Versatile synthesis of quinoline-3-carboxylic esters and indol-2-acetic esters by palladium-catalyzed carbonylation of 1-(2-aminoaryl)-2-Yn-1-Ols

Article abstract of DOI:10.1021/jo8006495

(Chemical Equation Presented) 1-(2-Aminoaryl)-2-yn-1-ols, easily obtained by the Grignard reaction between 1-(2-aminoaryl)ketones and alkynylmagnesium bromides, were subjected to carbonylative conditions in the presence of the PdI₂-KI catalytic

Full text of DOI:10.1021/jo8006495

Versatile Synthesis of Quinoline-3-Carboxylic Esters and
Indol-2-Acetic Esters by Palladium-Catalyzed Carbonylation of
1-(2-Aminoaryl)-2-Yn-1-Ols
Bartolo Gabriele,*,† Raffaella Mancuso,‡ Giuseppe Salerno,‡ Elvira Lupinacci,‡
Giuseppe Ruffolo,‡ and Mirco Costa§
Dipartimento di Scienze Farmaceutiche, UniVersita` della Calabria, 87036 ArcaVacata di Rende (Cosenza),
Italy, Dipartimento di Chimica, UniVersita` della Calabria, 87036 ArcaVacata di Rende (Cosenza), Italy,
and Dipartimento di Chimica Organica e Industriale, UniVersita` di Parma, 43100 Parma, Italy
b.gabriele@unical.it
ReceiVed March 25, 2008
1-(2-Aminoaryl)-2-yn-1-ols, easily obtained by the Grignard reaction between 1-(2-aminoaryl)ketones and
alkynylmagnesium bromides, were subjected to carbonylative conditions in the presence of the PdI2-KI catalytic
system, in the presence and in the absence of an external oxidant. Under oxidative conditions (80 atm of a 4:1
mixture of COsair, in MeOH as the solvent at 100 °C and in the presence of 2 mol % of PdI2 and 20 mol
% of KI), 1-(2-aminoaryl)-2-yn-1-ols bearing a primary amino group were selectively converted into quinoline-
3-carboxylic esters in fair to good yields [45-70%, based on starting 1-(2-aminoaryl)ketones], ensuing from
6-endo-dig cyclization followed by dehydration and oxidative methoxycarbonylation. On the other hand, indol-
2-acetic esters, deriving from 5-exo-dig cyclization followed by dehydrating methoxycarbonylation, were selectively
obtained in moderate to good yields [42-88%, based on starting 1-(2-aminoaryl)ketones] under nonoxidative
conditions (90 atm of CO, in MeOH as the solvent at 100 °C and in the presence of 2 mol % of PdI2 and 20 mol
% of KI), in the case of 1-(2-aminoaryl)-2-yn-1-ols bearing either a primary or secondary amino group and substituted
with a bulky group on the triple bond.
Introduction
Results and Discussion
During the last years, the intramolecular nucleophilic attack
to a triple bond coordinated to Pd(II) followed by alkoxycar-
bonylation has proved to be one of the most important and
powerful methodologies for the direct synthesis of carbonylated
heterocycles starting from acyclic precursors.1 In this area, we
have shown that PdI2 in conjunction with an excess of KI is a
very useful and versatile catalyst for achieving several conve-
nient syntheses of carbonylated heterocycles starting from
suitably functionalized alkynes, under oxidative as well as
nonoxidative conditions.1a,b,k–m,2
In this work, we have investigated the reactivity of 1-(2-
aminoaryl)-2-yn-1-ols under carbonylative conditions in the
presence of the PdI2-KI catalytic system to develop new and
selective synthetic approaches to carbonylated nitrogen hetero-
cycles.
1-(2-Aminoaryl)ketones 1-5 were reacted with an excess of
alkynylmagnesium bromides to give the corresponding (2-
aminoaryl)-2-yn-1-ols, according to Scheme 1. The crude
products 6-19 thus obtained could be used as substrates for
the subsequent carbonylation reactions without further purifica-
tion (see the Experimental Section for details).
(1) For recent reviews, see: (a) Gabriele, B.; Salerno, G.; Costa, M. Top.
