting mixture was stirred under nitrogen at 100 °C for 24 h. After
cooling to room temperature, MeONa (162 mg, 3 mmol) was added
under nitrogen, and the resulting mixture was heated at 100 °C for 15
h. After cooling, solvent was evaporated, and the crude product was
purified by column chromatography on silica gel using 95:5 hexane−
AcOEt as eluent. Yield: 124 mg, starting from 351 mg of 3f (53%)
(Scheme 2). Colorless solid: mp 91−92 °C; IR (KBr) ν = 3434 (m,
br), 1603 (m), 1513 (m), 1453 (w), 1214 (w), 1041 (m), 783 (w),
1
(w), 1366 (s), 1251 (m), 1106 (m), 1092 (m), 813 (m), cm−1; H
NMR (300 MHz, CDCl3) δ = 7.55−7.48 (m, 2 H), 7.29−7.21 (m, 2
H), 5.94 (s, br, 1 H), 2.80−2.70 (m, 2 H), 2.44 (s, 3 H), 2.38 (s, 3 H),
2.37 (t, J = 6.9, 2 H), 1.63−1.28 (m, 8 H), 0.92 (t, J = 7.1, 3 H), 0.89
(t, J = 7.1, 3 H); 13C NMR (75 MHz, CDCl3) δ = 144.6, 137.2, 136.6,
135.3, 130.0, 126.2, 113.1, 108.1, 92.9, 73.9, 31.1, 31.0, 28.3, 22.4, 22.0,
21.5, 19.2, 14.1, 13.9, 13.6; MS (ESI+, direct infusion) m/z = 394 [(M
+ Na)+]. Anal. calcd for C22H29NO2S (371.54): C, 71.12; H, 7.87; N,
3.77; S, 8.63. Found: C, 71.32; H, 7.86; N, 3.78; S, 8.61.
General Procedure for the Synthesis of 3-Acylfurans 5f−i by
CuCl2-Catalyzed Cyclodehydration/Acid-Catalyzed Water Ad-
dition of 2-Alkynyl-3-yne-1,2-diols 1f−i. In a typical experiment, a
solution of pure 1 [1f (236 mg), 1g (298 mg), 1h (236 mg), 1i (276
mg); 1.0 mmol] in anyhydrous MeOH (5.0 mL) was added to CuCl2
(2.7 mg, 2.0 × 10−2 mmol) and TsOH monohydrate (38.1 mg, 0.2
mmol) under nitrogen in a Schlenk flask. The resulting mixture was
stirred under nitrogen at 80 °C (for 1f−h) or 100 °C (for 1i) and was
monitored by TLC until complete conversion of the substrate (3 h for
1f and 1h; 15 h for 1i; 24 h for 1g). Solvent was evaporated, and the
crude products were purified by column chromatography on silica gel
using as eluent 99:1 hexane−acetone (for 5f, 5h, and 5i) or 98:2
hexane−AcOEt (for 5g).
1-(5-Butyl-2-methylfuran-3-yl)-hexan-1-one (5f). Yield: 199 mg,
starting from 236 mg of 1f (84%) (Table 2, entry 1). Colorless oil: IR
(film) ν = 2960 (m), 2931 (m), 2874 (m), 1713 (s), 1600 (m), 1467
(w), 1380 (m), 1217 (m), 759 (s) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 6.19 (s, 1 H), 2.65 (t, J = 7.3, 2 H), 2.56 (t, J = 7.7, 2 H), 2.54 (s, 3
H), 1.73−1.55 (m, 4 H), 1.45−1.26 (m, 6 H), 0.99−0.85 (m, 6 H);
13C NMR (75 MHz, CDCl3) δ = 196.9, 156.7, 154.4, 121.8, 105.0,
41.3, 31.7, 30.1, 27.5, 23.9, 22.6, 22.3, 14.3, 13.9, 13.8; GC−MS m/z =
236 (M+, 21), 221 (2), 193 (22), 180 (78), 165 (100), 147 (3), 137
(41), 123 (16), 108 (4), 95 (8), 81 (10). Anal. calcd for C15H24O2
(236.35): C, 76.23; H, 10.24. Found: C, 76.11; H, 10.24.
