Atom-economical chemoselective synthesis of 1,4-diynes and polysubstituted furans/pyrroles from propargyl alcohols and terminal alkynes

Article abstract of DOI:10.1021/ol201054z

Under different conditions, the reaction of propargyl alcohols and terminal alkynes leads to the selective formation of 1,4-diynes and polysubstituted furans/pyrroles. Water is the only byproduct in the selective synthesis of 1,4-diynes and pyrroles, and

Full text of DOI:10.1021/ol201054z

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3324–3327
Atom-Economical
Chemoselective Synthesis of 1,4-Diynes
and Polysubstituted Furans/Pyrroles
from Propargyl Alcohols and
Terminal Alkynes
Tao Wang, Xin-liang Chen, Li Chen, and Zhuang-ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen 361005, Fujian, P. R. China
zpzhan@xmu.edu.cn
Received April 20, 2011
ABSTRACT
Under different conditions, the reaction of propargyl alcohols and terminal alkynes leads to the selective formation of 1,4-diynes and
polysubstituted furans/pyrroles. Water is the only byproduct in the selective synthesis of 1,4-diynes and pyrroles, and the strategy for the
furan synthesis is of 100% atom economy.
In modern organic chemistry, a key but challenging goal
must be maximizing synthetic efficiency in the transformation
of starting materials to the target molecules. Readily available
starting materials, high selectivity, and atom economy are
three attractive features of efficient synthetic methods.1
Although considerable progress has been made, many
reactions still suffer from low efficiency. For instance, 1,
4-diynes are traditionally accessed by the nucleophilic sub-
stitution of propargyl halides or sulfonates with metal
acetylides. Thus, large amounts of salt waste are gener-
ated simultaneously.2 Recently, the coupling of propargyl
alcohols and alkynylsilanes has emerged as an attractive
alternative.3 However, in this protocol, a stoichiometric
amount of trimethylsilanol is formed as a byproduct.
Among the numerous approaches to polysubstituted fur-
ans and pyrroles, cycloisomerizations of alkynyl- and allenyl-
functionalized compounds are particularly attractive.4
(4) For representative examples on furan syntheses, see: (a) Kang,
J. Y.; Connell, B. T. J. Org. Chem. 2011, 76, 2379. (b) Chen, Z; Huang, G.;
Jiang, H.; Huang, H.; Pan, X. J. Org. Chem. 2011, 76, 1134. (c) Albrecht,
L.; Ransborg, L. K.; Gschwend, B.; Jorgensen, K. A. J. Am. Chem. Soc.
2010, 132, 17886. (d) Zhang, X.; Lu, Z.; Fu, C.; Ma, S. J. Org. Chem. 2010,
75, 2589. (e) Kao, T.-T.; Syu, S.-e.; Jhang, Y.-W.; Lin, W. Org. Lett. 2010,
12, 3066. (f) Li, W.; Zhang, J. Chem. Commun. 2011, 47, 809. For
representative examples on pyrrole syntheses, see: (g) Trost, B. M.; Lumb,
J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011, 133, 740. (h) Wang, Y.; Bi,
X.; Li, D.; Liao, P.; Wang, Y.; Yang, J.; Zhang, Q.; Liu, Q. Chem.
Commun. 2011, 47, 809. (i) Ngwerume, S.; Camp, J. E. Chem. Commun.
2011, 47, 1857. (j) Kramer, S.; Madsen, J. L. H.; Rottlander, M.;
Skrydstrup, T. Org. Lett. 2010, 12, 2758. (k) Donohoe, T. J.; Race,
N. J.; Bower, J. F.; Callens, C. K. A. Org. Lett. 2010, 12, 4094. (l) Saito,
A.; Konishi, T.; Hanzawa, Y. Org. Lett. 2010, 12, 372. (m) Yan, R.-L.;
Luo, J.; Wang, C.-X.; Ma, C.-W.; Huang, G.-S.; Liang, Y.-M. J. Org.
Chem. 2010, 75, 5395.
(1) Trost, B. M. Science 1991, 254, 1471.
ꢀ
(2) (a) Ege, S. N.; Wolovsky, R.; Gensler, W. J. J. Am. Chem. Soc.
1961, 83, 3080. (b) Taniguchi, H.; Mathai, I.; Miller, S. I. Org. Synth.
1970, 50, 97. (c) Normant, J. F. Synthesis 1992, 63. (d) Spinella, A.;
Caruso, T.; Martino, M.; Sessa, C. Synlett 2001, 1971. (e) Gardes-
ꢁ
Gariglio, H.; Pornet, J. J. Organomet. Chem. 2001, 620, 94. (f) Caruso,
T.; Spinella, A. Tetrahedron 2003, 59, 7787. (g) Qi, L.; Meijler, M. M.;
Lee, S.-H.; Sun, C.; Janda, K. D. Org. Lett. 2004, 6, 1673. (h) Montel, F.;
Beaudegnies, R.; Kessabi, J.; Martin, B.; Muller, E.; Wendeborn, S.;
Jung, P. M. J. Org. Lett. 2006, 8, 1905. (i) Kessabi, J.; Beaudegnies, R.;
Jung, P. M. J; Martin, B.; Montel, F.; Wendeborn, S. Org. Lett. 2006, 8,
5629.
(3) (a) Kuninobu, Y.; Ishii, E.; Takai, K. Angew. Chem., Int. Ed.
2007, 46, 3296. (b) Yadav, J. S.; Reddy, B. V. S.; Thrimurtulu, N.;
Reddy, N. M.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 2031. (c) Wang,
T.; Ma, R.; Liu, L.; Zhan, Z. Green Chem. 2010, 2, 1576.
r
10.1021/ol201054z
Published on Web 06/07/2011
2011 American Chemical Society