Organomet. Chem. 2006, 18, 239–272. (b) Gabriele, B.; Salerno, G. PdI2. In
e-EROS (Electronic Encyclopedia of Reagents for Organic Synthesis); Crich,
D., Ed.; Wiley-Interscience: New York, 2006. (c) Conreaux, D.; Bouyssi, D.;
Monteiro, N.; Balme, G. Curr. Org. Chem. 2006, 10, 1325–1340. (d) Cacchi,
S.; Fabrizi, G.; Goggiamani, A. Curr. Org. Chem. 2006, 10, 1423–1455. (e)
Muzart, J. Tetrahedron 2005, 61, 9423–9463. (f) Muzart, J. Tetrahedron 2005,
61, 5955–6008. (g) Vizer, S. A.; Yerzhanov, K. B.; Al Quntar, A. A. A.;
Dembitsky, V. M. Tetrahedron 2004, 60, 5499–5538. (h) Alonso, F.; Beletskaya,
I. P.; Yus, M. Chem. ReV. 2004, 104, 3079–3159. (i) Zeni, G.; Larock, R. C.
Chem. ReV. 2004, 104, 2285–2309. (j) Nakamura, I.; Yamamoto, Y. Chem. ReV.
2004, 104, 2127–2198. (k) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P.
Curr. Org. Chem. 2004, 8, 919–946. (l) Gabriele, B.; Salerno, G.; Costa, M.
Synlett 2004, 2468–2483. (m) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli,
G. P. J. Organomet. Chem. 2003, 687, 219–228.
† Dipartimento di Scienze Farmaceutiche, Universita` della Calabria.
‡ Dipartimento di Chimica, Universita` della Calabria.
§ Dipartimento di Chimica Organica e Industriale, Universita` di Parma.
10.1021/jo8006495 CCC: $40.75
Published on Web 06/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4971–4977 4971

Gabriele et al.
SCHEME 1
process leading to the quinoline-3-carboxylic ester 20 (path c)
may become catalytic only in the presence of an external
oxidant, such as oxygen, able to reoxidize Pd(0) to PdI2.6
However, in the absence of an oxidant, a catalytic cycle is
possible also starting with a 6-endo-dig cyclization mode,
because intermediate III may undergo protonolysis by HI to
give the noncarbonylated quinoline 22 with simultaneous
regeneration of PdI2 (path d). This latter reactivity has been
recently reported by us.7
On the basis of these mechanistic hypotheses, we have studied
the reactivity of 1-(2-aminoaryl)-2-yn-1-ols bearing a primary
amino group (R ) H), such as 6-18, with CO and MeOH in
the presence of the PdI2/KI catalytic system under oxidative
(using oxygen as the oxidant) as well as nonoxidative conditions
to verify the possibility to find novel approaches to important
carbonylated heterocyclic derivatives 20 and 21, starting from
readily available substrates.
The first substrate we tested was 2-(2-aminophenyl)oct-3-
yn-2-ol 6 (R ) R1 ) R2 ) H, R3 ) Me, R4 ) Bu). Crude 6,
obtained by the reaction between commercially available 1-(2-
aminophenyl)ethanone 1 and 1-hexynylmagnesium bromide,
was already suitable as substrate for the subsequent reactions
without further purification (see the Experimental Section for
details). Substrate 6 was initially reacted under oxidative
conditions, in MeOH as the solvent (0.22 mmol of substrate
per mL of MeOH) at 100 °C and under 20 atm of a 4:1 mixture
of COsair, and in the presence of PdI2 (2 mol %) and KI as
the catalyst (KI: PdI2 ) 10). The substrate conversion was
complete after 2 h, and the main reaction product turned out to
be 2-butyl-4-methylquinoline 23 (79% isolated yield, based on
starting 6), whereas the carbonylated quinoline 24 was formed
only in traces (Table 1, entry 1). This result shows that, under
the above conditions, 6 selectively undergoes 6-endo-dig
cyclization (Scheme 2, path b) followed by dehydration and
protonolysis (path d) rather than carbonylation (path c). Because
it is known that protonolysis by HI is slowed down working
under less concentrated conditions,8 we next tried the reaction
at 0.02 rather then 0.22 mmol of 6 per mL of MeOH. As
expected, the quinoline-3-carboxylic ester 24 was now obtained
in appreciable yield (33% isolated), quinoline 23 still being the
main reaction product (62% isolated yield, Table 1, entry 2).