1
760 (m), 721 (s), 690 (m) cm−1; H NMR (500 MHz, CDCl3) δ =
8.02 (s, br, 1 H); 7.43−7.22 (m, 9 H); 7.17−7.12 (m, 1 H), 6.46−6.41
(m, 1 H), 6.07−6.02 (m, 1 H), 4.02 (s, 2 H); 13C NMR (126 MHz,
CDCl3) δ = 139.3, 132.8, 132.0, 131.5, 128.8, 128.69, 128.67, 126.6,
125.8, 123.5, 108.6, 106.1, 34.3; GC−MS m/z = 233 (M+, 99), 232
(47), 156 (100), 128 (16), 115 (13), 104 (7), 89 (6), 77 (18). Anal.
calcd for C17H15N (233.31): C, 87.52; H, 6.48; N, 6.00. Found: C,
87.65; H, 6.47; N 6.01.
General Procedure for the Synthesis of 3-Acylpyrroles 7g−i,
7k, 7m−o and 9 by CuCl2-Catalyzed Heterocyclodehydration/
Acid- and CO2-Promoted Water Addition of N-Boc-2-alkynyl-1-
amino-3-yn-2-ols 3g−i, 3k, 3m−o, and of (S)-7-(Pyrrolidin-2-
yl)trideca-5,8-diyn-7-ol 8. A 250 mL stainless steel autoclave was
charged in the presence of air with CuCl2 (4.0 mg, 2.98 × 10−2 mmol),
anhydrous MeOH (7.4 mL), (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-
ol 8 (389 mg, 1.49 mmol) or N-Boc-2-alkynyl-1-amino-3-yn-2-ols [3g
(500 mg), 3h (613 mg), 3i (563 mg), 3k (559 mg), 3m (500 mg), 3n
(542 mg), 3o (563 mg), 1.49 mmol], TsOH monohydrate (56.6 mg,
0.3 mmol) and H2O (26.8 mg,1.49 mmol). The autoclave was sealed,
and while the mixture was stirred, the autoclave was pressurized with
CO2 (40 atm). After being stirred at 100 °C for 15 h, the autoclave was
cooled, degassed and opened. The crude products were purified by
column chromatography on silica gel (8:2 hexane−AcOEt for 7g−i,
7k, 7m, 7n, 9; 99:1 hexane−acetone for 7o).
1-(5-Butyl-2-phenylfuran-3-yl)-hexan-1-one (5g). Yield: 266 mg,
starting from 298 mg of 1g (89%) (Table 2, entry 2). Yellow oil: IR
(film) ν = 2957 (m), 2932 (m), 2872 (m), 1682 (s), 1541 (m), 1489
1-(5-Butyl-2-methyl-1H-pyrrol-3-yl)-hexan-1-one (7g). Yield: 245
mg, starting from 500 mg of 3g (70%) (Table 5, entry 1). Yellow solid:
mp 48−49 °C; IR (KBr) ν = 3266 (m), 2952 (m), 2929 (m), 2860
(w), 1636 (s), 1585 (m), 1522 (m), 1468 (m), 1384 (m), 1193 (m),
1
(m), 1386 (w), 1264 (w), 1169 (w), 768 (m), 692 (m) cm−1; H
NMR (300 MHz, CDCl3) δ = 7.94−7.86 (m, 2 H), 7.47−7.33 (m, 3
H), 6.38 (s, 1 H), 2.70 (t, J = 7.3, 2 H), 2.66 (t, J = 7.6, 2 H), 1.74−
1.58 (m, 4 H), 1.49−1.34 (m, 2 H), 1.34−1.23 (m, 4 H), 0.95 (t, J =
7.3, 3 H), 0.88 (t, J = 6.9, 3 H); 13C NMR (75 MHz, CDCl3) δ =
197.1, 155.6, 154.6, 130.5, 129.2, 128.2, 128.1, 122.6, 107.2, 41.8, 31.4,
29.9, 27.5, 24.0, 22.5, 22.2, 13.9, 13.8; GC−MS m/z = 298 (M+, 35),
255 (21), 242 (47), 241 (41), 227 (100), 213 (5), 199 (9), 185 (9),
1
961 (m), 788 (m), 728 (w) cm−1; H NMR (300 MHz, CDCl3) δ =
8.84 (s, br, 1 H), 6.20−6.14 (m, 1 H), 2.71 (t, J = 7.6, 2 H), 2.56−2.48
(m, 5 H), 1.75−1.52 (m, 4 H), 1.41−1.25 (m, 6 H), 0.95−0.85 (m, 6
H); 13C NMR (75 MHz, CDCl3) δ = 198.1, 134.0, 130.8, 120.6, 106.5,
40.6, 31.9, 31.6, 27.1, 24.7, 22.6, 22.4, 13.95, 13.91, 13.8; GC−MS m/z
H
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 235 (M+, 7), 192 (14), 179 (22), 164 (100), 150 (7), 136 (34), 122
(15), 107 (24), 93 (44). Anal. calcd for C15H25NO (235.37): C, 76.55;
H, 10.71; N, 5.95. Found: C, 76.58; H, 10.68; N, 5.96.