These strategies generally rely on noble metal catalysis,
multiple synthetic steps, or highly functionalized sub-
strates. As a result, the development of efficient synthetic
routes allowing the facile assembly of polysubstituted
furans and pyrroles from readily available precursors is
still of special interest.
Herein, we report a novel efficient synthetic method:
under different conditions, propargyl alcohols and term-
inal alkynes were selectively transformed into 1,4-diynes
and polysubstituted furans/pyrroles.
4-diynes and furans/pyrroles, was the major challenge
posed for us.
With this hypothesis in mind, we set out to examine the
reaction of propargyl alcohol 1a and ethynylbenzene
(2a) using Cu(OTf)2 as the catalyst. Our results indi-
cated that both the yield and selectivity of this reaction
showed remarkable sensitivity to solvents (Table 1, entries
1À6). Toourdelight, 3awas obtainedin76% yield without
any competitive formation of 4a and 5a when 1,2-dichlor-
oethane (DCE) was used as the solvent (Table 1, entry 6).
˚
Notably, removal of H2O using 4 A molecular sieves
resulted in an improved yield (81%; Table 1, entry 7).
Catalyst screening revealed that Cu(OTf)2 was still the
preferential catalyst for 1,4-diyne synthesis (Table 1,
entries 8À12).
Scheme 1. Proposed Reaction Pathways
Table 1. Optimization of Reaction Conditions a
catalyst
(mol %)
yield (%)b
entry
solvent
time
of 3a/4a/5a
1
2
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2(10)
Bi(OTf)3 (10)
Sc(OTf)3 (10)
Zn(OTf)2 (10)
AgOTf (10)
MeNO2
PhMe
THF
5 min
5 min
5 h
35/45/0
64/0/0
41/0/0
18/62/0
0/0//0 c
76/0/0
81/0/0
70/0/0
59/0/0
19/0/0
71/0/0
58/13/0
7/67/0
4/76/0
3/41/0
3/56/0
4/0/71
3
On the basis of our and others’ previous work,5 activa-
tion of propargyl alcohol 1 by Lewis or Brønsted acid was
presumed to afford carbocation A (Scheme 1). We antici-
pated that a nucleophilic attack of alkyne 2 would lead
to the formation of alkenyl cation B.6 Two competitive
pathways, protonelimination (pathI) and hydrolysis(path
II), could occur subsequently, leading to the formation of
1,4-diynes 3 and γ-alkynyl ketones 4, respectively. Our
continuous interest in heterocycle chemistry prompted
us to explore the possibility of using 4 as the precursor
for the synthesis of polysubstituted furans 5 and pyrroles
7.5bÀe Obviously, the search for different reaction condi-
tions, which would allow the selective synthesis of 1,
4
MeCN
DMF
5 min
5 min
5 min
5 min
20 min
5 h
5
6
DCE
7 d
8
DCE
DCE
9
DCE
10
11
12
13
14
15
16
17
DCE
12 h
DCE
30 min
5 min
5 min
5 min
2 h
HOTf (10)
DCE
HOTf (10)
MeCN
MeCN
MeCN
MeCN
MeCN/
PhMe
HOTf (20)
TFA (20)
p-TSA (20)
5 min
5 min/
30 min
HOTf (20)
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), catalyst,
solvent (2 mL), reflux. b Isolated yields refer to 1a. c 2a underwent a
self-coupling reaction, affording 1,4-diphenylbuta-1,3-diyne as the main
(5) (a) Zhan, Z.; Yu, J.; Liu, H.; Cui, Y.; Yang, R.; Yang, W.; Li, J.
J. Org. Chem. 2006, 71, 8298. (b) Zhan, Z.; Cai, X.; Wang, S.; Yu, J.; Liu,
H.; Cui, Y. J. Org. Chem. 2007, 72, 9838. (c) Liu, X.; Huang, L.; Zheng,
F.; Zhan, Z. Adv. Synth. Catal. 2008, 350, 2778. (d) Pan, Y.; Zheng, F.;
Lin, H.; Zhan, Z. J. Org. Chem. 2009, 74, 3148. (e) Hao, L.; Pan, Y.;
Wang, T.; Lin, M.; Chen, L.; Zhan, Z. Adv. Synth. Catal. 2010, 352,
3215. (f) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc.
2005, 127, 14180.
(6) The catalytic nucleophilic attack of terminal alkynes to unsatu-
rated electrophiles (CdO, CdN, and CtN bonds) has been largely
developed; see: (a) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009,
351, 963. (b) Li, C.-J. Acc. Chem. Res. 2010, 43, 581. (c) Shen, Q.; Huang,
W.; Wang, J.; Zhou, X. Organometallics 2008, 27, 301. (d) Chen, Z.;
Yang, X.; Wu, J. Chem. Commun. 2009, 3469. (e) Li, P.; Zhang, Y.;
Wang, L. Chem.;Eur. J. 2009, 15, 2045. (f) Han, J.; Xu, B.; Hammond,
G. B. J. Am. Chem. Soc. 2010, 132, 916. The nucleophilic attack of a
terminal alkyne to a cabocation to afford a vinyl cation has also been
reported, see: (g) Liu, Z.; Wang, J.; Zhao, Y.; Zhou, B. Adv. Synth. Catal.
2009, 351, 371.
product in 67% yield. d 4 A MS (200 mg) was added.
˚
Our next investigation indicated that acetonitrile favored
the formation of γ-alkynyl ketone 4a, and 4a could be
obtainedwithhighselectivitywhentrifluoromethanesulfonic
acid (HOTf, 20 mol %) was used as the catalyst (Table 1,
entry 14).
Inspired by our previous work on furan synthesis,5b we
supposed that 4a might undergo a cycloisomerization
to afford furan 5a in the presence of a catalytic
amount of TfOH. To evaluate this concept, MeCN was
removed under reduced pressure after 4a was obtained,
Org. Lett., Vol. 13, No. 13, 2011
3325