This result did not significantly change working under more
diluted conditions. In order to improve the selectivity toward
24, the reaction was then carried out under a higher CO pressure,
which was expected to favor the carbon monoxide insertion with
respect to protonolysis. Indeed, under the same conditions of
In principle, different reaction pathways can be followed when
1-(2-aminoaryl)-2-yn-1-ols bearing a primary amino group (R
) H) are reacted in the presence of the PdI2/KI catalytic system
under carbonylative conditions (Scheme 2, anionic iodide
ligands are omitted for clarity). In fact, the initial intramolecular
attack by the amino group to the coordinated triple bond can
occur in a 5-exo-dig (path a) or a 6-endo-dig (path b) cyclization
mode, leading to isomeric vinylpalladium intermediates I and
II, respectively, with formal elimination of HI. In contrast to
intermediate I, however, complex II can easily undergo loss of
water with simultaneous aromatization to give the 3-quinoli-
nylpalladium species III. Under CO pressure, both complexes
I and III can insert carbon monoxide, to give the corresponding
acylpalladium intermediates IV and V, respectively. Eventually,
nucleophilic displacement by an external alcohol should afford
the corresponding heterocyclic derivatives VI and 20, respec-
tively, with elimination of H-Pd-I [which is known to be in
equilibrium with Pd(0)+HI].3 Because intermediate VI still
contains an allyl alcoholic function, it can react further with
H-Pd-I, according to a known reactivity,4,5 to give the
allylpalladium complex VII. Protonolysis of the latter by HI
would then lead to the indol-2-acetic ester 21 with regeneration
of the catalytically active species PdI2. On the other hand, the
(2) (a) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. J. Org. Chem. 2007,
72, 9278–9282. (b) Gabriele, B.; Salerno, G.; Fazio, A.; Veltri, L. AdV. Synth.
Catal. 2006, 348, 2212–2222. (c) Gabriele, B.; Salerno, G.; Veltri, L.; Mancuso,
R.; Li, Z.; Crispini, A.; Bellusci, A. J. Org. Chem. 2006, 71, 7895–7898. (d)
Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. AdV. Synth. Catal. 2006, 348,
1101–1109. (e) Bacchi, A.; Costa, M.; Della Ca`, N.; Gabriele, B.; Salerno, G.;
Cassoni, S. J. Org. Chem. 2005, 70, 4971–4979. (f) Gabriele, B.; Mancuso, R.;
Salerno, G.; Veltri, L. Chem. Commun. 2005, 271–273. (g) Costa, M.; Della
Ca`, N.; Gabriele, B.; Massera, C.; Salerno, G.; Soliani, M. J. Org. Chem. 2004,
69, 2469–2477. (h) Bacchi, A.; Costa, M.; Della Ca`, N.; Fabbricatore, M.; Fazio,
A.; Gabriele, B.; Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004, 574–585. (i)
Bacchi, A.; Costa, M.; Gabriele, B.; Pelizzi, G.; Salerno, G. J. Org. Chem. 2002,
67, 4450–4457. (j) Gabriele, B.; Salerno, G.; Fazio, A.; Campana, F. B. Chem.
Commun. 2002, 1408–1409. (k) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa,
M.; Chiusoli, G. P. J. Organomet. Chem. 2000, 594, 409–415. (l) Gabriele, B.;
Salerno, G.; De Pascali, F.; Costa, M.; Chiusoli, G. P. J. Org. Chem. 1999, 64,
7693–7699. (m) Chiusoli, G. P.; Costa, M.; Gabriele, B.; Salerno, G. J. Mol.
Catal. A: Chem. 1999, 143, 297–310. (n) Bacchi, A.; Chiusoli, G. P.; Costa,
M.; Sani, C.; Gabriele, B.; Salerno, G. J. Organomet. Chem. 1998, 562, 35–43.
(o) Gabriele, B.; Salerno, G.; De Pascali, F.; Tomasi Sciano`, G.; Costa, M.;
Chiusoli, G. P. Tetrahedron Lett. 1997, 38, 6877–6880. (p) Bacchi, A.; Chiusoli,
G. P.; Costa, M.; Gabriele, B.; Righi, C.; Salerno, G. Chem. Commun. 1997,
1209–1210. (q) Bonardi, A.; Costa, M.; Gabriele, B.; Salerno, G.; Chiusoli, G. P.
Tetrahedron Lett. 1995, 36, 6495–7498.
(4) The possibility of obtaining aπ-allylpalladium complex directly from the
reaction between an allyl alcohol and a palladium hydride species without any
activator was disclosed by us some years ago: (a) Gabriele, B.; Salerno, G.; Costa,
M.; Chiusoli, G. P. J. Mol. Catal. 1996, 111, 43–48. (b) More recently, the
formation of an allylpalladium intermediate from allyl alcohols and a hydri-
dopalladium complex has been reported: Ozawa, F.; Ishiyama, T.; Yamamoto,
S.; Kawagishi, S.; Murakami, H. Organometallics 2004, 23, 1698–1707.
(5) The possibility of reducing an allyl alcohol moiety through the reaction
with an HsPdsI species with formation of aπ-allyl complex followed by
protonolysis has been recently demonstrated by us: see references 2a, d, f and:
(a) Gabriele, B.; Mancuso, R.; Salerno, G.; Plastina, P. J. Org. Chem. 2008, 73,
756–759. (b) Chiusoli, G. P.; Costa, M.; Cucchia, L.; Gabriele, B.; Salerno, G.;
Veltri, L. J. Mol. Catal. A: Chem. 2003, 204, 133–142.
