Microwave-assisted synthesis of indole- and azaindole-derivatives in water via cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by amines or catalytic amounts of neutral or basic salts

Article abstract of DOI:10.1016/j.tet.2010.06.083

An efficient methodology is described and exploited for the preparation of differently substituted indoles and azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alkynylpyridinamines, which is promoted by catalytic amounts of neutral or basic salts or by stoichiometric weak organic bases. Good to high yields in the cyclization can be achieved for a variety of 2-amino(hetero)aryl alkynes. Reactions are run without any added metal catalyst. A comparison with the cycloisomerization conducted under conventional heating is also described. An efficient methodology is described for the preparation of differently substituted 1H-indoles and 1H-azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alkynylpyridinamines, promoted by catalytic amounts of neutral or basic salts or by weak organic bases.

Full text of DOI:10.1016/j.tet.2010.06.083

Tetrahedron 66 (2010) 7169e7178
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Microwave-assisted synthesis of indole- and azaindole-derivatives in water via
cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by
amines or catalytic amounts of neutral or basic salts
,
b
Adriano Carpita a, Arianna Ribecai b , Paolo Stabile
*
a Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Risorgimento 35, I-56126 Pisa, Italy
b Chemical Development Department, GlaxoSmithKline Medicines Research Centre, via Fleming 4, I-37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient methodology is described and exploited for the preparation of differently substituted indoles
and azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alky-
nylpyridinamines, which is promoted by catalytic amounts of neutral or basic salts or by stoichiometric
weak organic bases. Good to high yields in the cyclization can be achieved for a variety of 2-amino
(hetero)aryl alkynes. Reactions are run without any added metal catalyst. A comparison with the cy-
cloisomerization conducted under conventional heating is also described.
Received 23 April 2010
Received in revised form 10 June 2010
Accepted 28 June 2010
Available online 3 July 2010
Keywords:
Microwaves
Ó 2010 Elsevier Ltd. All rights reserved.
Indoles
Azaindoles
Cycloisomerization of alkynes
Water
Green chemistry
1. Introduction
loadings,6g,h,13a with the additional drawback of potential metal-
contamination of the products.
The indole and azaindole ring systems are common moieties in
a vast number of biologically active natural and unnatural com-
pounds and in pharmaceutically important molecules.1 Among the
many approaches described for their synthesis and functionaliza-
tion, the cyclization reactions of 2-alkynylanilines and alkynylpyr-
idinamines represent a major procedure to obtain 2-substituted
and 2,3-disubstituted indoles2 and their aza-analogues.3 In fact, the
starting 2-alkynylanilines and aminopyridines can be prepared
easily by a Sonogashira-type alkynylation from a large variety of
commercially available substrates.4,16c Typically, the cyclization of
the alkynes is achieved using strong bases3e,5 (like metal alkoxides,
metal hydrides and metal amides) or transition metal cata-
lysts.2,6e16 Moreover, most of the cited methods require the use of
moisture-sensitive bases, harsh or strong basic conditions, which
are incompatible with a wide range of functional groups. None-
theless, only a small number of these methods deal with N-un-
protected 2-alkynylanilines or aminopyridines, which cyclize in the
presence of expensive metal sources and/or high catalyst
With the aim of developing cleaner and more benign processes,
the use of microwaves for reaction mixture heating has found
significant application in heterocyclic synthesis.17e19 Among the
applications of microwaves, particularly worthy of note are syn-
thetic organic reactions run in water and under superheated
conditions.20
In a previous work,21 we presented the first example of micro-
wave-assisted cyclization of 2-alkynylanilines achieved without
any added metal catalyst (Scheme 1). We demonstrated that 1H-
indole and 2-substituted indoles can be obtained by a straightfor-
ward methodology, which involves a microwave-promoted cyclo-
isomerization in water, taking place via intramolecular
hydroamination from the corresponding 2-alkynylanilines. The
cyclization proceeds without any additive, either acid or basic and
without any metal catalyst.
R
H2O, 200 °C
R
R'
R'
N
H
MW heating
20-79 %
NH2
2
1
R = H, aryl, alkyl
* Corresponding author. Tel.: þ39 045 821 9360; fax: þ39 045 821 8117; e-mail
Scheme 1.
addresses: arianna.ribecai@gmail.com, arianna.ribecai@gsk.com (A. Ribecai).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.083

7170
A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
Table 1
For the preparation of the required 2-alkynylanilines without
Microwave-assisted cycloisomerization: screening of neutral saltsa
significant metal-contamination, we applied a copper-free pro-
cedure we had previously developed employing Pd EnCatÔ cata-
lysts; the products were obtained with Pd contents lower than
0.1 ppm by AAS.22 In addition, we showed that the residual Pd salts
(ppb) that could be present in the precursors do not affect the yields
significantly, and that the reactions do not proceed under thermal
heating conditions.
R
H2O, neutral salt
R
MW heating
N
H
NH2
2
1
Entry
R
1
Salt
Equiv of
salt
Temperature,
ꢀC (time, min)
2
Yield
of 2b (%)
However, even if moderate to good yields were achieved for
a variety of substrates, the methodology presented clear limitations
especially in terms of applicability. In fact, if high yields were
obtained for compounds bearing electron-donating substituents,
the introduction of electron-withdrawing groups caused a signifi-
cant decrease in yields. Moreover, when we tried to increase the
concentration of the substrates above 0.1 mmol/mL, the yield
dropped in most cases, and, after significant efforts, it appeared
clear that a further improvement of these conditions was not
straightforward. In this paper we describe the work performed to
develop a more efficient method, which still makes use of water
and applies simple conditions, but appears suitable for a wider
range of both substrates and concentrations.
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
e
d
200 (15)
200 (15)
200 (15)
200 (15)
200 (15)
200 (5)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
15c
35c
25c
23c
27c
15c
25c
14
30
41
60
40
38
37
38
30
33
15
16
21
KCl
KBr
KI
(n-Bu)4NBr
KCl
KCl
0.1
0.1
0.1
0.1
0.1
0.1
e
e
9
LiCl
NaCl
KCl
LiBr
NaBr
KBr
LiI
NaI
KI
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
10
11
12
13
14
15
16
17
18
19
20
(n-Bu)4NCl
(n-Bu)4NBr
(n-Bu)4NI
2. Results and discussion
In the search for more efficient cyclization conditions and with
the aim of expanding our own efforts towards the development of
a more general method suitable for diversified substituents and
substrates, we tried to find species that, if added to water, could
help the cyclization, enhance the interaction of the substrates with
microwaves and/or possibly increase the solubility in water of the
less reactive substrates. Our first intent was to explore the effect of
the addition of small amounts of inorganic salts (neutral, acid or
basic). In fact, it is well known20a,b that the dielectric loss of water
(and as a consequence the loss tangent) can be significantly in-
creased by the addition of small amounts of inorganic salts, thus
improving microwave absorbance by ionic conduction. Moreover,
we speculated that relatively low salt concentrations
(0.03e0.001 M) could influence the reactivity of the near-critical
water medium.
Several salt screens were performed to identifya possible effecton
the cycloisomerization. We worked on two model substrates, the
terminal alkyne 2-ethynylaniline,1a, to obtain 1H-indole, 2a, and the
diarylalkyne 2-(phenylethynyl)aniline, 1b, to obtain 2-phenylindole,
2b. Both substrates 1a and 1b were prepared according to our
aforementioned procedure.22 The results obtained from the neutral
salt screening are summarized in Table 1. Although substrate 1a
showed a considerable instability under our set of conditions, an
encouraging yield of 35% in indole, 2a, could be obtained after 15 min
at 200 ꢀC by adding 0.1 equiv of KCl (Table 1, entry 2). However, all the
other salts tested under the same conditions gave rise to degradation
and/or to hydrolysis to 2-aminoacetophenone (Table 1, entries 3e7).
On the other hand, the second model compound, 1b, proved stable
under the applied conditions without significant hydrolysis but
appeared rather less reactive than 1a. For this reason the salt
screening was run at 200 ꢀC with 30 min of microwave irradiation,
where significant amounts of indole 2b were formed. The screening
indicated that, also for 2b, most of the salts are able to improve the
yields respect to water alone. In particular, the best result was
obtained in the presence of KCl, where after 30 min a 60% yield in 2b
was observed (Table 1, entry 11).
a
Reaction conditions: 2-aminophenylalkyne 1 (0.1 mmol) was suspended in
water (2 mL) and heated to 200 ꢀC in the presence of the corresponding salt by
microwave irradiation for the time reported in the table.
b
Yields in solution determined by HPLC, using a calibration curve.
2-Aminoacetophenone was the main product, along with considerable
c
degradation.
