A simple and convenient synthesis of substituted furans and pyrroles by CuCl2-catalyzed heterocyclodehydration of 3-yne-1,2-diols and N-Boc- or N-tosyl-1-amino-3-yn-2-ols

Article abstract of DOI:10.1016/j.tetlet.2010.05.001

A simple and economical synthesis of substituted furans and pyrroles, by ligand-free CuCl₂-catalyzed heterocyclodehydration of readily available 3-yne-1,2-diols and N-Boc- or N-tosyl-1-amino-3-yn-2-ols, respectively, is presented. Reactions are carried out in MeOH at 80-100 °C for 1-24 h and afford the corresponding heterocyclic derivatives in 53-99% isolated yields.

Full text of DOI:10.1016/j.tetlet.2010.05.001

Tetrahedron Letters 51 (2010) 3565–3567
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Tetrahedron Letters
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A simple and convenient synthesis of substituted furans and pyrroles by
CuCl2-catalyzed heterocyclodehydration of 3-yne-1,2-diols and N-Boc- or
N-tosyl-1-amino-3-yn-2-ols
a
b
b
b
Bartolo Gabriele a, , Pierluigi Plastina , Mabel V. Vetere , Lucia Veltri , Raffaella Mancuso ,
*
Giuseppe Salerno b
a Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
b Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and economical synthesis of substituted furans and pyrroles, by ligand-free CuCl2-catalyzed het-
erocyclodehydration of readily available 3-yne-1,2-diols and N-Boc- or N-tosyl-1-amino-3-yn-2-ols,
respectively, is presented. Reactions are carried out in MeOH at 80–100 °C for 1–24 h and afford the cor-
responding heterocyclic derivatives in 53–99% isolated yields.
Received 7 April 2010
Revised 29 April 2010
Accepted 3 May 2010
Available online 7 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Cyclization
Heterocycles
Furans
Pyrroles
Copper catalysis has recently acquired an increasing impor-
tance, in view of the higher availability, lower toxicity, and lower
environmental impact of copper-based catalysts when compared
with other commonly employed transition metal catalysts.1 We
have recently reported several examples of synthesis of heterocy-
clic derivatives by heteroannulation reactions by using inexpensive
CuCl2 as catalyst under ligand-free conditions.2
We have now found that CuCl2 is also an excellent catalyst for
realizing the 5-endo-dig heterocyclodehydration of readily avail-
able 3-yne-1,2-diols3 and N-Boc- or N-tosyl-1-amino-3-yn-2-ols,4
to produce substituted furans and pyrroles, respectively, in good
to high yields (Eq. (1)).
It is important to point out that the heterocyclodehydration of
3-yne-1,2-diols to give the corresponding furans was previously
reported under Au,5a,b Ru,5c Ag,5d,e Mo,5f,g or Pd5h,i catalysis. In par-
ticular, mild and efficient reaction conditions have been recently
developed under Au–Ag co-catalysis.5a,b To the best of our knowl-
edge, however, no examples of copper-catalyzed formation of fur-
ans from 3-yne-1,2-diols have been reported so far in the
literature. Also, the heterocyclodehydration of N-substituted 1-
amino-3-yn-2-ols to give the corresponding pyrroles was previ-
ously reported to occur under palladium5i and gold catalysis.5a,b
However, no general method for the conversion of N-substituted
1-amino-3-yn-2-ols into pyrroles in the presence of catalytic
amounts of copper has so far appeared in the literature.6–8
We began our investigations with 3-yne-1,2-diols. When 2-
methyl-4-phenylbut-3-yne-1,2-diol 1a (R1 = H, R2 = Me, R3 = Ph,
Y = O) was let to react at 80 °C in MeOH for 1 h in the presence
of 2 mol % of CuCl2, we observed the formation of 4-methyl-2-
phenylfuran 2a in 37% GLC yield at 47% substrate conversion
(Table 1, entry 1). Substrate conversion achieved 100% after 5 h,
with a GLC yield of 2a of 60% (55% isolated, Table 1, entry 2). The
same reaction, carried out at 100 °C for 2 h, led to furan 2a in
75% isolated yield (Table 1, entry 3). The reaction did not take place
in aprotic solvents, such as 1,2-dimethoxyethane (DME), dioxane,
or acetonitrile (Table 1, entries 4–6), or using CuI as the catalyst
(Table 1, entry 7), while CuCl led to less satisfactory results (Table 1,
entry 8).