(m), 1003 (w), 975 (w), 794 (m) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 8.27 (s, br), 6.17−6.12 (m, 1 H), 2.81 (d, J = 6.8, 2 H), 2.60 (s, 2
H), 1.97 (nonuplet, J = 6.8, 1 H), 1.29 (s, 9 H), 1.05 (s, 9 H), 0.88 (d,
J = 6.8, 6 H); 13C NMR (75 MHz, CDCl3) δ = 197.4, 139.0, 137.8,
121.5, 104.9, 52.4, 36.9, 31.4, 31.0, 30.31, 30.27, 28.8, 22.4; GC−MS
m/z = 277 (M+, 49), 262 (50), 234 (100), 221 (27), 220 (45), 206
(76), 190 (7), 178 (72), 164 (14), 148 (8), 135 (13), 120 (14). Anal.
calcd for C18H31NO (277.44): C, 77.92; H, 11.26; N, 5.05. Found: C,
77.90; H, 11.29; N, 5.04.
1-(3-Butyl-6,7-dihydro-5H-pyrrolizin-1-yl)-hexan-1-one (9). Yield:
265 mg, starting from 389 mg of 8 (68%) (eq 2). Yellow oil: IR (film)
ν = 2957 (m), 2931 (s), 2872 (m), 1652 (s), 1520 (m), 1431 (m),
1299 (w), 754 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 6.30−6.26
(m, 1 H), 3.85 (t, J = 7.2, 2 H), 3.09 (t, J = 7.5, 2 H), 2.64 (t, J = 7.5, 2
H), 2.56−2.46 (m, 4 H), 1.75−1.52 (m, 4 H), 1.46−1.28 (m, 6 H),
0.98−0.84 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ = 196.2, 142.0,
129.4, 116.9, 109.1, 44.9, 39.9, 31.9, 31.1, 27.0, 26.5, 26.2, 24.8, 22.6,
22.4, 14.0, 13.8; MS (ESI+, direct infusion) m/z = 284 [(M + Na)+].
Anal. calcd for C17H27NO (261.40): C, 78.11; H, 10.41; N, 5.36.
Found: C, 78.13; H, 10.43; N, 5.35.
1-(2-Benzyl-5-butyl-1H-pyrrol-3-yl)-hexan-1-one (7h). Yield: 381
mg, starting from 613 mg of 3h (82%) (Table 5, entry 2). Yellow oil:
IR (film) ν = 3375 (m, br), 2956 (m), 2930 (m), 2859 (m), 1635 (s),
1587 (m), 1516 (m), 1461 (s), 1396 (m), 1191 (m), 959 (m), 794
1
(m), 725 (m) cm−1; H NMR (300 MHz, CDCl3) δ = 8.97 (s, br, 1
H), 7.23−7.16 (m, 5 H), 6.22−6.18 (m, 1 H), 2.68 (t, J = 7.6, 2 H),
2.44 (t, J = 7.6, 2 H), 1.71−1.46 (m, 4 H), 1.37−1.20 (m, 6 H), 0.92−
0.83 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ = 198.1, 138.9, 136.1,
131.6, 128.9, 128.6, 126.4, 120.5, 106.6, 40.6, 33.7, 31.8, 31.5, 27.1,
24.7, 22.6, 22.3, 13.9, 13.8; GC−MS m/z = 311 (M+, 36), 268 (38),
255 (25), 240 (100), 212 (47), 196 (19), 183 (89), 168 (92), 164
(53), 154 (21), 141 (11), 115 (14), 91 (46). Anal. calcd for C21H29NO
(311.46): C, 80.98; H, 9.38; N, 4.50. Found: C, 81.0; H, 9.35; N, 4.49.