(6) As we demonstrated some years ago, the reoxidation of Pd(0) to PdI2
with oxygen occurs via the intermediate formation of I2 (formed by oxidation
of HI) followed by oxidative addition of I2 to Pd(0): (a) Gabriele, B.; Costa, M.;
Salerno, G.; Chiusoli, G. P. J. Chem. Soc., Perkin Trans. 1994, 1, 83–87.
(7) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org.
Chem. 2007, 72, 6873–6877.
(8) See, for example: (a) Gabriele, B.; Costa, M.; Salerno, G.; Chiusoli, G. P.
J. Chem. Soc., Chem. Commun. 1992, 1007–1008.
(3) Grushin, V. V. Chem. ReV 1996, 96, 2011–2033.
4972 J. Org. Chem. Vol. 73, No. 13, 2008

Carbonylation of 1-(2-Aminoaryl)-2-Yn-1-Ols
SCHEME 2
TABLE 1. Reactions of 1-(2-Aminoaryl)-2-yn-1-ols 6-14 with CO, O2, and MeOH in the Presence of the PdI2sKI Catalytic Systema
entry
R1
R2
R3
R4
yieldb (%)
yieldb (%)
1c, d
2d
3
4
5
1
1
1
2
3
1
2
3
1
2
3
6
6
6
7
8
9
10
11
12
13
14
H
H
H
OMe
H
H
OMe
H
H
OMe
H
H
H
H
H
Cl
H
H
Cl
H
H
Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Ph
Ph
Ph
24
24
24
25
26
27
28
29
30
31
32
traces
33
69
65
60
45
63
65
69
23
23
23
33
79
62
24
28
6
7
34
35
30
25
8
9e
10
11
t-Bu
t-Bu
t-Bu
36
37
13
10
70
58
a Crude substrates 6-14 [obtained from the reaction between 1-(2-aminoaryl) ketones 1-3 and alkynylmagnesium bromides] were directly used as
substrates without need for further purification (see the Experimental Section for details). Unless otherwise noted, all reactions were carried out in
MeOH as the solvent (0.02 mmol of starting 1-3 per mL of MeOH, 1 mmol scale based on 1-3) for 2 h in the presence of PdI2 and KI (1-3/KI/PdI2
molar ratio ) 50:10:1) at 100 °C and under 80 atm of a 4:1 mixture of COsair. Substrate conversion was quantitative in all cases. b Isolated yield
based on starting 1-3. c Substrate concentration was 0.22 mmol/mL of MeOH. d The reaction was carried out under 20 atm of a 4:1 mixture COsair.
e The reaction also led to the formation of small amounts of 3,3-dimethyl-2-(3-methyl-1H-indol-2-yl)butyric acid methyl ester 38 (7%, based on starting
1).
entry 2, but under 80 atm of a 4:1 mixture of COsair, 24 was
the main reaction product (69% isolated yield), quinoline 23
being formed in only 24% yield (Table 1, entry 3). Under the
same conditions of entry 3, other 1-(2-aminoaryl)-2-yn-1-ols
7-14, bearing different substituents on the triple bond and on
the aromatic ring, were converted into the corresponding
quinoline-3-carboxylic esters 25-32 in fair to good yields, thus
allowing a general synthesis of this class of heterocyclic
compounds (Table 1, entries 4-11). Minor amounts of non-
carbonylated quinolines 33-37 were obtained in some cases
(entries 4, 6, 7, 9, 10).
The reaction worked well also with substrates bearing a tert-
butyl group on the triple bond, such as 30-32, which led to
the corresponding quinolines in 58-70% isolated yields based
on starting amino ketones 1-3 (Table 1, entries 9-11). In the
case of 12, the formation of small amounts (7%) of 3,3-
J. Org. Chem. Vol. 73, No. 13, 2008 4973

Gabriele et al.