and toluene (2 mL) was added. Pleasingly, without em-
ployment of any other catalyst, the cycloisomerization
of 4a readily provided 5a in 71% yield in one pot
(Table 1, entry 17).7 Significantly, this furan synthesis from
a propargyl alcohol and a terminal alkyne is of 100%
atom economy.8
Table 2. Selective Synthesis of 1,4-Diynes a
With the optimal reaction conditions identified
(Table 1, entry 7), attention was focused on the selec-
tive synthesis of 1,4-diynes. A wide range of propargyl
alcohols underwent this reaction, offering a facile
access to 1,4-diynes (Table 2). The alkyne terminus
of 1 could accommodate different substituted groups
(R2 = n-butyl, phenyl and TMS). The alkynylation
of 1d containing a terminal alkyne moiety also pro-
ceeded readily (R2 = H; Table 2, entries 4 and 12).
While an electron-donating substituent had no obser-
vable influence on this reaction (Table 2, entry 5 vs 3),
the presence of a strong electron-withdrawing group
had an adverse impact (Table 2, entry 6 vs 2). Treat-
ment of aliphatic propargyl alcohol 1g with 2a in
the presence of Cu(OTf)2 led to the formation of 3g
in a fair yield (Table 2, entry 7). This result could be
attributed to the instability of the cationic inter-
mediate A.
The scope of terminal alkyne 2 was subsequently
examined. Both electron-rich and electron-poor aro-
matic alkynes reacted smoothly with propargyl alco-
hols (Table 2, entries 8À13). Nonaromatic alkyne
2d also participated in the alkynylation of 1b, gener-
ating 3n in 68% yield with a prolonged reac-
tion time (Table 2, entry 14). Notably, small amounts
of γ-alkynyl ketones 4 were observed in the alky-
nylation of propargyl alcohols with 2b (Table 2,
entries 8À10). We reasoned that the electron-donat-
ing group (R3 = 4-MeO-C6H4) might stabilize
alkenyl cation B, facilitating the nucleophilic attack
of water.
Next, we focused our efforts on the selective synthesis
of furans (Table 3). The reaction occurred with a wide
variety of propargyl alcohols. Alkyl or strong electron-
withdrawing substituents at the propargylic position led to
decreased efficiency (Table 3, entries 3 and 9). The TMS
group was not tolerated under these conditions and fell off
during workup (Table 3, entries 2, 6, and 13). Although the
same product was obtained in the examples involving 1c
and 1d, the employment of a TMS group led to an
improved yield in a shorter duration (Table 3, entry 6 vs 7),
providing an valuable alternative route to 2-methyl-sub-
stituted furans.
a Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), Cu(OTf)2
(0.05 mmol), 4 A MS (200 mg), DCE (2 mL), reflux, 5 min. b Isolated
˚
yields refer to 1. c 5 equiv of 2a was employed. d Reaction ran for
1 h.
Small amounts of 1,4-diynes were observed while
alkynes 2a and 2c,d were employed as substrate. The
reaction of 1b and nonaromatic alkyne 2d afforded
γ-alkynyl ketone 4b in 65% yield. The subjection of
4b to cyclization conditions failed to afford the desired
furan (Table 3, entry 14). The reaction of substrate 1a
and an internal alkyne (prop-1-ynylbenzene) has also
been tested; however, the reaction led to a complex
mixture and no desired tetrasubstituted furan was
observed.
As a demonstration of the synthetic utility of this
methodology, several polysubstituted pyrroles were pre-
pared in a one-pot procedure (Scheme 2). After the
(7) When 1/1 mixed acetonitrile/toluene was used as the solvent,
the reaction proceeded with low selectivity (3a/4a/5a = 43%/12%/
18%).
(8) Cao, H.; Jiang, H.; Mai, R.; Zhu, S.; Qi, C. Adv. Synth. Catal.
2010, 352, 143.
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Org. Lett., Vol. 13, No. 13, 2011