1-(5-Butyl-2-isobutyl-1H-pyrrol-3-yl)-hexan-1-one (7i). Yield: 281
mg, starting from 563 mg of 3i (68%) (Table 5, entry 3). Yellow oil:
IR (film) ν = 3281 (m), 2957 (s), 2925 (s), 2868 (m), 1631 (s), 1588
(w), 1517 (m), 1466 (s), 1394 (m), 1288 (w), 961 (w), 795 (m)
1
cm−1; H NMR (300 MHz, CDCl3) δ = 9.26 (s, br, 1 H), 6.22−6.16
Synthesis of 3-Acylpyrrole 7p by CuCl2-Catalyzed Hetero-
cyclodehydration/Acid- and CO2-Promoted Water addition of
(S)-N-Boc-4-amino-3-ethynyl-6-methylhept-1-yn-3-ol 3p. (S)-
N-Boc-4-Amino-6-methyl-1-trimethylsilanyl-3-trimethylsilanylethynyl-
hept-1-yn-3-ol 3p′ (5.87 g, 14.3 mmol) was dissolved in 50 mL of
anhydrous methanol. To the solution was added anhydrous K2CO3
(0.36 g, 2.86 mmol), and the resulting mixture was stirred under
nitrogen at room temperature for 15 h. Methanol was evaporated in
order to remove ca. three-fourths of the initial volume, and
successively to the crude product were added diethyl ether (50 mL)
and water (50 mL). The two phases were separated, and the aqueous
phase was extracted with diethyl ether (2 × 50 mL). The collected
organic layers were dried over Na2SO4. Filtration and evaporation of
the solvent led to crude (S)-N-Boc-4-amino-3-ethynyl-6-methylhept-1-
yn-3-ol 3p, which was used as such without further purification for the
next step. A 250 mL stainless steel autoclave was charged in the
presence of air with CuCl2 (4.0 mg, 2.98 × 10−2 mmol), anhydrous
MeOH (7.4 mL), crude 3p (395 mg, formally deriving from 500 mg of
3p′, 1.49 mmol], TsOH monohydrate (56.6 mg, 0.3 mmol) and H2O
(26.8 mg, 1.49 mmol). The autoclave was sealed, and while the
mixture was stirred, the autoclave was pressurized with CO2 (40 atm).
After being stirred at 100 °C for 15 h, the autoclave was cooled,
degassed and opened. The crude product 1-(2-isobutyl-furan-3-yl)-
ethanone 7p was purified by column chromatography on silica gel
using 8:2 hexane−AcOEt as eluent. Yield: 202 mg, starting from 500
mg of 3p′ (82%). Colorless oil: IR (KBr) ν = 3264 (m, br), 2957 (m),
1637 (s), 1560 (m), 1464 (m), 1389 (m), 938 (m), 896 (w), 719 (w)
(m, 1 H), 2.81 (d, J = 6.9, 2 H), 2.72 (t, J = 7.6, 2 H), 2.54 (t, J = 7.6, 2
H), 1.99 (nonuplet, J = 6.9, 1 H), 1.75−1.53 (m, 4 H), 1.42−1.23 (m,
6 H), 0.94−0.85 (m, 12 H); 13C NMR (75 MHz, CDCl3) δ = 198.0,
138.2, 130.9, 120.3, 106.6, 40.7, 36.8, 31.8, 31.6, 28.9, 27.1, 24.9, 22.6,
22.5, 22.4, 13.9, 13.8; GC−MS m/z = 277 (M+, 25), 234 (93), 221
(20), 206 (76), 178 (88), 164 (100), 136 (32), 120 (23), 107 (27), 93
(69). Anal. calcd for C18H31NO (277.44): C, 77.92; H, 11.26; N, 5.05.
Found: C, 77.94; H, 11.29; N, 5.03.