Table 2
Microwave-assisted cycloisomerization: screening of basic and acid saltsa
R
H2O,basic or acid salt
MW heating
R
N
H
NH2
2
1
Entry
R
1
Salt
Equiv of
salt
Temperature,
ꢀC (time, min)
2
Yield
of 2b (%)
1
2
3
4
5
6
7
8
H
H
H
H
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
NaOH
NaHCO3
NaHCO3
NH4Cl
LiOH
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
200 (30)
200 (15)
200 (30)
200 (15)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
66
45
60
<1c
65
53
40
70
48
58
66
46
55
30
10d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NaOH
KOH
NaHCO3
Na2CO3
KHCO3
K2CO3
Na2HPO4
KF
9
10
11
12
13
14
15
AcONa
NH4Cl
a
Reaction conditions: 2-aminophenylalkyne 1 (0.1 mmol) was suspended in
water (2 mL) and heated to 200 ꢀC in the presence of the corresponding salt by
microwave irradiation for the time reported in the table.
b
Yields in solution determined by HPLC, using a calibration curve.
2-Aminoacetophenone was the main product isolated in 75% yield.
1-(2-Aminophenyl)-2-phenylethanone was the main product isolated in 85% yield.
c
d
In a second instance we examined basic and acid inorganic
additives with both model substrates (Table 2).
Not surprisingly, all the basic salts tested allowed a signifi-
cant improvement in the cyclization yields with respect to water
alone after 30 min at 200 ꢀC. Nonetheless, the best results were
obtained with NaHCO3 for both 1a and 1b with 60% and 70%
yield, respectively (see Table 2, entries 3 and 8). On the other
hand, when an acid salt like ammonium chloride was used,
hydrolysis of the triple bond was the main reaction observed
(Table 2, entries 4 and 15).

A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
7171
Having demonstrated that the addition of a salt (neutral or basic)
facilitates the cycloisomerization, we worked with the objective to
render our reaction even more attractive not only for the novelty of
the methodology but also for its applicability. In our previous work
we showed that an increase in the concentration of the substrates
caused a drastic decrease in the yield of the cycloisomerization in
water alone. The use of aqueous salt solutions as the cyclization
media proved extremely effective to overcome this limitation.
However, the presence of the salt, even if beneficial for the yield, was
accompanied by a significant increase of the pressure, which was
developed during the heating to 200 ꢀC inside the reaction vials. In
ourequipment, this caused leakages fromthe reaction caps with loss
of water and compounds, especially at the higher substrate con-
centrations. As we previously described,21 the application of short
cycles of microwave-heating circumvented the problem and pro-
vided the same irradiation times in conditions less stressful for the
equipment (reaction vials are cooled and de-pressurized between
one cycle of heating and the other). The effect of salt and substrate
concentrations and of MW irradiation times were investigated for
a group of model substrates, as shown in Table 3.
cyclization of 2-(phenylethynyl)aniline, 1b, very good yields of 75%
and 70% were obtained with 0.1 equiv of both KCl and NaHCO3,
respectively, after 1.5 h of MW-irradiation cycles (Table 3, entries 16
and 21). However, for substrate 1b, a raise in the concentration
above 0.25 mmol/mL caused a certain decrease in yields (Table 3,
compare entries 16 and 21 with entries 18 and 22, respectively).
The data in Table 3 show a definite effect of neutral and basic
inorganic salts. However, the results obtained were only moder-
ately satisfactory in the instance of 1a. The literature describes that
strong bases, such as NaOH, t-BuOK or KH,5 promote the cyclization
of 2-alkynylanilines. Remarkably, a few examples report the use of
Et3N in the cyclization of 2-alkynyl(trifluoroanilides) to indoles.3d,6d
We decided to investigate the effect of milder organic bases under
our conditions to improve the yields. Catalytic to stoichiometric
amounts of organic bases were tested, presuming they could offer
a good compatibility with various functionalities in the starting 2-
alkynylanilines. The screening was run working on a selection of
model substrates as shown in Table 4.
Notably, most of the organic bases tested did show an effect on
all the model compounds, with really good results obtained espe-
Table 3
a
Condition optimization for the cycloisomerization of 2-aminophenylalkynes in water with KCl or NaHCO3
R
H2O, KCl or NaHCO3
R
N
H
200 °C, MW heating
NH2
2
1
Entry
R
1
MW cycles
mmol of 1
Total time (h)
Salt
Equiv of salt
2
Yieldb (%)
Cycle number
Cycle time (min)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1
1
4
4
6
1
6
1
1
1
1
1
1
20
20
5
5
5
0.2
0.5
0.5
0.5
2
0.33
0.33
0.33
0.33
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
KCl
KCl
KCl
KCl
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.1
0.2
0.05
0.3
0.4
0.5
0.1
0.1
0.1
0.2
0.1
0.1
0.2
0.1
0.1
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
30
28
50
60
51
60
61
56
77
14
66
55
54
69
73
75
59
45
68
60
70
46
KCl
30
5
2
2
NaHCO3
NaHCO3
KCl
KCl
KCl
KCl
KCl
KCl
KCl
KCl
KCl
KCl
KCl
NaHCO3
NaHCO3
NaHCO3
NaHCO3
30
30
30
30
30
30
10
5
5
5
5
30
30
5
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.5
0.5
1.0
0.1
0.1
0.5
1.0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
6
12
18
18
18
1
1
18
18
1
1.5
1.5
1.5
0.5
0.5
1.5
1.5
5
a
Reaction conditions: the specified amount of 2-aminophenylalkyne 1 was suspended in water (2 mL) and the corresponding amount of salt was added. The mixture was
heated to 200 ꢀC under MW irradiation for the time reported in the table.
b
Yields in solution determined by HPLC, using a calibration curve.
The study demonstrates that the addition of catalytic amounts
of a salt like KCl or NaHCO3 is able to accelerate the cyclization
considerably and, in addition, to work with substrate concentra-
tions up to 1 mmol/mL. After a careful optimization which involved
salt concentration, reaction times, number and time of MW-cycles,
we were able to obtain good yields for the indoles 2a and 2b. The
cyclization of 2-ethynylaniline, 1a, proceeded with a yield of 30% in
the presence of 0.1 equiv of KCl but it could be raised up to 60%
when 0.2 equiv of KCl and MW-irradiation in cycles of 5 min were
applied (Table 3, entries 1e4). Also, satisfying results could be
achieved using NaHCO3, which allowed a rise in the cyclization
yield up to 61% minimizing the decomposition of 1a (Table 3, en-
tries 6 and 7). Moreover, we verified that an increase in loading of
1a up to 1 mmol/mL did not affect the yields significantly. As for the
cially when pyrrolidine was added (Table 4, entries 6, 8, 15 and 22).
The beneficial effect was particularly evident for substrate 1a,
where a yield of 90% was obtained after 15 min at 200 ꢀC in the
presence of 2 equiv of pyrrolidine (Table 4, entry 8). Also good re-
sults were obtained when piperidine was used (Table 4, entries 4
and 5). In addition, pyrrolidine gave remarkable results in the case
of 2-(arylethynyl)anilines with a 54% yield for 1b and a 74% for 1c
after 30 min at 200 ꢀC (Table 4, entries 15 and 22). Good yields were
obtained also for 1d, which cyclized with a 65% yield after 30 min
(Table 4, entry 24).
The screening and optimization studies done for the model
substrates 1aed showed that the yields previously described for
the cyclization in water alone can be considerably improved if a salt
like KCl or NaHCO3 or an organic base, pyrrolidine in particular,

7172
A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
Table 4
Microwave-assisted cycloisomerization: screening of organic basesa
R
H2O, base
R
N
H
MW heating
NH2
2
1
Entry
R
1
Base
Base equiv
Temperature, ꢀC (time, min)
2
Yield (%)b
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
1d
1d
Et3N
DBU
1
1
1
1
2
1
0.5
2
1
1
1
1
1
1
1
1
2
1
2
2
1
2
1
2
200 (15)
200 (15)
200 (15)
200 (15)
200 (15)
200 (15)
200 (15)
200 (15)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (60)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
2c
2d
2d
28
41
65
84
85
79
49
90
8
DABCO
Piperidine
Piperidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Et3N
(i-Pr)2EtN
t-BuNH2
DABCO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
9
12
38
46
10
54c
53
36
26
50
12
70
74
56
65
DBU
Pyridine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Piperidine
Piperidine
Morpholine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Ph
Ph
Ph
Ph
4-MeOePh
4-MeOePh
4-ClePh
4-ClePh
a
Reaction conditions: 2-aminoarylalkyne 1 (0.1 mmol) and the specified base were added to water (2 mL) and the mixture heated to 200 ꢀC by microwave irradiation for the
time reported in the table.
b
Yields in solution determined by HPLC, using a calibration curve.
A similar yield of 52% was obtained when 6 cycles of 5 min of MW-irradiation was applied.
c
were added. With the aim of extending the scope of these cycli-
zation conditions, we explored the reactivity of different substrates.