TABLE 2. Reactions of 1-(2-Aminoaryl)-2-yn-1-ols 8-19, 49 with CO and MeOH in the Presence of the PdI2sKI Catalytic Systema
entry
R
R1
R2
R3
R4
Ph
Ph
Ph
yieldb (%)
yieldb (%)
12c
13c
14c
15c
16c
17
18
19
20
21
1
2
3
3
1
1
2
3
4
1
2
4
5
5
9
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
OMe
H
H
H
H
OMe
H
H
H
H
H
Cl
Cl
H
H
H
Cl
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Ph
Me
Me
34
35
39
40
36
36
37
59
54
39
49
36
6
10
11
8
Bu
12
12
13
14
15
16
17
18
49
19
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
TMS
TMS
TMS
Bu
38
38
41
42
66
75
45
68
60
88
42
63
30
43
44
22
14
45d
46d
47d
22
OMe
H
H
23
48d
24e
25
H
t-Bu
50
44
a Crude 8-19, 49 [obtained from the reaction between 1-(2-aminoaryl) ketones 1-5 and alkynylmagnesium bromides] were directly used as
substrates without need for further purification (see the Experimental Section for details). Unless otherwise noted, all reactions were carried out in
MeOH as the solvent (0.02 mmol of 1-5/mL of MeOH, 1 mmol scale based on 1-5) for 2 h in the presence of PdI2 and KI (1-5/KI/PdI2 molar ratio
) 50:10:1) at 100 °C and under 90 atm of CO. Substrate conversion was quantitative in all cases. b Isolated yield based on starting 1-5. c Reaction was
d
carried out under 60 atm of CO. R4 ) H in the final product (see text for details). e Decomposition of the substrate, with formation of unidentified
chromatographically immobile materials, was observed.
dimethyl-2-(3-methyl-1H-indol-2-yl)butyric acid methyl ester
38, deriving from path a (Scheme 2), was observed (Table 1,
entry 9). Thus, under oxidative conditions, the reaction pathway
beginning with a 6-endo-dig cyclization (Scheme 2, path b) is
preferentially followed with respect to that beginning with a
5-exo-dig cyclization (Scheme 2, path a), even in the presence
of a bulky substituent on the terminal sp carbon. This apparently
unusual result can be explained as follows. The pathway
beginning with a 6-endo-dig cyclization is particularly favored
by the stabilization ensuing from the subsequent aromatization
with formation of the quinoline ring. On the other hand, the
pathway beginning with a 5-exo-dig cyclization can lead to
aromatization only after the reaction between intermediate VI
and the H-Pd-I species; however, this latter reaction is
hindered by the fact that, under oxidative conditions, H-Pd-I
is readily reconverted to PdI2,1a,b,k–m,6 which may begin a new
catalytic cycle leading to 20.
It was interesting at this point to test the reactivity of 1-(2-
aminoaryl)-2-yn-1-ols under nonoxidative conditions. We found
that substrates not bearing a bulky group on the triple bond
preferentially underwent 6-endo-dig rather than 5-exo-dig cy-
clization. For example, the reaction of 2-(2-aminophenyl)-4-
phenylbut-3-yn-2-ol 9 (bearing a phenyl group on the triple
bond), carried out under the same conditions of entry 3 (Table
1) but under 60 atm of CO and in the absence of oxygen,
selectively led to 4-methyl-2-phenylquinoline 34 (59% isolated
yield, Table 2, entry 12), ensuing from 6-endo-dig cyclization
(Scheme 2, path b) followed by aromatization and protonolysis
(Scheme 2, path d). This result shows that, for a substrate
bearing a phenyl on the triple bond, the route leading to indoles
21 (Scheme 2, path a) it is not competitive with the pathway
leading to quinolines 22. As expected, other substrates bearing
a phenyl or a butyl group on the triple bond, such as 10, 11,
and 8, behaved similarly, leading to the corresponding noncar-
bonylated quinolines 35, 39, and 40 in 39-49% yields, as shown
by the results reported in Table 2, entries 13-15.
On the basis of these results and observations, the next logical
step was to test the reactivity of substrates bearing a bulky tert-
butyl or TMS group on the triple bond, under nonoxidative
conditions. In this case, in fact, the 5-exo-dig pathway leading
to indoles 21 was expected to become competitive with the
6-endo-dig route leading to quinolines 22 (Scheme 2) for steric
reasons. Indeed, the reaction of 2-(2-aminophenyl)-5,5-dimeth-
ylhex-3-yn-2-ol 12 (R4 ) tert-butyl) carried out under the same
conditions as those of entries 12-15 (Table 2) led to 3,3-
dimethyl-2-(3-methyl-1H-indol-2-yl)butyric acid methyl ester
38 in 66% isolated yield [based on starting 1-(2-aminophe-
nyl)ethanone 1], 2-tert-butyl-4-methylquinoline 36 being formed
as byproduct (36% isolated yield based on 1a, Table 2, entry
16). The selectivity toward 38 could be improved working under
a higher CO pressure: at 90 atm, the yields of 38 and 36 were
75 and 6%, respectively, based on 1 (entry 17, Table 2). Under
these latter conditions, other substrates bearing a tert-butyl group
on the triple bond, such as 13-15, led to the corresponding
indoles 41-43 with good yields and selectivities (entries 18-20,
Table 2). Minor amounts of noncarbonylated quinolines 37 and
44 were obtained from substrates 13 and 15, respectively (entries
18 and 20).