Table 3. Selective Synthesis of Furansa
a Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), HOTf (0.1 mmol), CH3CN (2 mL), reflux, t1. CH3CN was then removed under reduced pressure,
followed by the addition of toluene (2 mL), reflux, t2. b Isolated yields refer to 1. c 5 equiv of 2a was employed.
γ-alkynyl ketones were obtained, various amines 6 were
subjected to the Cu(OTf)2-catalyzed consendationÀ
polysubstituted pyrroles 7.9
Scheme 2. One-Pot Synthesis of Pyrrolesa
cycloisomerization tandem reaction, readily affording
In summary, starting from propargyl alcohols and
terminal alkynes, 1,4-diynes and polysubstituted furans/
pyrroles have been prepared with high selectivity. Three
attractive features of this methodology are readily avail-
able starting materials, high selectivity, and high atom
economy.
Acknowledgment. We thank the National Nature
Science Foundation of China (No. 21072159) for financial
support.
Supporting Information Available. Detailed experimen-
1
tal procedure and copies of H NMR and 13C NMR
spectra of all compounds. This material is available free
a Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), HOTf (0.1
of charge via the Internet at http://pubs.acs.org.
mmol), CH3CN (2 mL), reflux, 5 min; CH3CN was then removed,
amines 6 (0.5 mmol), Cu(OTf)2 (0.05 mmol), and toluene (2 mL) were
added, reflux, t. b Isolated yields refer to 1.
(9) In the absence of Cu(OTf)2, the reactions provided pyrroles 7 in
low yields.
Org. Lett., Vol. 13, No. 13, 2011
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