We used our procedure, which ensures low Pd-contents21,22 to
prepare a series of differently substituted 2-aminoarylacetylenes
and 2-aminopyridinylacetylenes and we applied the most efficient
conditions found (methods AeC in Table 5). After a screening, we
chose a substrate concentration of 0.25 mmol/mL, which repre-
sents, as already shown, a good compromise between efficiency
and applicability.
In Table 5, we summarized the results obtained for a series of
(hetero)arylalkynylanilines and arylalkynylpyridines. Good to very
good isolated yields ranging from 60 to 99% could be observed for
the majority of both electron-rich and electron-poor substrates.
Worthy of note is the behaviour of the heteroarylalkynes examined
since in most instances they seemed to cyclize more easily than the
considered arylalkynes, giving elevated yields by using both KCl
and NaHCO3. Only low or moderate yields were obtained for
octynylpyridinamine 1o, which gave 5% yield with 0.2 equiv KCl
and 52% with 0.2 equiv of NaHCO3 (Table 5, entry 14). The use of
pyrrolidine was tested only for some representative substrates
(1bed, entries 1e3, Table 5), or when neither KCl nor NaHCO3 gave
acceptable results as for the propynol 1m, which cyclized rather
effectively in the presence of 2 equiv of base (entry 12, Table 5).
Differently from 1a, substituted 2-ethynylanilines 1p and 1q and
2-ethynylaminopyridines 1r and 1s were less unstable under the
applied conditions and gave the corresponding indoles 2p and 2q
and azaindoles 2r and 2s in very high yields and without significant
degradation or hydrolysis. In particular, each of the three methods
applied (the addition of catalytic amounts of KCl and NaHCO3 or of
2 equiv of pyrrolidine) proved efficient in promoting the cycliza-
tion. In Table 6 we reported these results.
ethynylaniline, 1a, and 2-(phenylethynyl)aniline, 1b, using pressure
resistant sealed tubes. In the trials, 0.1 mmol of substrate were
suspended in 2 mL of Ultra Trace water and the required amount of
additive was introduced. The reactions were heated to 200 ꢀC in an
oil bath and monitored for 7 h, sampling at different reaction times.
The results are summarized in Table 7.
In the instance of 2-ethynylaniline, 1a, the cycloisomerization
proceeds efficiently under thermal heating conditions just in the
presence of pyrrolidine, and, even if considerably slower than un-
der microwave irradiation, it gives a 95% yield in 2a after 4 h at
200 ꢀC (Table 7, entry 3). On the other hand, in pure water or when
KCl or NaHCO3 were added, negligible amounts of indole were
obtained (Table 7, entries 1, 4 and 5).
In the instance of 2-phenylindole, 2b, only traces of product
could be observed in most cases from 1b under thermal heating
conditions. Not reacted starting material was the only recovered
product, even after 7 h at 200 ꢀC and just when 0.1 equiv of KCl
were added, a 21% yield was observed after 7 h at 200 ꢀC (Table 7,
entry 8). Neither NaHCO3 nor pyrrolidine proved more efficient
than pure water (Table 7, entries 6, 10 and 11).
3. Conclusions
In summary, we demonstrated that differently substituted in-
doles and azaindoles can be obtained by a simple and straightfor-
ward methodology, which involves the microwave-promoted
cycloisomerization of 2-alkynylanilines and alkynylpyridinamines
in water. The cyclization is efficiently expedited by the use of cat-
alytic amounts of inorganic salts such as KCl and NaHCO3 or by the
addition of pyrrolidine. We obtained good to very good yields for
a variety of both electron-rich and electron-poor substrates, even
bearing labile functional groups. By comparing the results obtained
under thermal heating conditions, we showed that microwave
To have a comparison between thermal heating and microwave
irradiation we did some cycloisomerization trials on 2-

A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
Table 5 (continued)
7173
Table 5
Preparation of 2-substituted indoles and azaindoles via cycloisomerization reactions
Entry
Alkyne 1
Product 2
Methodb Yieldsc (%)
of 2-amino(hetero)arylalkynesa
R
H2O, 200°C, MW heating
Y
R
Y
R'
OH
OH
A
B
C
10
23
R'
N
H
Method A, B or C
X, Y = C or N
X
12
X
NH2
N
H
2
53h
1m
1
NH2
2m
Entry
Alkyne 1
Product 2
Methodb Yieldsc (%)
A
B
C
75
70
85
C6H13
A
B
C
31i
60j
25
1
2
C6H13
N
13
H
N
2b
H
1b
NH2
1n
2n
NH2
A
B
5i
O
C6H13
52j
A
B
C
72
61
79
C6H13
14
O
N
N
N
H
1o
2o
N
NH2
H
2c
1c
NH2
NH2
a
Reactions were run in sealed tubes where 0.5 mmol of 2-amino(hetero)ary-
lalkyne 1 were suspended in 2 mL of water and the suspension heated to 200 ꢀC by
microwave irradiation applied in 18 cycles of 5 min for a total time of 90 min in the
presence of the corresponding salt or base.
Cl
A
B
C
55
62
77
Cl
3
4
b
N
Method A: 0.1 equiv of KCl were added. Method B: 0.1 equiv of NaHCO3 were
H
2d
added. Method C: 2 equiv of pyrrolidine were added.
1d
c
Isolated yields.
d
Microwave irradiation was applied in 9 cycles of 5 min for a total time of
45 min.
O
e
A
B
83
87
Microwave irradiation was applied in 12 cycles of 5 min for a total time of
O
60 min.
N
H
f
2-Phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was obtained as a by-
2e
1e
NH2
product in 35% yield after chromatography.
g
Complete hydrolysis to 6-amino-5-(phenylethynyl)-3-pyridinecarboxylic acid
O
O
was observed, without cyclization product.
O
h
A
B
60
48
1 equiv of pyrrolidine was added. The use of 2 equiv of pyrrolidine gave a 25%
5
6
7
8
O
yield.
i
N
H
0.2 equiv of KCl were added.
0.2 equiv of NaHCO3 were added.
2f
j
1f
NH2
heating is necessary to obtain significant yields in short reaction
times.
Cl
A
B
68
67
Cl
N
H
2g
1g
NH2
4. Experimental section
4.1. General experimental
O
O
A
B
77
88
N
H
All materials were obtained from commercial suppliers and
used without further purification. 2-Alkynylanilines and pyridines
1bes were prepared from commercially available starting mate-
rials, according to the procedure for the copper-free Sonogashira
coupling described below. 2-Ethynylaniline, 1a, and Pd EnCatÔ 40
used in the copper-free Sonogashira couplings were purchased
from Aldrich; all the calculations for the required amount of cata-
lyst were based on a Pd loading of 0.4 mmol/g (as given in the
Aldrich catalogue). KCl and NaHCO3 were purchased from Aldrich
with a purity of 99.99% trace metal basis. All reactions were carried
out in air without particular care for anhydrous or inert environ-
ment. For the microwave-assisted reactions a CEM Explorer with
infrared temperature control system was applied as a focused mi-
crowave unit; the reactions were conducted in 10 mL reaction tubes
sealed with septa caps. The pressure was measured by the system
by an IntelliventÒ pressure control module. Purifications of the
crude products were conducted with a Biotage FlashþÒ Purification
System with pre-packed silica cartridges. The yields in solutions
indicated in Tables 1e4 and 7 were determined using an Agilent
1100 HPLC system. 1H NMR and 13C NMR spectra were recorded on
a Varian Inova 400 spectrometer. For mass spectra an Agilent 1100
Series LC/MSD with APCI source was used. Atomic absorption
spectrophotometry (AAS) analyses for compounds 1bed were
carried out with a PerkineElmer 4100 ZL spectrophotometer,
1h
2h
NH2
A
B
85d
96
N
N
N
H
2i
1i
NH2
87e
95e
S
A
B
9
N
S
H
2j
1j
NH2
NH2
N
A
B
98e
99
10
N
H
N
2k
1k
A
B
45f
NC
NC
eg
11
N
H
N
1l
N
NH2
2l

7174
A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
Table 6
Preparation of indoles and azaindoles via cycloisomerization reactions of different 2-amino(hetero)arylalkynesa
H2O, 200 oC, MW heating
Y
Y
R'
R'
N
H
Additive
X, Y = C or N
X
X
NH2
2
1
Entry
Alkyne 1
Product 2
Additive
Equiv
of additive
Temperature, ꢀC (time,
min)
Yieldsb (%)
KCl
NaHCO3
Pyrrolidine
0.2
0.2
2
200 (20)c
200 (20)c
200 (15)
60
61
90
1
2
3
4
N
NH2
H
2a
1a
O
O
KCl
NaHCO3
Pyrrolidine
0.1
0.1
2
200 (20)c
200 (20)c
200 (15)
87
89
90
N
NH2
H
2p
1p
KCl
NaHCO3
Pyrrolidine
0.1
0.1
2
200 (20)c
200 (20)c
200 (15)
72
78
86
KCl
NaHCO3
Pyrrolidine
0.1
0.1
2
200 (20)c
200 (20)c
200 (15)
79
80
82
KCl
NaHCO3
Pyrrolidine
0.1
0.1
2
200 (30)c
200 (20)c
200 (15)
98
60
72
5
2s
a
Reactions were run in sealed tubes with 0.5 mmol of 2-amino(hetero)arylalkyne 1 suspended in 2 mL of water according to conditions reported in the table.