As we have already observed in other PdI2-catalyzed cy-
clization and oxidative carbonylation reactions,1a,b,k–m,2b,h,j,l,7 in
the case of substrates bearing a trimethylsilyl substituent on the
triple bond, such as 16-18, the TMS group was lost in the
course of the process, thus allowing the synthesis of R-unsub-
stituted indol-2-acetic esters 45-47 (entries 21-23, Table 2).
4-Phenylquinoline 48 was obtained as byproduct in the case of
the reaction of 18 (entry 23).
We also tested the reactivity of 1-(2-alkylaminoaryl)-2-yn-
1-ols bearing a secondary rather than a primary amino group.
Clearly, for these substrates, bearing only one hydrogen bonded
to nitrogen, paths c and d (Scheme 2) could not be followed,
thus the possibility to obtain quinoline derivatives 20 or 22 was
prevented. The reaction of 2-(2-methylaminophenyl)-oct-3-yn-
4974 J. Org. Chem. Vol. 73, No. 13, 2008

Carbonylation of 1-(2-Aminoaryl)-2-Yn-1-Ols
2-ol 49 (substituted with a butyl group on the triple bond),
carried out under nonoxidative conditions, similar to those
reported in entry 17 (Table 2), led to decomposition of the
starting material, with formation of unidentified chromatographi-
cally immobile materials (Table 2, entry 24). This is conceivable,
because, as we have seen, if the substituent on the triple bond
is not sterically demanding, the 5-exo-dig cyclization (path a,
Scheme 2) is not favored and, as a consequence, the substrate
preferentially undergoes decomposition. On the other hand, the
reaction of 5,5-dimethyl-2-(2-methylaminophenyl)-hex-3-yn-2-
ol 19, bearing a tert-butyl group on the triple bond, did afford
the corresponding indol-2-acetic derivative 50, even though in
moderate yield [44% isolated, based on starting 1-(2-methyl-
aminophenyl)ethanone 5, Table 2, entry 25].
group, such as 6-14, selectively undergo 6-endo-dig cyclization
when allowed to react under oxidative conditions, with selective
formation of quinoline-3-carboxylic esters 24-32 in fair to good
yields [45-70% isolated, based on starting 1-(2-aminoaryl)ke-
tones 1-3]. On the other hand, indol-2-acetic esters 38, 41-43,
45-47, and 50, deriving from 5-exo-dig cyclization, are obtained
in moderate to good yields [42-88%, based on starting 1-(2-
aminoaryl)ketones 1-5] under nonoxidative conditions, when
the starting material is substituted with a bulky group on the
triple bond, as in the case of 12-19. In this latter case, a primary
as well as a secondary amino group can be present in the
substrate, and R-unsubstituted indol-2-acetic esters are formed
from substrates bearing a TMS group on the triple bond, ensuing
from loss of the TMS group in the course of the process.
Quinoline and indole derivatives are particular important classes
of heterocyclic derivatives, with many important applications.9–11
The present methodology represents a simple and direct
approach to the synthesis of functionalized quinolines and
indoles starting from readily available starting materials.12–15
Conclusions
In conclusion, we have shown that 1-(2-aminoaryl)-2-yn-1-
ols 6-19 [used as crude products deriving from the Grignard
reaction between 1-(2-aminoaryl)ketones 1-5 and alkynylmag-
nesium bromides] may follow different reaction pathways when
let to react in the presence of the PdI2-KI catalytic system under
oxidative or nonoxidative carbonylation conditions, depending
on the nature of the substrate and on reaction conditions. In
particular, 1-(2-aminoaryl)-2-yn-1-ols, bearing a primary amino
Experimental Section
Typical Procedure for the Synthesis of Quinoline-3-carboxy-
lic Esters. We report here as a typical procedure the preparation
of 2-butyl-4-methylquinoline-3-carboxylic acid methyl ester 24
(Table 1, entry 3). Details for the preparation of all the other
quinoline-3-carboxylic esters 25-32 can be found in the Supporting
Information. To a suspension of Mg turnings (700.0 mg, 28.8 mmol)
in anhydrous THF (2.0 mL), maintained under nitrogen and under
reflux, was added pure EtBr (0.5 mL) to start the formation of the
Grignard reagent. The remaining bromide was added dropwise (ca.