R2
OH
R2
R1
R3
CuCl2 cat
R1
R3
2 (53-99%)
H2O
Y
YH
1
ð1Þ
1
2
3
(R = H, alkyl; R = H, alkynyl, aryl; R = alkyl, aryl;
Y = O, NR, R = Boc or Ts)
* Corresponding author. Tel.: +39 0984 492813; fax: +39 0984 492044.
E-mail address: b.gabriele@unical.it (B. Gabriele).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.001

3566
B. Gabriele et al. / Tetrahedron Letters 51 (2010) 3565–3567
Table 1
Heterocyclodehydration reactions of 2-methyl-4-phenylbut-3-yne-1,2-diol 1a under different conditionsa
OH
OH
Me
Me
catalyst
H2O
Ph
1a
Ph
O
2a
Entry
Catalyst
Solvent
T (°C)
Time (h)
Conversion of 1ab (%)
Yield of 2ac (%)
1
2
3
4
5
6
7
8
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuI
MeOH
MeOH
MeOH
DME
Dioxane
MeCN
MeOH
MeOH
80
80
100
80
80
80
1
5
2
1
1
1
1
1
47
100
100
3
1
3
37
60 (55)
80 (75)
0
0
0
0
19
80
80
0
30
CuCl
a
b
c
All reactions were carried out using 0.2 mmol of 1a per mL of solvent (1 mmol scale based on 1a) in the presence of 2% of catalyst.
Based on starting 1a, by GLC.
GLC yields (isolated yields), based on starting 1a.
Having established the possibility to realize the heterocyclode-
by CuCl2-catalyzed heterocyclodehydration of N-Boc-1-amino-3-
yn-2-ols. In order to compensate for the lower reactivity of 1e with
respect to 1a–d, we carried out the reaction with a lower sub-
strate-to-catalyst ratio: with 5 mol % of CuCl2 at 100 °C, substrate
conversion reached 100% after 15 h, with an isolated yield of 2e
of 70% (Table 2, entry 5). N-Boc-2-aminonon-4-yn-3-ol 1f
(Y = NBoc, R1 = Me, R2 = H, R3 = Bu) behaved similarly, as shown
in Table 2, entries 6 and 7 (to be compared with entries 4 and 5,
respectively). On the other hand, a substrate bearing an additional
alkynyl group at C-2, such as N-Boc-7-(1-aminoethyl)trideca-5,8-
diyn-7-ol 1g (Y = NBoc, R1 = Me, R2 = C„CBu, R3 = Bu), was signifi-
cantly more reactive, leading to the corresponding pyrrole 2g in
practically quantitative yield after only 1 h reaction time at 80 °C
(Table 2, entry 8). N-Ts-1-amino-3-yn-2-ols could also be success-
fully used, as shown by the result obtained in the case of N-Ts-7-
(1-aminoethyl)trideca-5,8-diyn-7-ol 1h (Y = Ts, R1 = Me, R2 = C„CBu,
R3 = Bu) (Table 2, entry 9).9,10
hydration of 1a in MeOH with CuCl2 as catalyst, we then tested the
reactivity of differently substituted 3-yne-1,2-diols, in order to as-
sess the generality of the method. The reactivity of 2,4-diphenyl-
but-3-yne-1,2-diol 1b was similar to that of 1a, with the
corresponding furan 2b being formed in 53% isolated yield (Table
2, entry 1). On the other hand, 2-phenyloct-3-yne-1,2-diol 1c, bear-
ing an alkyl rather than a phenyl group at C-4, turned out to be
more reactive, and the reaction could be carried out at 80 °C for
2 h, with an isolated yield of furan 2c of 80% (Table 2, entry 2).
The reaction also worked nicely with substrates bearing an
additional alkynyl group at C-2, as in the case of 3-hex-1-ynyl-
non-4-yne-2,3-diol 1d, which was converted into the correspond-
ing 5-butyl-3-hex-1-ynyl-2-methylfuran 2d with an isolated
yield as high as 91% working at 80 °C for 2 h (Table 2, entry 3).9,10
The reaction was then extended to N-Boc-1-amino-3-yn-2-ols,
for the synthesis of substituted pyrroles. Under the same condi-
tions already optimized for 3-yne-1,2-diols 1a–d (2 mol % of CuCl2,
in MeOH as the solvent at 80–100 °C), N-Boc-2-amino-1-phenyl-
non-4-yn-3-ol 1e (Y = NBoc, R1 = Bn, R2 = H, R3 = Bu) turned out
to be less reactive, as shown by the results reported in Table 2, en-
try 4 (to be compared with those reported in Table 2, entry 1). In
any case, the formation of N-Boc-2-benzyl-5-butylpyrrole 2e was
indeed observed, thus confirming the possibility to obtain pyrroles
The plausible mechanism for the formation of heterocyclic deriv-
atives 2 starting from substrates 1 is shown in Scheme 1. It involves
the intramolecular 5-endo-dig nucleophilic attack of the –YH group
to the triple bond coordinated to CuCl2, followed by protonolysis
and dehydration or vice versa.