Isolated yields.
Microwave irradiation was applied in cycles of 5 min, until complete consumption of starting material was achieved.
b
c
a saturated NH4Cl aqueous solution (20 mL) were added and the
collected organic layers washed with water (20 mL), separated and
dried over Na2SO4. After filtration and evaporation of the solvent
the resulting crude products were purified by chromatography on
silica gel using cyclohexane/ethyl acetate as eluent.
Table 7
Thermal heating experimentsa
Entry
Aryl alkyne
Additive
Time
Yield of 2b (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
None
7 h
30 min
4 h
7 h
7 h
7 h
30 min
7 h
30 min
7 h
7 h
2
Pyrrolidine (2 equiv)
Pyrrolidine (2 equiv)
KCl (0.1 equiv)
NaHCO3 (0.1 equiv)
None
KCl (0.1 equiv)
KCl (0.1 equiv)
NaHCO3 (0.1 equiv)
NaHCO3 (0.1 equiv)
Pyrrolidine (2 equiv)
11
95
2
1
n.d.
1
21
n.d.
1
4.2.1. 2-(Phenylethynyl)aniline (1b). White solid (650 mg, 84%); 1H
NMR (400 MHz, CDCl3):
(ddd, J¼8.29, 7.32, 1.56 Hz, 1H), 6.77e6.70 (m, 2H), 4.29 (br s, 2H);
13C NMR (100 MHz, CDCl3):
147.8, 132.2, 131.5, 129.7, 128.4, 128.2,
d 7.58e7.51 (m, 2H), 7.43e7.31 (m, 4H), 7.16
d
123.3, 118.0, 114.4, 108.0, 94.7, 85.8. Spectral properties were in
accordance with the literature.23
9
10
11
n.d.
4.2.2. 2-{[4-(Methyloxy)phenyl]ethynyl}aniline (1c). White solid
(804 mg, 90%); 1H NMR (400 MHz, CDCl3):
d
7.48 (d, J¼9.0 Hz, 2H), 7.36
(dd, J¼8.2,1.6 Hz,1H), 7.17e7.11 (m, 1H), 6.89 (d, J¼9.0 Hz, 2H), 6.75e6.70
(m, 2H), 4.27 (br s, 2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3):
159.6,
a
Reaction conditions: 2-aminophenylalkyne 1 (0.1 mmol) was suspended in
water (2 mL) with the corresponding amount of additive, and heated to 200 ꢀC in an
oil bath for the time reported in the table.
d
b
Yields in solution determined by HPLC, using a calibration curve.
147.6, 132.9, 132.0, 129.4, 118.0, 115.4, 114.3, 114.0, 108.3, 94.6, 84.4, 55.3.
Spectral properties were in accordance with the literature.24
equipped with an electrothermally heated graphite furnace and
a longitudinal Zeeman effect background corrector. The limit of
detection (lod) calculated for palladium and copper was 2 ppb.
4.2.3. 2-[(4-Chlorophenyl)ethynyl]aniline
(1d). White
7.46 (d, J¼8.6 Hz, 2H),
solid
(802 mg, 88%); 1H NMR (400 MHz, CDCl3):
d
7.38e7.31 (m, 3H), 7.19e7.13 (m, 1H), 6.76e6.71 (m, 2H), 4.27 (br s,
4.2. Typical procedure for the copper-free Sonogashira cross-
coupling of (hetero)aryl halides with acetylenes to prepare
(hetero)arylethynylanilines and aminopyridines 1bel
2H); 13C NMR (100 MHz, CDCl3):
d
147.8, 134.2, 132.6, 132.2, 129.9,
128.7, 121.8, 118.0, 114.4, 107.5, 93.5, 86.9. Spectral properties were
in accordance with the literature.8a
The (hetero)aryl halide (4 mmol), the alkyne (1.5 equiv,
6 mmol), pyrrolidine (2 equiv, 8 mmol) and 1 mg of Pd EnCat 40
catalyst (0.01 mol % of Pd) were mixed and the resulting mixture
was stirred at 85 ꢀC for the required time until consumption of
starting (hetero)aryl halide. Ethyl acetate (2ꢁ20 mL) and
4.2.4. 4-(Methyloxy)-2-(phenylethynyl)aniline (1e). Pale yellow
solid (581 mg, 65%); 1H NMR (400 MHz, CDCl3):
d 7.57e7.51 (m,
2H), 7.40e7.32 (m, 3H), 6.94 (d, J¼2.8 Hz, 1H), 6.80 (dd, J¼8.8,
2.8 Hz, 1H), 6.70 (d, J¼8.8 Hz, 1H), 4.02 (br s, 2H), 3.77 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d 151.9, 142.0, 131.5, 128.4, 128.3, 123.2,

A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
7175
117.4, 115.9, 115.8, 108.6, 94.6, 85.9, 55.8. Anal. Calcd for C15H13NO:
C, 80.69; H, 5.87. Found: C, 80.86; H, 5.93. [MþH]þ¼224. Spectral
properties were in accordance with the literature.25
acetate (2ꢁ20 mL) and a saturated NH4Cl aqueous solution (20 mL)
were added and the collected organic layers washed with water
(20 mL), separated and dried over Na2SO4. The resulting crudes
were purified by chromatography on silica gel using cyclohexane/
ethyl acetate as eluent.
4.2.5. 2-{[2,4-bis(Methyloxy)phenyl]ethynyl}aniline (1f). Pale yel-
low solid (517 mg, 51%); 1H NMR (400 MHz, CDCl3):
d 7.41 (d,
J¼8.2 Hz, 1H), 7.35 (dd, J¼7.6, 1.4 Hz, 1H), 7.15e7.08 (m, 1H),
4.3.1. 3-(2-Aminophenyl)-2-propyn-1-ol (1m). Pale yellow solid
(230 mg, 39%); 1H NMR (400 MHz, CDCl3):
d
7.30e7.26 (m, 1H),
7.16e7.12 (m, 1H), 6.71e6.67 (m, 2H), 4.55 (s, 2H), 4.34e4.14 (br s,
2H), 1.99e1.58 (br s, 1H); 13C NMR (100 MHz, CDCl3):
150.0, 132.3,
6.76e6.67 (m, 2H), 6.53e6.47 (m, 2H), 4.47 (br s, 2H), 3.90 (s, 3H),
3.85 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 161.0, 160.9, 147.8, 133.2,
131.1, 129.1, 117.6, 114.0, 108.6, 105.3, 104.8, 98.4, 91.3, 89.1, 55.8,
55.5. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97. Found: C, 75.97;
H, 6.12. [MþH]þ¼254.
d
129.9, 117.9, 114.4, 107.2, 92.6, 82.4, 51.7. Spectral properties were in
accordance with the literature.5d
4.2.6. 4-Chloro-2-(phenylethynyl)aniline (1g). Yellow solid (811 mg,
4.3.2. 2-(1-Octyn-1-yl)aniline (1n). Yellow oil (322 mg, 40%); 1H
89%); 1H NMR (400 MHz, CDCl3):
d
7.56e7.50 (m, 2H), 7.40e7.34 (m,
4H), 7.09 (dd, J¼8.7, 2.5 Hz, 1H), 6.67 (d, J¼8.7 Hz, 1H), 4.28 (br s,
2H); 13C NMR (100 MHz, CDCl3):
146.3, 131.5, 131.3, 129.6, 128.5,
NMR (400 MHz, CDCl3):
d
7.25 (dd, J¼7.7, 1.5 Hz, 1H), 7.11e7.05 (m,
1H), 6.71e6.64 (m, 2H), 4.17 (br s, 2H), 2.47 (t, J¼7.0 Hz, 2H),
d
1.68e1.59 (m, 2H), 1.53e1.43 (m, 2H), 1.37e1.31 (m, 4H), 0.92 (t,
128.4, 122.8, 122.3, 115.4, 109.3, 95.6, 84.6. Anal. Calcd for
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 147.6, 132.0, 128.7,
C14H10ClN: C, 73.85; H, 4.43. Found: C, 73.47; H, 4.62. [MþH]þ¼228.