20 min) in THF solution (1.5 mL of EtBr in 15.0 mL of THF; total
amount of EtBr added: 2.92 g, 26.8 mmol). The mixture was then
allowed to reflux for an additional 20 min. After cooling, the
(9) Substituted quinolines are known to display a wide range of pharmaco-
logical activities, such as antiinflammatory, antibacterial, antiprotozoan, anti-
malarial, antiasthmatic, antituberculosis, anti-Alzheimer, antihypertensive, an-
thelmintic, anti-HIV, and anti-cancer activity. For representative recent examples,
see: (a) Altenbach, R. J.; Liu, H. Q.; Banfor, P. N.; Brownian, K. E.; Fox, G. B.;
Fryer, R. M.; Komater, V. A.; Krueger, K. M.; Marsh, K.; Miller, T. R.; Pan,
J. B.; Pan, L. P.; Sun, M. H.; Thiffault, C.; Wetter, J.; Zhao, C.; Zhou, D. L.;
Esbenshade, T. A.; Hancock, A: A.; Cowart, M. D. J. Med. Chem. 2007, 50,
5439–5488. (b) Guandalini, L.; Norcini, M.; Varani, K.; Pistolozzi, M.; Gotti,
C.; Bazzicalupi, C.; Martini, E.; Dei, S.; Manetti, D.; Scapecchi, S.; Teodori,
E.; Bertucci, C.; Ghelardini, C.; Romanelli, M. N. J. Med. Chem. 2007, 50,
4993–5002. (c) Nandhakumar, R.; Suresh, T.; Jude, A. L. C.; Kannan, V. R.;
Mohan, P. S. Eur. J. Med. Chem. 2007, 42, 1128–1136. (d) Fujimoto, S. Biol.
Pharm. Bull. 2007, 30, 1923–1929. (e) Desrivot, J.; Edlund, P. O.; Svensson,
R.; Baranczewski, P.; Fournet, A.; Figadere, B.; Herrenknecht, C. Toxicology
2007, 235, 27–38. (f) Huy, N. T.; Mizunama, K.; Kaur, K.; Nhien, N. T. T.;
Jain, M.; Uyen, D. T.; Harada, S.; Jain, R.; Kamei, K. Antimicrob. Agents Ch.
2007, 51, 2842–2847. (g) Smith, A. T.; Livingston, M. R.; Mai, A.; Filetici, P.;
Queener, S. F.; Sullivan, W. J., Jr. Antimicrob. Agents Ch. 2007, 51, 1109–
1111. (h) Musiol, R.; Jampilek, J.; Kralova, K.; Richardson, D. R.; Kalinowski,
D.; Podeszwa, B.; Finster, J.; Niedbala, H.; Palka, A.; Polanski, J. Bioorg. Med.
Chem. 2007, 15, 1280–1288. (i) Jiang, R.; Duckett, D.; Chen, W.; Habel, J.;
Ling, Y. Y.; LoGrasso, P.; Kamanecka, T. M. Bioorg. Med. Chem. Lett. 2007,
17, 6378–6382. (j) Nayyar, A.; Monga, V.; Malde, A.; Coutinho, E.; Jain, R.
Bioorg. Med. Chem. 2007, 15, 626–640. (k) Robinett, R. G.; Freemerman, A. J.;
Skinner, M. A.; Shewchuk, L.; Lackey, K. Bioorg. Med. Chem. Lett. 2007, 17,
5886–5893. (l) Paliakov, E.; Henary, M.; Say, M.; Patterson, S. E.; Parker, A.;
Manzel, L.; Macfarlane, D. E.; Bojarski, A. J.; Strekowski, L. Bioorg. Med.
Chem. 2007, 15, 324–332. (m) Pannala, M.; Kher, S.; Wilson, N.; Gaudette, J.;
Sircar, I.; Zhang, S. H.; Bakhiver, A.; Yang, G.; Yuen, P.; Gorcsan, F.; Sakurai,
N.; Barbosa, M.; Cheng, J. F. Bioorg. Med. Chem. Lett. 2007, 17, 5978–5982.