1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-phenyl-ethanone (7k).
Yield: 328 mg, starting from 559 mg of 3k (80%) (Table 5, entry
4). Yellow solid: mp 176 −178 °C; IR (KBr) ν = 3273 (m), 1623 (s),
1475 (m), 1448 (m), 1197 (m), 1144 (w), 1071 (w), 988 (w), 815
(m), 765 (m), 729 (m), 693 (m) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 9.04 (s, br, 1 H), 7.48−7.42 (m, 2 H), 7.38−7.15 (m, 8 H), 6.86−
6.83 (m, 1 H), 4.10 (s, 2 H), 2.53 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 194.8, 137.3, 135.5, 131.7, 130.0, 129.5, 129.0, 128.5,
126.7, 126.6, 123.8, 121.4, 107.1, 47.2, 14.1; GC−MS m/z = 275 (M+,
8), 184 (100), 156 (5), 129 (17), 115 (7), 104 (8), 91 (10), 77 (7).
Anal. calcd for C19H17NO (275.34): C, 82.88; H, 6.22; N, 5.09.
Found: C, 82.90; H, 6.27; N, 5.08.
1-(5-tert-Butyl-2-methyl-1H-pyrrol-3-yl)-3,3-dimethylbutan-1-
one (7m). Yield: 305 mg, starting from 500 mg of 3m (87%) (Table 5,
entry 5). Yellow solid: mp 202−204 °C; IR (KBr) ν = 3283 (m, br),
2959 (m), 2867 (w), 1628 (s), 1576 (m), 1515 (m), 1474 (m), 1385
1
(m), 1362 (m), 1241 (m), 974 (m), 794 (m) cm−1; H NMR (300
MHz, CDCl3) δ = 8.51 (s, br), 6.16−6.13 (m, 1 H); 2.23 (s, 2 H), 3.16
(s, 3 H), 1.29 (s, 9 H), 1.06 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ =
197.6, 139.3, 133.8, 121.8, 104.7, 52.3, 31.1, 30.4, 30.3, 28.4, 14.1;
GC−MS m/z = 235 (25), 220 (43), 179 (23), 164 (100), 148 (7), 121
(15). Anal. calcd for C15H25NO (235.37): C, 76.55; H, 10.71; N, 5.95.
Found: C, 76.54; H, 10.69; N, 5.96.
1
cm−1; H NMR (300 MHz, CDCl3) δ = 9.95 (s, br, 1 H), 6.62−6.57
(m, 1 H), 6.56−6.51 (m, 1 H), 2.86 (d, J = 6.8, 2 H), 2.44 (s, 3 H),
2.03 (nonuplet, J = 6.8, 1 H), 0.90 (d, J = 6.8, 6 H); 13C NMR (75
MHz, CDCl3) δ = 195.7, 139.5, 120.4, 116.0, 110.8, 36.7, 28.8, 28.5,
22.5; GC−MS m/z = 165 (M+, 41), 150 (19), 132 (3), 122 (100), 108
(26), 94 (9), 79 (9). Anal. calcd for C10H15NO (165.23): C, 72.69; H,
9.15; N, 8.48. Found: C, 72.80; H, 9.17; N, 8.46.
1-(5-Butyl-2-isopropyl-1H-pyrrol-3-yl)-hexan-1-one (7n). Yield:
279 mg, starting from 542 mg of 3n (71%) (Table 5, entry 6).
Yellow oil: IR (film) ν = 3297 (m, br), 2957 (m), 2930 (s), 2869 (m),
1630 (s), 1591 (m), 1514 (m), 1467 (s), 1402 (m), 1293 (m), 1191
1
(w), 1164 (w), 1074 (w), 953 (m), 796 (m) cm−1; H NMR (300
ASSOCIATED CONTENT
■
MHz, CDCl3) δ = 9.32 (s, br, 1 H), 6.22−6.16 (m, 1 H), 3.89
(heptuplet, J = 6.9, 1 H, 1 H), 2.74 (t, J = 7.5, 2 H), 2.55 (t, J = 7.6, 2
H), 1.77−1.54 (m, 4 H), 1.44−1.29 (m, 6 H), 1.25 (d, J = 6.9, 6 H),
0.95−0.84 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ = 198.0, 144.3,
130.9, 118.9, 106.6, 40.9, 31.9, 31.6, 27.2, 26.4, 24.9, 22.6, 22.5, 21.8,
14.0, 13.8; GC−MS m/z = 263 (M+, 17), 248 (6), 220 (21), 207 (20),
192 (100), 178 (8), 164 (21), 150 (12), 120 (16), 106 (35). Anal.
calcd for C17H29NO (263.42): C, 77.51; H, 11.10; N, 5.32. Found: C,
77.49; H, 11.07; N, 5.31.