117.8,114.1,109.0, 95.8, 76.9, 31.3, 28.9, 28.6, 22.6,19.6,14.0. Spectral
properties were in accordance with the literature.16b
4.2.7. 1-[4-Amino-3-(phenylethynyl)phenyl]ethanone
(1h). Pale
8.03 (d,
yellow solid (470 mg, 50%); 1H NMR (400 MHz, CDCl3):
d
4.3.3. 5-Methyl-3-(1-octyn-1-yl)-2-pyridinamine (1o). Pale yellow
J¼1.9 Hz, 1H), 7.81 (dd, J¼8.6, 1.9 Hz, 1H), 7.58e7.51 (m, 2H),
solid (510 mg, 59%); 1H NMR (400 MHz, CDCl3):
d
7.81 (d, J¼2.2 Hz,
7.41e7.35 (m, 3H), 6.73 (d, J¼8.6 Hz,1H), 4.76 (br s, 2H), 2.54 (s, 3H);
1H), 7.31 (d, J¼2.2 Hz, 1H), 4.78 (br s, 2H), 2.45 (t, J¼7.2 Hz, 2H), 2.15
(s, 3H), 1.65e1.58 (m, 2H), 1.49e1.42 (m, 2H), 1.36e1.29 (m, 4H),
13C NMR (100 MHz, CDCl3):
d 195.9, 151.6, 133.8, 131.5, 130.4, 128.6,
128.5, 127.5, 122.7, 113.3, 106.7, 95.2, 84.6, 26.09. Anal. Calcd for
0.93e0.89 (m, 3H); 13C NMR (100 MHz, CDCl3):
d 157.0, 146.9, 140.4,
C16H13NO: C, 81.68; H, 5.57. Found: C, 81.85; H, 5.71. [MþH]þ¼236.
122.4, 103.8, 96.6, 75.9, 31.3, 28.7, 28.6, 22.5, 19.6, 17.2, 14.0. Anal.
Calcd for C14H20N2: C, 77.73; H, 9.32. Found: C, 77.91; H, 9.74.
[MþH]þ¼217.
4.2.8. 2-(2-Pyridinylethynyl)aniline (1i). Yellow solid (661 mg,
85%); 1H NMR (400 MHz, CDCl3):
d
8.62 (d, J¼5.3 Hz, 1H), 7.68 (dd,
J¼7.9, 1.8 Hz, 1H), 7.52 (d, J¼7.9 Hz, 1H), 7.42 (d, J¼8.3 Hz, 1H), 7.23
(dd, J¼7.5, 4.8 Hz, 1H), 7.19e7.14 (m, 1H), 6.72 (d, J¼7.9 Hz, 2H), 4.41
(br s, 2H); 13C NMR (100 MHz, CDCl3):
d 150.0, 148.5, 143.5, 136.1,
132.6, 130.4, 126.9, 122.5, 117.8, 114.3, 106.6, 94.0, 86.1. Spectral
4.4. Typical procedure for the copper-free Sonogashira cross-
coupling of (hetero)aryl halides with acetylenes to prepare 2-
(ethynyl)anilines and pyridines 1pes
properties were in accordance with the literature.16b
4.2.9. 2-(2-Thienylethynyl)aniline (1j). Yellow oil (574 mg, 72%); 1H
NMR (400 MHz, CDCl3):
7.19e7.13 (m, 1H), 7.04e7.01 (m,1H), 6.76e6.69 (m,2H), 4.26 (br s,
2H); 13C NMR (100 MHz, CDCl3):
147.7, 132.0, 131.7, 129.9, 127.2,
d 7.38e7.35 (m, 1H), 7.30e7.28 (m, 2H),
The (hetero)aryl halide (4 mmol), ethynyl(trimethyl)silane
(1.5 equiv, 6 mmol), pyrrolidine (2 equiv, 8 mmol) and 10 mg of Pd
EnCat 40 catalyst (0.1 mol % of Pd) were mixed in a 10 mL glass
microwave vial equipped with a magnetic stirrer. The vessel was
placed in the microwave apparatus and irradiated at an initial
power of 200 W to ramp the temperature from room temperature
to 100 ꢀC where it was held with stirring by modulating the mi-
crowave power for 30 min or until consumption of starting (hetero)
aryl halide. Ethyl acetate (2ꢁ20 mL) and a saturated NH4Cl aqueous
solution (20 mL) were added and the collected organic layers
washed with water (20 mL), separated and dried over Na2SO4. After
filtration and evaporation of the solvent the resulting crude prod-
ucts were dissolved in 20 mL of MeOH and 20 mL of 2 N NaOH were
added. The mixture was stirred overnight at room temperature
then evaporated to dryness. The resulting crude was purified by
chromatography on silica gel using cyclohexane/ethyl acetate as
eluent.
d
127.1,123.2,117.9,114.3,107.5, 89.5, 87.6. Spectral properties were in
accordance with the literature.26
4.2.10. 3-(Phenylethynyl)-4-pyridinamine
(1k). Yellow
d 8.45 (s, 1H), 8.16 (d,
solid
(715 mg, 92%); 1H NMR (400 MHz, CDCl3):
J¼5.7 Hz, 1H), 7.57e7.50 (m, 2H), 7.42e7.32 (m, 3H), 6.58 (d,
J¼5.7 Hz, 1H), 4.80 (br s, 2H); 13C NMR (100 MHz, CDCl3):
d 153.0,
152.6, 149.1, 131.5, 128.6, 128.4, 122.6, 108.2, 104.9, 97.1, 82.5.
Spectral properties were in accordance with the literature.27
4.2.11. 6-Amino-5-(phenylethynyl)-3-pyridinecarbonitrile (1l). Off-
white solid (579 mg, 66%); 1H NMR (400 MHz, DMSO-d6):
d 8.37 (d,
J¼2.2 Hz, 1H), 8.01(d, J¼2.2 Hz, 1H), 7.69e7.65 (m, 3H), 7.45e7.41
(m, 2H), 7.40e7.20 (br s, 2H); 13C NMR (100 MHz, DMSO-d6):
d
160.8, 155.7, 152.6, 142.2, 131.7, 129.0, 128.5, 121.9, 118.0, 101.4,
95.3, 83.2. Anal. Calcd for C14H9N3: C, 76.70; H, 4.14. Found: C,
4.4.1. 2-Ethynyl-4-(methyloxy)aniline (1p). Yellow oil (289 mg,
76.81; H, 4.53. [MþH]þ¼220.
49%); 1H NMR (400 MHz, CDCl3):
d
6.88 (d, J¼2.6 Hz, 1H), 6.79 (dd,
J¼8.8, 3.0 Hz, 1H), 6.66 (d, J¼8.8 Hz, 1H), 3.98 (br s, 2H), 3.79 (s, 3H),
3.39 (s, 1H); 13C NMR (100 MHz, CDCl3):
151.7, 142.7, 117.8, 116.3,
4.3. Typical procedure for the copper-free Sonogashira cross-
coupling of aryl halides with alkylacetylenes to prepare
2-(ethynyl)anilines and pyridines 1meo
d
115.9, 107.2, 82.4, 80.6, 55.8. Anal. Calcd for C9H9NO: C, 73.45; H,
6.16. Found: C, 73.73; H, 5.97. [MþH]þ¼148.
The (hetero)aryl halide (4 mmol), alkynylethyne (1.5 equiv,
6 mmol), pyrrolidine (2 equiv, 8 mmol) and 20 mg of Pd EnCat 40
catalyst (0.2 mol % of Pd) were mixed and the reaction mixture was
heated to 85 ꢀC until consumption of starting aryl halide. Ethyl
4.4.2. 4-Chloro-2-ethynylaniline (1q). Pale yellow solid (479 mg,
79%); 1H NMR (400 MHz, CDCl3):
d
7.29 (d, J¼2.2 Hz, 1H), 7.10 (dd,
J¼8.5, 2.4 Hz, 1H), 6.63 (d, J¼8.3 Hz, 1H), 4.25 (br s, 2H), 3.42 (s, 1H);
13C NMR (100 MHz, CDCl3):
147.1, 131.8, 130.2, 122.0, 115.4, 107.9,
d

7176
A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
83.4, 79.3. Spectral properties were in accordance with the
literature.28
(100 MHz, CDCl3): d 154.5, 138.6, 132.4, 132.0, 129.7, 129.0, 127.6,
125.0, 112.6, 111.6, 102.2, 99.8, 55.8. Spectral properties were in
accordance with the literature.30
4.4.3. 3-Ethynyl-4-pyridinamine (1r). Yellow oil (388 mg, 82%); 1H
NMR (400 MHz, CDCl3):
d
8.40 (s, 1H), 8.15 (d, J¼5.7 Hz, 1H), 6.55 (d,
4.5.6. 2-[2,4-Bis(methyloxy)phenyl]-1H-indole (2f). Pale yellow
J¼5.7 Hz, 1H), 4.76 (br s, 2H), 3.48 (s, 1H); 13C NMR (100 MHz,
solid; 1H NMR (400 MHz, CDCl3):
d
9.53 (br s, 1H), 7.76 (d, J¼8.4 Hz,
CDCl3):
d
157.1, 153.1, 149.5, 149.4, 109.3, 108.2, 85.1. Anal. Calcd for
1H), 7.62 (d, J¼7.5 Hz, 1H), 7.41 (d, J¼8.1 Hz, 1H), 7.19e7.07 (m, 2H),
6.79 (dd, J¼2.1, 0.8 Hz, 1H), 6.65e6.58 (m, 2H), 4.01 (s, 3H), 3.88 (s,
C7H6N2: C, 71.17; H, 5.12. Found: C, 70.93; H, 5.37. [MþH]þ¼119.