(n) Boschelli, D. H.; Wu, B. Q.; Ye, F.; Wang, Y.; Golas, J. M.; Lucas, J.;
Boschelli, F. J. Med. Chem. 2006, 49, 7868–7876. (o) Hoglund, L. P. J.; Silver,
S.; Engstrom, M. T.; Salo, H.; Tauber, A.; Kyyronen, H.-K.; Saarenketo, P.;
Hoffren, A. M.; Kokko, K.; Pohjanoska, K.; Sallinen, J.; Savola, J.-M.; Wurster,
S.; Kallatsa, O. A. J. Med. Chem. 2006, 49, 6351–6363. (p) Pokalwar, R. U.;
Hangarge, R. V.; Maske, P. V.; Shingare, M. S. ArkiVoc 2006, 11, 196–204. (q)
Narender, P.; Srinivas, U.; Ravinder, M.; Rao, B. A.; Ramesh, C.; Harakishore,
K.; Gangadasu, B.; Murthy, U. S. N.; Rao, V. J. Bioorg. Med. Chem. 2006, 14,
4600–4609. (r) Klingenstein, R.; Melnyk, P.; Leliveld, S. R.; Ryckebusch, A.;
Korth, C. J. Med. Chem. 2006, 49, 5300–5308. (s) Isaacs, J. T.; Pili, R.; Qian,
D. Z.; Dalrymple, S. L.; Garrison, J. B.; Kyprianou, N.; Bjork, A.; Olsson, A.;
Leanderson, T. Prostate 2006, 66, 1768–1778. (t) Henry, M.; Alibert, S.; Orlandi-
Pradines, E.; Bogreau, H.; Fusai, T.; Rogier, C.; Barbe, J.; Pradines, B. Curr.
Drug Targets 2006, 7, 935–948. (u) Joshi, A. A.; Viswanathan, C. L. Bioorg.
Med. Chem. Lett. 2006, 16, 2613–2617. (v) Nayyar, A.; Malde, A.; Coutinho,
E.; Jain, R. Bioorg. Med. Chem. 2006, 14, 7302–7310. (w) Nayyar, A.; Malde,
A.; Jain, R.; Coutinho, E. Bioorg. Med. Chem. 2006, 14, 847–856. (x) Marco-
Contelles, J.; Leon, R.; Lopez, M. G.; Garia, A. G.; Villarroya, M. Eur. J. Med.
Chem. 2006, 41, 1464–1469.
(10) For pharmacological data on quinolin-3-carboxylic ester derivatives, see:
(a) Mai, A.; Rotili, D.; Tarantino, D.; Ornaghi, P.; Tosi, F.; Vicidomini, C.;
Sbardella, G.; Nebbioso, A.; Miceli, M.; Altucci, L.; Filetici, P. J. Med. Chem.
2006, 49, 6897–6907. (b) Kim, N. D.; Yoon, J.; Kim, J. H.; Lee, J. T.; Chon,
Y. S.; Hwang, M.-K.; Ha, I.; Song, W.-J. Bioorg. Med. Chem. Lett. 2006, 16,
3772–3776. (c) Sestili, I.; Borioni, A.; Mustazza, C.; Rodomonte, A.; Turchetto,
L.; Sbraccia, M.; Riitano, D.; Del Giudice, M. R. Eur. J. Med. Chem. Chim.
Ther. 2004, 39, 1047–1058. (d) Edwards, B. S.; Bologa, C.; Young, S. M.;
Balakin, K. V.; Prossnitz, E. R.; Savchuck, N. P.; Sklar, L. A.; Oprea, T. I. Mol.
Pharmacol. 2005, 68, 1301–1310. (e) Sosa, A.; Carolina, B.; Boschelli, D. H.;
Ye, F.; Golas, J. M.; Boschelli, F. Bioorg. Med. Chem. Lett. 2004, 14, 2155–
2158. (f) Bi, Y.; Stoy, P.; Adam, L.; He, B.; Krupinski, J.; Normandin, D.;
Pongrac, R.; Seliger, L.; Watson, A.; Macor, J. E. Bioorg. Med. Chem. Lett.
2004, 14, 1577–1580. (g) Ghorab, M. M.; Abdel-Hamide, S. G.; Farrag, Hala,
A. Acta Pol. Pharm. 2001, 58, 175–184. (h) Boschelli, D. H.; Wang, Y. D.; Ye,
F.; Wu, B.; Zhang, N.; Dutia, M.; Powell, D. W.; Wissner, A.; Arndt, K.; Weber,
J. M.; Boschelli, F. J. Med. Chem. 2001, 44, 822–833.
(11) Substituted indoles are known to display a wide range of pharmacological
activities. For representative recent examples, see: (a) Jump, S. M.; Kung, J.;
Staub, R.; Kinseth, M. A.; Cram, E. J.; Yunida, L. N.; Preobrazhenskaya, M. N.;
Bjeldanes, L. F.; Firestone, G. L. Biochem. Pharmacol. 2008, 75, 713–724. (b)
Park, M.-K.; Rhee, Y.-H.; Lee, H.-J.; Lee, E.-O.; Kim, K.-H.; Park, M.-J.; Jeon,
B.-H.; Shim, B.-S.; Jung, C.-H.; Choi, S.-H.; Ahn, K.-S.; Kim, S.-H. Phytother.
Res. 2008, 22, 58–64. (c) Tsotinis, A.; Afroudakis, P. A.; Davidson, K.; