Organic Letters
Letter
(
NBnP), N-cyclohexylpyrrolidone (NCP)), and to N-hydrox-
The incomplete conversion in all the reactions reported above
is mainly due to the competing side reaction of alkyne
homocoupling.
yethylpyrrolidone (HEP). In addition, anisole and tert-butyl
acetate (tBuOAc) have been included, since they are
sustainable dipolar aprotic solvents.
The target of this study is the identification of protocols for
fast and efficient HCS reactions under mild conditions, using
green solvents. We selected the model reaction between
iodobenzene 1a and phenylacetylene 2a, in the presence of
Pd(PPh ) Cl and CuI at 30 °C to test the efficiency of new
19,20
One of the worst performing solvents, NOP, was used to
optimize the reaction conditions in further experiments. An
excess of 2a increased the conversion to 92% (Table 1, entry
11). Nevertheless, the strongest effect was observed when the
reaction was performed by using N,N,N,N-tetramethyl
guanidine (TMG) in place of the most commonly used
TEA. Under these conditions, the reaction complete
conversion was achieved within only 30 min, even in the
presence of 1% copper co-catalyst (Table 1, entries 12 and 13).
No excess of 2a was required, since the acceleration of the
HCS reaction won the competition with the homocoupling.
These conditions were successfully applied to all of the other
green solvents (Table 1, entries 14−19) affording 3a in 90%−
3
2
2
greener solvents, by screening several parameters (see Scheme
1
2
1
and Table 1). A high-performance liquid chromatography−
Scheme 1. HCS Model Reaction in Green Solvents
9
5% isolated yield. Copper-free conditions were also attempted
but did not afford satisfactory results (Table 1, entries 20 and
1). HEP allowed an easy recovery of 3a (97%), because of the
2
complete migration of this solvent in water during the workup.
This reaction was also performed on 10 mmol scale, with
comparable results, in order to verify HEP recovery.
Distillation of the HEP/water phase afforded the pyrrolidone
in >90% yield. The E factor is comparable to the one
23
achievable in DMF. However, HEP is a nontoxic solvent,
manageable at high temperatures and easily removable by a
simple workup as reported above. Furthermore, HEP can be
potentially very inexpensive, being an intermediate in the green
Table 1. HCS Model Reaction Screening
2
a
CuI
time
conversion [%]
a
24
synthesis of N-vinylpyrrolidone from biogenic acids.
solvent
[equiv]
base
[mol %] [h]
(yield [%])
The reaction was extended to substituted aryl iodides and
acetylenes (see Scheme 2 and Table 2). For each couple of
substrates, the mildest conditions to reach complete
conversion were investigated, starting from the best conditions
identified in the model reaction between 1a and 2a. Thus, all
of the reactions were performed in HEP, using Pd(PPh ) Cl
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
DMF
Cyrene
NMP
HEP
NBnP
NCP
NBP
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.5
1.05
1.05
1.05
1.05
1.05
1.05
1.5
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TEA
TMG
4
4
4
4
4
4
4
4
4
4
4
4
1
1
1
1
1
1
1
−
−
1
1
1
1
1
1
1
1
90
91
86
96 (90)
83
66
65
72
86
3
2
2
(
2 mol %) as a precatalyst, copper iodide (1 mmol %), and
TMG (1.1 equiv) (see Scheme 2). The results are reported in
Table 2.
NOP
An
1
1
1
The presence of electron-withdrawing and electron-donating
groups and the nature of the aromatic ring of the iodide (1b−
1
1
1
1
1
1
1
1
1
1
2
2
tBuOAc
NOP
NOP
NOP
NBP
NBnP
NCP
HEP
92
92
1
g) did not affect reactivity, since all tested reagents displayed
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
>99 (92)
>99 (93)
95 (90)
>99 (90)
>99 (94)
>99 (97)
>99 (94)
>99 (95)
49
9
complete conversions to 3b−3g at 30 °C in 30 min (Table 2,
entries 1−6).
In contrast, the transformation of differently substituted
acetylenes required to modify the reaction conditions, mainly
as a consequence of a variable tendency to afford
homodimerization. The cross-coupling of 2-methyl-3-butyn-
b
An
tBuOAc
HEP
2-ol 2h with 1a afforded complete conversion to 3h under the
1.5
1.05
1.05
standard conditions in 1 h (see Table 2, entry 7). In a similar
way, 3-dimethylamino-1-propyne 2i and 3-phenyl-1-propyne
2j reacted with 1a at 30 °C to give 3i and 3j in 1 h and 30 min,
respectively (see Table 2, entries 8 and 9). In both cases, an
excess of acetylene reagent (1.5 equiv) was required to reach
HEP
1
a
Conversion monitored at HPLC-UV at 210 nm. The product was
isolated only when conversion was >95%. This reaction was also
performed in 10 mmol scale with similar results.
b
>
99% conversion.
Propargyl alcohol 2k and 1-hexyne 2l showed a lower
ultraviolet (HPLC-UV) signal at 210 nm was used to follow
the transformation of the reagents to diphenylacetylene 3a.
reactivity and the increase of reaction temperature to 50 °C,
together with an excess of reagent, was required. Under these
conditions, products 3k and 3l were obtained in 30 min and 1
h, respectively (see Table 2, entries 10 and 11). Moving from
iodides to aryl bromides, stronger reaction conditions were
needed.
22
The reactions were stopped when no further evolution in time
was observed. DMF and Cyrene experiments were performed
10
as reference reactions and compared with literature data.
Under the selected conditions, all of the solvents did not afford
complete conversion (Table 1, entries 1−10). HEP gave
promising results, allowing 96% conversion (Table 1, entry 4).
Using the best protocol reported in Table 1, entry 17,
bromobenzene 4a did not react (see Table 3, entry 1).
B
Org. Lett. XXXX, XXX, XXX−XXX