In conclusion, we have developed a convenient, practical, and
economical synthesis of substituted furans and pyrroles, by hetero-
Table 2
CuCl2-catalyzed synthesis of substituted furans and pyrroles 2 by 5-endo-dig heterocyclodehydration of 3-yne-1,2-diols and N-Boc- or N-tosyl-1-amino-3-yn-2-ols 1a
R2
OH
R2
R1
R3
CuCl2 cat
H2O
R1
R3
Y
2
YH
1
Entry
1
Y
R1
R2
R3
Mol % of CuCl2
T (°C)
Time (h)
Conversion of 1ab (%)
2
Yield of 2c (%)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1e
1f
1f
1g
1h
O
O
O
NBoc
NBoc
NBoc
NBoc
NBoc
NTs
H
H
Ph
Ph
C„CBu
H
H
H
H
Ph
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
2
2
2
2
5
2
5
2
2
100
80
80
100
100
100
100
80
3
2
2
24
15
24
15
1
100
100
100
94
100
95
100
100
100
2b
2c
2d
2e
2e
2f
2f
2g
2h
53
80
91
42
70
56
56
99
83
Me
Bn
Bn
Me
Me
Me
Me
C„CBu
C„CBu
80
8
a
b
c
All reactions were carried out in MeOH in the presence of CuCl2, using 0.2 mmol of 1 per mL of solvent (1 mmol scale based on 1).
Based on starting 1, by GLC.
Isolated yield, based on starting 1.

B. Gabriele et al. / Tetrahedron Letters 51 (2010) 3565–3567
3567
J.; Knight, D. W.; Menzies, M. D.; O’Halloran, M.; Tan, W.-F. Tetrahedron Lett.
2007, 48, 7709–7712; (e) Sakai, M.; Sasaki, M.; Tanino, K.; Miyashita, M.
Tetrahedron Lett. 2002, 43, 1705–1708; (f) McDonald, F. E.; Connolly, C. B.;
Gleason, M. M.; Towne, T. B.; Treiber, K. D. J. Org. Chem. 1993, 58, 6952–6953;
(g) McDonald, F. E.; Gleason, M. M. J. Am. Chem. Soc. 1996, 118, 6648–6659; (h)
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CuCl2
R3
2 OH
Y
2 OH
Y
OH
YH
R2
R1
CuCl
R3
R
R1
R
R1
HCl
CuCl2
R3
HCl
H2O
H2O
R2 CuCl
HCl
CuCl2
2
6. The formation of pyrrole-2-carboxylate esters as by-products (0–29%) from N-
tosyl-2-amino-3-hydroxy-4-ynoic esters in the presence of a stoichiometric
amount of copper(I) acetate was reported some years ago: Knight, D. W.;
Sharland, C. M. Synlett 2004, 119–121.
7. The formation of pyrrole-2-carboxylate esters by acid-promoted cyclization of
N-tosyl-2-amino-3-hydroxy-4-ynoic esters (carried out in the presence of
0.5 equiv of TsOH) has been reported: Knight, D. W.; Sharland, C. M. Synlett
2003, 2258–2260.
R1
R3
Y
Scheme 1. Plausible reaction mechanism for the formation of substituted furans
and pyrroles 2 by CuCl2-catalyzed heterocyclization of 3-yne-1,2-diols and N-Boc-
or N-tosyl-1-amino-3-yn-2-ols 1.
8. The stoichiometric conversion of N-Boc-2-aminopent-4-yne-1,3-diol into N-
Boc-2-hydroxymethylpyrrole by the reaction with (THF)W(CO)5 was reported
several years ago: McDonald, F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061–
11068.