3H); 13C NMR (100 MHz, CDCl3):
d 160.3, 156.9, 136.1, 135.9, 129.2,
4.4.4. 3-Ethynyl-5-methyl-2-pyridinamine
(1s). Yellow
7.89 (d, J¼1.6 Hz, 1H),
solid
128.2, 121.3, 119.9, 119.7, 113.8, 110.7, 105.8, 99.3, 98.5, 55.8, 55.5.
(355 mg, 67%); 1H NMR (400 MHz, CDCl3):
d
Spectral properties were in accordance with the literature.31
7.40 (d, J¼2.0 Hz, 1H), 4.90 (br s, 2H), 3.39 (s, 1H), 2.17 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d
157.5, 148.4, 141.2, 122.3, 101.4, 83.2, 79.5,
4.5.7. 5-Chloro-2-phenyl-1H-indole (2g). Off-white solid; 1H NMR
17.2. Spectral properties were in accordance with the literature.16b
(400 MHz, CDCl3):
(m,1H), 7.51e7.43 (m, 2H), 7.40e7.29 (m, 2H), 7.15 (dd, J¼8.6,1.9 Hz,
1H), 6.80e6.75 (m, 1H); 13C NMR (100 MHz, CDCl3):
139.3, 135.1,
d 8.36 (br s, 1H), 7.70e7.63 (m, 2H), 7.62e7.58
4.5. Typical procedure for the microwave-assisted
d
cycloisomerization to prepare 1H-(aza)indoles 2aes
131.8, 130.3, 129.1, 128.1, 125.8, 125.2, 122.6, 120.0, 111.8, 99.5.
Spectral properties were in accordance with the literature.32
The required 2-alkynylaniline or alkynylpyridine (0.5 mmol)
and 2 mL of water were charged in a 10 mL glass microwave vial
equipped with a magnetic stirrer. The corresponding amount of salt
or base was added as indicated in Tables 5 and 6 where the yields
obtained were also reported. The vessel was placed in the micro-
wave apparatus and irradiated at an initial power of 200 W to ramp
the temperature from room temperature to 200 ꢀC where it was
held with stirring by modulating the microwave power for the
specified reaction times. The mixture was then cooled down to
room temperature and extracted twice with ethyl acetate
(2ꢁ20 mL). The organic layer was dried over Na2SO4. After filtration
and evaporation of the solvent the resulting crude product was
purified by chromatography on silica gel using dichloromethane or
methanol/ethyl acetate as eluent.
4.5.8. 1-(2-Phenyl-1H-indol-5-yl)ethanone (2h). Yellow solid; 1H
NMR (400 MHz, CDCl3):
d 8.73 (br s, 1H), 8.33e8.30 (m, 1H), 7.89
(dd, J¼8.6, 1.6 Hz, 1H), 7.73e7.67 (m, 2H), 7.51e7.34 (m, 4H), 6.93
(dd, J¼2.1, 0.8 Hz, 1H), 2.69 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
198.4, 139.5, 139.5, 131.7, 130.3, 129.1, 128.8, 128.2, 125.2, 122.8,
122.6, 110.8, 101.1, 26.6. Anal. Calcd for C16H13NO: C, 81.68; H, 5.57.
Found: C, 81.93; H, 5.67. [MþH]þ¼236.
4.5.9. 2-(2-Pyridinyl)-1H-indole (2i). Off-white solid; 1H NMR
(400 MHz, CDCl3):
d
9.89 (br s, 1H), 8.60 (d, J¼4.8 Hz, 1H), 7.83 (d,
J¼7.9 Hz, 1H), 7.73 (dd, J¼7.9, 1.8 Hz, 1H), 7.68 (d, J¼7.9 Hz, 1H), 7.40
(d, J¼7.5 Hz, 1H), 7.24 (t, 7.5 Hz, 1H), 7.21e7.16 (m, 1H), 7.15e7.11 (m,
1H), 7.05 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 150.4, 149.1, 136.7,
136.6, 129.1, 123.1, 122.0, 121.1, 120.1, 119.9, 111.4, 111.3, 100.6.
4.5.1. 1H-Indole (2a). White solid; 1H NMR (400 MHz, CDCl3):
Spectral properties were in accordance with the literature.16b
d
8.14 (br s, 1H), 7.73 (dd, J¼7.8, 1.0 Hz, 1H), 7.45 (dd, J¼8.1, 1.0 Hz,
1H), 7.31e7.24 (m, 2H), 7.23e7.17 (m, 1H), 6.65e6.61 (m, 1H); 13C
4.5.10. 2-(2-Thienyl)-1H-indole (2j). Off-white solid; 1H NMR
NMR (100 MHz, CDCl3):
d
135.7,127.8,124.1,121.9,120.7,119.8,111.0,
(400 MHz, CDCl3):
d
8.20 (br s, 1H), 7.62 (d, J¼8.3 Hz, 1H), 7.38 (d,
102.6. Spectral properties were in accordance with the literature.29
J¼8.3 Hz, 1H), 7.30 (d, J¼6.1 Hz, 1H), 7.27e7.25 (m, 1H), 7.21(m, 1H),
7.15 (d, J¼7.9 Hz, 1H), 7.11e7.08 (m, 1H), 6.75 (s, 1H); 13C NMR
4.5.2. 2-Phenyl-1H-indole (2b). White solid; 1H NMR (400 MHz,
(100 MHz, CDCl3): d 136.5, 135.6, 132.3, 129.1, 127.9, 124.6, 122.9,
CDCl3):
7.38e7.32 (m, 1H), 7.25e7.20 (m, 1H), 7.18e7.13 (m, 1H), 6.87e6.84
(m, 1H); 13C NMR (100 MHz, CDCl3):
137.9, 136.8, 132.4, 129.2,
129.0, 127.7, 125.1, 122.3, 120.6, 120.3, 110.9, 100.0. Spectral prop-
erties were in accordance with the literature.30
d
8.33 (br s, 1H), 7.71e7.64 (m, 3H), 7.50e7.40 (m, 3H),
122.5, 120.5, 120.4, 110.7, 100.4. Spectral properties were in accor-
dance with the literature.33
d
4.5.11. 2-Phenyl-1H-pyrrolo[3,2-c]pyridine (2k). Yellow solid; 1H
NMR (400 MHz, DMSO-d6):
J¼5.7 Hz,1H), 7.90 (d, J¼7.5 Hz, 2H), 7.49 (t, J¼7.7 Hz, 2H), 7.40e7.33
(m, 2H), 7.04 (s, 1H); 13C NMR (100 MHz, DMSO-d6):
142.9, 140.4,
d 12.01 (br s, 1H), 8.81 (s, 1H), 8.17 (d,
4.5.3. 2-[4-(Methyloxy)phenyl]-1H-indole (2c). White solid; 1H
d
NMR (400 MHz, DMSO-d6):
d
11.40 (s, 1H), 7.79 (d, J¼9.0 Hz, 2H),
140.3, 138.9, 131.4, 129.0, 128.1, 125.7, 125.4, 106.6, 97.5. Spectral
properties were in accordance with the literature.34
7.49 (d, J¼7.8 Hz, 1H), 7.37 (dd, J¼8.0, 1.0 Hz, 1H), 7.09e6.94 (m, 4H),
6.76 (dd, J¼2.1, 0.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, DMSO-
d6):
d
158.7, 137.7, 136.9, 128.8, 126.3, 124.9, 121.0, 119.6, 119.2, 114.3,
4.5.12. 2-Phenyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile
(2l).