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
1-(5-tert-Butyl-2-isobutyl-1H-pyrrol-3-yl)-3,3-dimethyl-butan-1-
one (7o). Yield: 322 mg, starting from 563 mg of 3o (78%) (Table 5,
entry 7). Yellow solid: mp 126−128 °C; IR (KBr) ν = 3287 (m, br),
2958 (m), 2868 (w), 1628 (s), 1580 (m), 1470 (m), 1365 (m), 1232
*E-mail: bartolo.gabriele@unical.it.
Notes
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Mancuso, R.; Lupinacci, E.; Spina, R.; Salerno, G.; Veltri, L.;
Dibenedetto, A. Tetrahedron 2009, 65, 8507−8512. (g) Gabriele, B.;
Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org.
Chem. 2008, 73, 4971−4977. (h) Gabriele, B.; Mancuso, R.; Salerno,
G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873−6877.
(5) A preliminary communication of this work was published
recently: Gabriele, B.; Plastina, P.; Vetere, M. V.; Veltri, L.; Mancuso,
R.; Salerno, G. Tetrahedron Lett. 2010, 51, 3565−3567.
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione, dell’Uni-
■
versita
̀
e della Ricerca (MIUR, Rome, Italy) is gratefully
acknowledged (Progetto di Ricerca d’Interesse Nazionale PRIN
2008A7P7YJ). Thanks are due to the European Commission,
FSE (Fondo Sociale Europeo) and Calabria Region for a
fellowship grant to R.M.
(6) Furans are a very important class of heterocycles, with many
important applications. For recent reviews on synthesis and
applications of furans, see: (a) Moran, W. J.; Rodriguez, A. Org.
Prep. Proced. Int. 2012, 44, 103−130. (b) Gandini, A. Polym. Chem.
2010, 1, 245−251. (c) Bodovskaya, L. A.; Povarova, L. V. Chem.
Heterocycl. Compd. 2009, 45, 1023−1034. (d) Cadierno, V.; Crochet,
P. Curr. Org. Synth. 2008, 5, 343−364. (e) Montagnon, T.; Tofi, N.;
Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41, 1001−1011. (f) Balme,
G.; Bouyssi, D.; Monteiro, N. Heterocycles 2007, 73, 87−124.
(g) Merino, P.; Tejero, T.; Delso, J. I.; Matute, R. Curr. Org. Chem.
2007, 11, 1076−1091. (h) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug
Discovery Dev. 2005, 8, 723−740. (i) Moreau, C.; Belgacem, M. N.;
Gandini, A. Top. Catal 2004, 27, 11−30. (j) Cacchi, S.; Fabrizi, G.;
Goggiomani, A. Heterocycles 2002, 56, 613−632.
(7) Pyrroles are a very important class of heterocycles, with many
important applications. For recent reviews on synthesis and
applications of pyrroles, see: (a) Dydio, P.; Lichosyt, D.; Jurczak, J.
Chem. Soc. Rev. 2011, 40, 2971−2985. (b) Estevez, V.; Villacampa, M.;
Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402−4421. (c) Schmuck,
C.; Rupprecht, D. Synthesis 2007, 3095−3110. (d) Biava, M.; Porretta,
G. C.; Manetti, F. Mini-Rev. Med. Chem. 2007, 7, 65−78. (e) Jolicoeur,
B.; Chapman, E. E.; Thompson, A.; Lubell, W. D. Tetrahedron 2006,
62, 11531−11563. (f) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith,
J. A.; Wong, D. J. Eur. J. Org. Chem. 2006, 3043−3060. (g) Roman, G.
Mini-Rev. Org. Chem. 2006, 3, 167−184. (h) Walsh, C. T.; Garneau-
Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517−531.
(i) Agarwal, S.; Cammerer, S.; Filali, S.; Frohner, W.; Knoll, J.; Krahl,
M. P.; Reddy, K. R.; Knolker, H. J. Curr. Org. Chem. 2005, 9, 1601−
1614. (j) Joshi, U.; Pipelier, M.; Naud, S.; Dubreuil, D. Curr. Org.
Chem 2005, 9, 261−288. (k) Huffman, J. W.; Padgett, L. W. Curr. Med.
Chem. 2005, 12, 1395−1411. (l) Trofimov, B. A.; Sobenine, L. N.;
Demenev, A. P.; Mikhaleva, A. Chem. Rev. 2004, 104, 2481−2506.
(m) Guernion, N. J. L.; Hayes, W. Curr. Org. Chem 2004, 8, 637−651.
(n) Schmuck, C.; Geiger, L. Curr. Org. Chem. 2003, 7, 1485−1502.
(o) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O.
R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411−454.
(8) We also tested the acid-catalyzed hydration reaction of pure 3-
alkynylfuran 2f under the same conditions as those of entry 1 (Table
2) in the absence of CuCl2 and in the presence of 1 equiv of H2O and
20 mol % of TsOH·H2O. The isolated yield of furan 5f was ca. 90%.
(9) See, for example, Nemoto, K.; Onozawa, S.; Egusa, N.;
Morohashi, N.; Hattori, T. Tetrahedron Lett. 2009, 50, 4512−4514.
(10) The reaction of pure 3-alkynylpyrrole 4k, carried out under the
same conditions as those of entry 4 (Table 5) in the absence of CuCl2
and in the presence of 1 equiv of H2O and 20 mol % of TsOH·H2O,
led to the formation of 3-acylpyrrole 7k in 92% isolated yield.
(11) Bew, S. P.; El-Taeb, G. M. M.; Jones, S.; Knight, D. W.; Tan, W.
Eur. J. Org. Chem. 2007, 5759−5770.
REFERENCES
■
(1) For recent reviews, see: (a) Liu, T.; Fu, H. Synthesis 2012, 44,
2805−2824. (b) Jin, T.; Yan, M.; Yamamoto, Y. ChemCatChem 2012,
4, 1217−1229. (c) Liu, Y.; Wan, J.-P. Chem.Asian J. 2012, 7, 1488−
1501. (d) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177−185.
(e) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464−3484.
(f) Ranu, B. C.; Dey, R.; Chatterjee, T.; Ahammed, S. ChemSusChem
2012, 5, 22−44. (g) Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255,
2933−2945. (h) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew.
Chem., Int. Ed. 2011, 50, 11062−11087. (i) Sadig, J. E. R.; Willis, M. C.
Synthesis 2011, 1−22. (j) Zhang, M. Appl. Organomet. Chem. 2010, 24,
269−284. (k) Zhang, M. Appl. Organomet. Chem. 2010, 24, 269−284.
(l) Eckenhoff, W. T. Catal. Rev. 2010, 52, 1−59. (m) Hein, J. E.;
Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302−1315.
(2) For selected very recent examples of copper-catalyzed reactions,
see: (a) Mac Leod, T. C. O.; Kopylovich, M. N.; Da Silva, M. F. C. G.;
Mahmudova, K. T.; Pombeiro, A. J. L. Appl. Catal., A 2012, 439, 15−
23. (b) Grigg, R. D.; van Hoveln, R.; Schomaker, J. M. J. Am. Chem.
Soc. 2012, 134, 16131−16134. (c) Inamoto, K.; Nozawa, K.;
Kadokawa, J.; Kondo, Y. Tetrahedron 2012, 68, 7794−7798.