cyclodehydration of readily available 3-yne-1,2-diols and N-substi-
tuted 1-amino-3-yn-2-ols, catalyzed by CuCl2 under ligand-free
conditions. The possibility to obtain furan and pyrrole derivatives
starting from readily available substrates and employing a simple
and inexpensive catalyst appears particularly attractive, also in view
of the importance of these classes of heterocyclic compounds.11,12
9. Typical procedure for the CuCl2-catalyzed heterocyclodehydration of 3-yne-1,2-
diols 1a–d and N-substituted 1-amino-3-yn-2-ols 1e–g to the corresponding
furans 2a–d and pyrroles 2e–g: In a typical experiment, to a solution of 1
(1.0 mmol) in anhydrous MeOH (5.0 mL) was added CuCl2 (2.7 mg,
2.0 ꢀ 10ꢁ2 mmol, or 6.8 mg, 5 ꢀ 10ꢁ2 mmol, see Tables
1 and 2) under
nitrogen in a Schlenk flask. The resulting mixture was stirred under nitrogen
at 80 °C or 100 °C for the required time (see Tables 1 and 2). The solvent was
evaporated, and the crude products were purified by column chromatography
on silica gel (eluent: 99:1 hexane–acetone for 2a, 2b, and 2c; hexane–AcOEt
from 9:1 to 8:2 for 2e, 2f, 2g, and 2h) or neutral alumina (for 2d; eluent: 99:1
hexane–acetone) to give the pure products 2, which were fully characterized
by spectroscopic techniques and elemental analysis.10 The yields obtained in
each experiment are given in Tables 1 and 2.
Acknowledgments
Financial support from the Ministero dell’Istruzione, dell’Uni-
versità e della Ricerca (MIUR, Rome, Italy) and from the University
of Calabria (Rende, Italy) is gratefully acknowledged (Progetto di
Ricerca d’Interesse Nazionale PRIN 2008A7P7YJ).
10. Characterization data for selected products: For 2d: Pale yellow oil. IR (film):
m
= 2932 (m), 2862 (m), 2230 (w), 1580 (m), 1465 (m), 1232 (m), 1124 (w), 951
(w), 799 (w), 734 (w) cmꢁ1 1H NMR (300 MHz, CDCl3): d = 5.87 (s, 1H, H-4),
;
References and notes
2.51 (t, J = 7.7, 2H, @CCH2), 2.37 (t, J = 6.9, 2H, „CCH2), 2.28 (s, 3H, Me at C-2),
1.63–1.24 (m, 8H, 2CH2CH2CH3), 0.93 (t, J = 7.4, 3H, CH2CH3), 0.91 (t, J = 7.4, 3H,
CH2CH3); 13C NMR (75 MHz, CDCl3): d = 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), 176 (14), 175 (100), 145 (4), 133 (11), 117 (4), 105 (5), 91 (8), 77 (6);
Anal. Calcd for C15H22O (218.33): C, 82.52; H, 10.16. Found: C, 82.45; H, 10.19.
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For 2g: Pale yellow oil. IR (film):
m
= 2968 (m), 2878 (m), 2229 (w), 1752 (s),
1548 (w), 1459 (w), 1338 (s), 1171 (m), 1108 (m), 856 (w) cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d = 5.87 (t, J = 0.9, 1H, H-4), 2.77–2.69 (m, 2H, @CCH2), 2.43
(s, 3H, Me at C-2), 2.39 (t, J = 7.0, 2H, „CCH2), 1.62–1.30 (m, 8H, 2CH2CH2CH3),
1.58 (s, 9H, t-Bu), 0.93 (t, J = 7.1, 3H, CH2CH3), 0.92 (t, J = 7.1, 3H, CH2CH3); 13C
NMR (75 MHz, CDCl3): d = 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+): 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.
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3. 3-Yne-1,2-diols 1a–d were easily prepared by alkynylation of the appropriate
a
-hydroxy ketone or a-hydroxy ester (a-hydroxyacetone in the case of 1a; a-
hydroxyacetophenone in the case of 1b and 1c; ethyl
a-hydroxypropionate in
the case of 1d) with an excess of R3C„CLi.
4. N-Substituted 1-amino-3-yn-2-ols 1e–h were easily prepared by alkynylation,
with an excess of R3C„CMgBr, of the appropriate N-Boc-
Boc- -amino ester, or N-tosyl- -amino ester
a
-amino aldehyde, N-
(N-Boc-2-amino-3-
a
a
phenylpropionaldehyde in the case of 1e; N-Boc-2-aminopropionaldehyde in
the case of 1f; methyl N-Boc-2-aminopropionate in the case of 1g; methyl N-
tosyl-2-aminopropionate in the case of 1h).
5. (a) Egi, M.; Azechi, K.; Akai, S. Org. Lett. 2009, 11, 5002–5005; (b) Aponick, A.; Li,
C.-Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009, 11, 4624–4627; (c) Yada, Y.;
Miyake, Y.; Nishibayashi, Y. Organometallics 2008, 27, 3614–3617; (d) Hayes, S.