111.0, 97.3, 55.2. Spectral properties were in accordance with the
White solid; 1H NMR (400 MHz, CDCl3):
d
12.8 (br s, 1H), 8.60 (d,
literature.30
J¼2.2 Hz, 1H), 8.48 (d, J¼2.2 Hz, 1H), 8.01e7.93 (m, 2H), 7.52e7.47
(m, 2H), 7.43e7.39 (m, 1H), 7.08 (s, 1H); 13C NMR (100 MHz, CDCl3):
4.5.4. 2-(4-Chlorophenyl)-1H-indole (2d). White solid; 1H NMR
d 150.3, 145.4, 139.6, 132.1, 131.2, 130.6, 129.0, 128.9, 125.7, 120.3,
(400 MHz, CDCl3):
d
8.27 (br s, 1H), 7.65 (d, J¼7.8 Hz, 1H), 7.59 (d,
97.9. Anal. Calcd for C14H9N3: C, 76.70; H, 4.14. Found: C, 76.67; H,
J¼8.6 Hz, 2H), 7.45e7.39 (m, 3H), 7.26e7.20 (m, 1H), 7.18e7.12 (m,
4.18. [MþH]þ¼220. 2-Phenyl-1H-pyrrolo[2,3-b]pyridine-5-carbox-
1H), 6.83 (dd, J¼2.0, 0.7 Hz, 1H); 13C NMR (100 MHz, CDCl3):
ylic acid. White solid; 1H NMR (400 MHz, CDCl3):
d 12.4 (br s, 1H),
d
136.9, 136.6, 133.4, 130.8, 129.2, 129.1, 126.3, 122.7, 120.7, 120.4,
8.75 (d, J¼2.2 Hz, 1H), 8.44 (d, J¼1.8 Hz, 1H), 8.01e7.94 (m, 2H),
110.9, 100.5. Spectral properties were in accordance with the
7.52e7.47 (m, 2H), 7.43e7.39 (m, 1H), 7.04 (s, 1H); 13C NMR
literature.30
(100 MHz, CDCl3):
d 167.6, 150.8, 143.1, 128.9, 128.3, 127.4, 125.4,
122.5, 119.9, 97.9. [MþH]þ¼239.
4.5.5. 5-(Methyloxy)-2-phenyl-1H-indole (2e). White solid; 1H
NMR (400 MHz, CDCl3):
d
8.24 (br s, 1H), 7.68e7.63 (m, 2H),
4.5.13. 1-H-Indol-2-ylmethanol (2m). White solid; 1H NMR
7.48e7.42 (m, 2H), 7.36e7.28 (m, 2H), 7.11 (d, J¼2.3 Hz, 1H), 6.88
(400 MHz, CDCl3):
J¼8.12 Hz, 1H), 7.22e7.18 (m, 1H), 7.14e7.11 (m, 1H), 6.49 (d,
d
8.34 (br s, 1H), 7.60 (d, J¼7.7 Hz, 1H), 7.29 (d,
(dd, J¼8.8, 2.3 Hz, 1H), 6.79e6.76 (m, 1H), 3.89 (s, 3H); 13C NMR

A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
7177
J¼1.1 Hz, 1H), 4.79 (s, 2H), 2.16e2.02 (br s, 1H); 13C NMR (100 MHz,
2153e2167; (d) Russel, J. S.; Pelkey, E. T. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Joule, J. A., Eds.; Elsevier Science: New York, NY, 2008; Vol. 20,
pp 122e151; (e) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644e4680; (f)
Patil, S.; Patil, R. Curr. Org. Synth. 2007, 4, 201e222; (g) Patil, S.; Buolamwini, J. K.
Curr Org. Synth. 2006, 3, 477e498; (h) Ziegert, R. E.; Knepper, K.; Braese, S. In
Targets in Heterocyclic Chemistry; Attanasi, O., Spinelli, D., Eds.; Società Chimica
Italiana: Roma, 2006; Vol. 9, pp 230e256.
3. (a) Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. Synlett 2005, 3121e3125; (b)
Hopkins, C. R.; Collar, N. Tetrahedron Lett. 2004, 45, 8087e8090; (c) Rodriguez,
A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39,
2488e2490; (d) Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2007, 48,
6951e6953; (e) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3307e3310; (f) Cacchi, S.; Fabrizi, G.; Parisi, L. M.; Bernini, R. Synlett 2004,
287e290; (g) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355e5358.
4. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.1975, 50, 4467e4470;
(b) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834e871; (c)
Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874e922; (d) Arcadi, A.; Cacchi, S.;
Marinelli, F. Tetrahedron Lett. 1989, 30, 2581e2584; (e) Takahashi, S.; Kuroyama,
Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627e630.
5. (a) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron
2003, 59, 1571e1587; (b) Stoll, A. H.; Knochel, P. Org. Lett. 2008, 10, 113e116; (c)
Villemin, D.; Goussu, D. Heterocycles 1989, 29, 1255e1261; (d) Fiandanese, V.;
Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron 2008, 64, 7301e7306.
6. (a) Ye, S.; Ding, Q.; Wang, Z.; Zhou, H.; Wu, J. Org. Biomol. Chem. 2008, 6,
4406e4412; (b) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 2007, 43,
7721e7725; (c) Abbiati, G.; Arcadi, A.; Beccalli, E.; Bianchi, G.; Marinelli, F.;
Rossi, E. Tetrahedron 2006, 62, 3033e3039; (d) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Parisi, L. M. Heterocycles 2004, 64, 475e482; (e) Cacchi, S.;
Carnicelli, V.; Marinelli, F. J. Org. Chem. 1994, 475, 289e296; (f) Cacchi, S.;
Fabrizi, G.; Goggiamani, A. Adv. Synth. Catal. 2006, 348,1301e1305; (g) Tyrrell, E.;
Whiteman, L.; Williams, N. Synthesis 2009, 5, 829e835; (h) Capelli, L.; Manini, P.;
Pezzella, A.; Napolitano, A.; d’Ischia, M. J. Org. Chem. 2009, 74, 7191e7194.
7. (a) Lee, J.-Y.; Lee, M. H.; Jeong, K.-S. Supramol. Chem. 2007, 19, 257e263; (b)
Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126e1136; (c) Hiroya,
K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43,
1277e1280; (d) Hiroya, K.; Itoh, S.; Sakamoto, T. Tetrahedron 2005, 61,
10958e10964.
CDCl3):
d 137.5, 136.3, 128.0, 122.1, 120.6, 119.9, 110.9, 100.5, 58.6.
Spectral properties were in accordance with the literature.35
4.5.14. 2-Hexyl-1H-indole (2n). Pale yellow oil; 1H NMR (400 MHz,
CDCl3):
d 7.87 (br s, 1H), 7.55e7.51 (m, 1H), 7.33e7.28 (m, 1H),
7.14e7.04 (m, 2H), 6.26e6.23 (m, 1H), 2.76 (t, J¼7.6 Hz, 2H),
1.78e1.68 (m, 2H), 1.46e1.29 (m, 6H), 0.95e0.87 (m, 3H); 13C NMR
(100 MHz, CDCl3):
d 139.9, 136.0, 128.9, 120.9, 119.7, 119.5, 110.2,
99.4, 31.6, 29.2, 29.0, 28.3, 22.6, 14.1. Spectral properties were in
accordance with the literature.35
4.5.15. 2-Hexyl-5-methyl-1H-pyrrolo[2,3-b]pyridine (2o). Pale yel-
low solid; 1H NMR (400 MHz, CDCl3):
d
8.92 (d, J¼2.0 Hz, 1H), 8.00
(d, J¼8.3 Hz, 1H), 7.89 (s, 1H), 7.34 (d, J¼8.3 Hz, 1H), 3.08e2.93 (m,
2H), 2.53 (s, 3H), 1.88 (quin, J¼7.0 Hz, 2H), 1.51e1.14 (m, 6H), 0.90 (t,
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 165.8, 155.1, 136.2,
135.2, 130.8, 122.4, 120.5, 39.2, 31.7, 29.2, 22.5, 18.5, 14.0. Spectral
properties were in accordance with the literature.36
4.5.16. 5-Methyloxy-1H-indole (2p). White solid; 1H NMR
(400 MHz, CDCl3):
J¼2.6 Hz, 1H), 7.14 (d, J¼2.2 Hz, 1H), 6.89 (dd, J¼8.8, 2.2 Hz, 1H),
6.53e6.48 (m, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3):
154.2,
d
8.05 (br s, 1H), 7.29 (d, J¼8.8 Hz, 1H), 7.19 (t,
d
130.9, 128.2, 124.8, 112.3, 111.7, 102.4, 102.3, 55.8. Spectral proper-
ties were in accordance with the literature.36
4.5.17. 5-Chloro-1H-indole (2q). White solid; 1H NMR (400 MHz,
CDCl3):
7.26e7.22 (m, 1H), 7.17 (dd, J¼8.6, 2.0 Hz, 1H), 6.54e6.48 (m, 1H);
13C NMR (100 MHz, CDCl3):
134.1, 129.2, 128.9, 125.5, 122.3, 120.1,
d
8.17 (br s, 1H), 7.65e7.60 (m, 1H), 7.32 (d, J¼8.4 Hz, 1H),
8. (a) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 4, 610e618; (b)
Ambrogio, I.; Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2007,
1775e1779; (c) Majumdar, K. C.; Samanta, S.; Chattopadhyay, B. Tetrahedron
Lett. 2008, 49, 7213e7216; (d) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9,
627e630; (e) Miyazaki, Y.; Kobayashi, J. J. Comb. Chem. 2008, 10, 355e357.
9. Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126,
10546e10547.
d
111.9, 102.4. Spectral properties were in accordance with the
literature.37
10. McDonald, F. E.; Chatterjee, A. K. Tetrahedron Lett. 1997, 38, 7687e7690.
11. Lai, R.-Y.; Hayashi, A.; Ozawa, F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics
2007, 26, 1062e1068.
12. (a) Ebrahimi, D.; Kemedi, D. F.; Messerla, A. B.; Hibbert, D. B. Analyst 2008, 133,
817e822; (b) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46,
2074e2077; (c) Dabb, S. L.; Ho, J. H. H.; Hodgson, R.; Messerle, B. A.; Wagler, J.
Dalton Trans. 2009, 634e642.
13. (a) Okuma, K.; Seto, J.; Sakaguchi, K.; Ozaki, S.; Nagahora, N.; Shioji, K.
Tetrahedron Lett. 2009, 50, 2943e2945; (b) Yin, Y.; Ma, W.; Chai, Z.; Zhao, G.
J. Org. Chem. 2007, 72, 5731e5736.
4.5.18. 1H-Pyrrolo[3,2-c]pyridine (2r). White solid; 1H NMR
(400 MHz, CDCl3):
d
8.96 (s, 1H), 8.28 (d, J¼5.7 Hz, 1H), 7.36 (d,
J¼5.7 Hz, 1H), 7.32 (d, J¼3.1 Hz, 1H), 6.67 (d, J¼4.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3):
d 142.8, 139.9, 139.5, 126.0, 125.0, 106.9, 101.8.
Spectral properties were in accordance with the literature.38
4.5.19. 5-Methyl-1H-pyrrolo[2,3-b]pyridine (2s). White solid; 1H
NMR (400 MHz, CDCl3):
1H), 7.77 (s, 1H), 7.34 (d, J¼3.5 Hz, 1H), 6.44 (d, J¼3.3 Hz, 1H), 2.46
(s, 3H); 13C NMR (100 MHz, CDCl3):
147.4, 143.5, 128.9, 125.2,
d
10.86e10.64 (m, 1H), 8.20 (d, J¼1.8 Hz,
14. (a) Namba, K.; Nakagawa, Y.; Yamamoto, H.; Imagawa, I.; Nishizawa, M. Synlett
2008, 1719e1723; (b) Kurisaki, T.; Naniwa, T.; Yamamoto, H.; Imagawa, H.;
Nishizawa, M. Tetrahedron Lett. 2007, 48, 1871e1874.
d
15. Terrasson, V.; Michaux, J.; Gaucher, A.; Wehbe, J.; Marque, S.; Prim, D.; Cam-
124.7, 120.2, 100.0, 18.5. Anal. Calcd for C8H8N2: C, 72.70; H, 6.10.
pagne, J.-M. Eur. J. Org. Chem. 2007, 5332e5335.
Found: C, 72.27; H, 5.98. [MþH]þ¼133.
16. (a) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006, 47, 631e634; (b)
Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J. Org. Chem. 2008, 73,
4160e4165; (c) Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6,
1527e1530; (d) Murai, K.; Hayashi, S.; Takaichi, N.; Nobuhiro, K.; Fujioka, H.
J. Org. Chem. 2009, 74, 1418e1421.
Acknowledgements
17. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250e6284; (b) Kappe, C. O.;
Stadler, A. “Microwaves in Heterocyclic Chemistry”, pp 253e290. Microwaves in
Organic and Medicinal Chemistry; WILEY-VCH GmbH & KGaA: Weinheim, 2005;
(c) Bazureau, J. P.; Hamelin, J.; Mongin, F.; Texier-Boullet, F. “Microwaves in
Heterocylic Chemistry” In. Microwaves in Organic Synthesis, 2nd ed.; Loupy, A.,
Ed.; WILEY-VCH GmbH & KGaA: Weinheim, 2006; Vol. 1, pp 456e523; (d) Bes-
son, T.; Brain, C. T. “Heterocyclic chemistry using microwave-assisted approaches”.
Microwave Assisted Organic Synthesis; Blackwell Publishing Ltd: Oxford, 2005;
Vol. 74, pp 44e74; (e) Suna, E.; Mutule, I. Top. Curr. Chem. 2006, 266, 49e101.
18. (a) Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett 2004,
2175e2179; (b) Le Bras, G.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tet-
rahedron Lett. 2006, 47, 5497e5501; (c) Jacubert, M.; Hamze, A.; Provot, O.;
Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2009, 50, 3588e3592.
19. (a) Sanz, R.; Guilarte, V.; Castroviejo, M. P. Synlett 2008, 3006e3010; (b) Ka-
balka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017e8028; (c) Binet,
J.; Boubia, B.; Dodey, P.; Legendre, C.; Barth, M. EP1919869 B1 20100414 Ap-
plication: EP20060808258 20060829.
We thank Dr. Andrea Rota from CEM Corporation for the valu-
able support.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.083.
References and notes
1. (a) Joule, J. A. Indole and its dervatives Category 2 In. Science of Synthesis:
HoubeneWeyl Methods of Molecular Transformations; Thomas, E. J., Ed.; George
Thieme: Stuttgart, Germany, 2000; Vol. 10, Chapter 10.13; (b) Indoles; Sundberg,
R. J., Ed.; Academic: London, 1996; (c) Higasio, Y. S.; Shoji, T. Appl. Catal. A Gen.
2001, 221, 197e207; (d) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22,
761e793.
2. For some recent general reviews: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873e2920; (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875e2911; (c) Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350,
20. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563e2591; (b) Kremsner, J.
M.; Kappe, C. O. Eur. J. Org. Chem. 2005, 3672e3679; (c) Nolen, S.; Liotta, C. L.;
€
Eckert, C. A.; Glaser, R. Green Chem. 2003, 5, 663e669; (d) Vasudevan, A.;
Verzal, M. K. Synlett 2004, 631e634.
21. Carpita, A.; Ribecai, A. Tetrahedron Lett. 2009, 50, 6877e6881.

7178
A. Carpita et al. / Tetrahedron 66 (2010) 7169e7178
22. Carpita, A.; Ribecai, A. Tetrahedron Lett. 2009, 50, 204e207.
23. Ren, T.; Zhang, Y.; Zhu, W.; Zhou, J. Synth. Commun. 2007, 37, 3279e3290.
24. Ding, Q.; Wu, J. J. Comb. Chem. 2008, 10, 541e545.
32. McKew, J. C.; Foley, M. A.; Thakker, P.; Behnke, M. L.; Lovering, F. E.; Sum, F.-W.;
Tam, S.; Wu, K.; Shen, M. W. H.; Zhang, W.; Gonzalez, M.; Liu, S.; Mahadevan,
A.; Sard, H.; Peang Khor, S.; Clark, J. D. J. Med. Chem. 2006, 49, 135e158.
33. Sakai, H.; Tsutsumi, K.; Morimoto, T.; Kakiuchi, K. Adv. Synth. Catal. 2008, 350,
2498e2502.
34. Kuzmich, D.; Mulrooney, C. Synthesis 2003, 11, 1671e1678.
35. Mahanty, J. S.; De, M.; Das, P.; Kundu, N. G. Tetrahedron 1997, 53, 13397e13418.
36. Li, P.; Wang, L.; Wang, M.; You, F. Eur. J. Org. Chem. 2008, 5946e5951.
37. Choy, J.; Jaime-Figueroa, S.; Jiang, L.; Wagner, P. Synth. Commun. 2008, 38,
3840e3853.
25. Sun, K.; Sachwani, R.; Richert, K. L.; Driver, T. G. Org. Lett. 2009, 11, 3598e3601.
26. Fleckenstein, C. A.; Plenio, H. Green Chem. 2008, 10, 563e570.
27. Lu, X.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2002, 67, 5412e5415.
28. Isobe, A.; Takagi, J.; Katagiri, T.; Uneyama, K. Org. Lett. 2008, 10, 2657e2659.
29. Schoenebeck, F.; Murphy, J. A.; Zhou, S.-Z.; Uenoyama, Y.; Miclo, Y.; Tuttle, T. J.
Am. Chem. Soc. 2007, 129, 13368e13369.
30. Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428e7431.
31. Bazile, Y.; Bras, J.-P.; De Cointet, P.; Nanthavong, S.; Pigerol, C.; Broll, M.; Ey-
mard, P.; Werbenec, J.-P.; Fournier, J. Eur. J. Med. Chem. 1977, 12, 525e530.
38. Whelligan, D. K.; Thomson, D. W.; Taylor, D.; Hoelder, S. J. Org. Chem. 2010, 75,
11e15.