(d) Rad, M. N. S.; Behrouz, S.; Doroodmand, M. M.; Movahediyan,
A. Tetrahedron 2012, 68, 7812−7821. (e) Zhang, Y.-J.; Dayoub, W.;
Chen, G.-R.; Chen, G.-R.; Lemaire, M. Tetrahedron 2012, 68, 7400−
7407. (f) Zeng, J.; Tan, Y. J.; Leow, M. L.; Liu, X.-W. Org. Lett. 2012,
14, 4386−4389. (g) Ding, J.; Lee, J. C. H.; Hall, D. G. Org. Lett. 2012,
14, 4462−4465. (h) Qu, G.-R.; Liang, L.; Niu, H.-Y.; Rao, W.-H.; Guo,
H.-M.; Fossey, J. S. Org. Lett. 2012, 14, 4494−4497. (i) Liu, C.; Zhang,
W.; Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14, 4525−4527. (j) Guo, N.;
Ji, J.-X. Tetrahedron Lett. 2012, 53, 4797−4801. (k) Germain, N.;
Magrez, M.; Kehrli, S.; Mauduit, M.; Alexakis, A. Eur. J. Org. Chem.
2012, 5301−5306. (l) Chen, J.; Liu, B.; Liu, D.; Liu, S.; Cheng, J. Adv.
Synth. Catal. 2012, 354, 2438−2442. (m) Boobalan, R.; Lee, G.-H.;
Chen, C. Adv. Synth. Catal. 2012, 354, 2511−2520. (n) Bridier, B.;
Karhanek, D.; Perez-Ramirez, J. ChemCatChem 2012, 4, 1420−1427.
(3) For representative examples, see: (a) Tsuchikama, K.;
Hashimoto, Y.; Endo, K.; Shibata, T. Adv. Synth. Catal. 2009, 351,
2850−2854. (b) Egi, M.; Azechi, K.; Akai, S. Org. Lett. 2009, 11,
5002−5005. (c) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org.
Lett. 2009, 11, 4624−4627. (d) Yada, Y.; Miyake, Y.; Nishibayashi, Y.
Organometallics 2008, 27, 3614−3617. (e) Hayes, S. J.; Knight, D. W.;
Menzies, M. D.; O’Halloran, M.; Tan, W.-F. Tetrahedron Lett. 2007,
48, 7709−7712. (f) Knight, D. W.; Sharland, C. M. Synlett 2004, 119−
121. (g) Sakai, M.; Sasaki, M.; Tanino, K.; Miyashita, M. Tetrahedron
Lett. 2002, 43, 1705−1708. (h) McDonald, F. E.; Zhu, H. Y. H.
Tetrahedron 1997, 53, 11061−11068. (i) McDonald, F. E.; Gleason,
M. M. J. Am. Chem. Soc. 1996, 118, 6648−6659. (j) McDonald, F. E.;
Connolly, C. B.; Gleason, M. M.; Towne, T. B.; Treiber, K. D. J. Org.
Chem. 1993, 58, 6952−6953. (k) Wakabayashi, Y.; Fukuda, Y.;
Shiragami, H.; Utimoto, K.; Nozaki, H. Tetrahedron 1985, 41, 3655−
3661. (l) Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981,
22, 4277−4278.
(12) Harris, C. M.; Cleary, J. J.; Harris, T. M. J. Org. Chem. 1974, 39,
72−77.
(13) Paulus, O.; Alcaraz, G.; Vaultier, M. Eur. J. Org. Chem. 2002,
2565−2572.
(4) In this field, we have contributed several examples: (a) Gabriele,
B.; Mancuso, R.; Maltese, V.; Veltri, L.; Salerno, G. J. Org. Chem. 2012,
77, 9905−9909. (b) Gabriele, B.; Mancuso, R.; Veltri, L.; Maltese, V.;
Salerno, G. J. Org. Chem. 2012, 77, 8657−8668. (c) Gabriele, B.;
Veltri, L.; Mancuso, R.; Salerno, G.; Maggi, S.; Aresta, B. M. J. Org.
Chem. 2012, 77, 4005−4016. (d) Gabriele, B.; Mancuso, R.; Lupinacci,
E.; Veltri, L.; Salerno, G.; Carfagna, C. J. Org. Chem. 2011, 76, 8277−
8286. (e) Gabriele, B.; Veltri, L.; Mancuso, R.; Plastina, P.; Salerno, G.;
Costa, M. Tetrahedron Lett. 2010, 51, 1663−1665. (f) Gabriele, B.;
J
dx.doi.org/10.1021/jo400533j | J. Org. Chem. XXXX, XXX, XXX−XXX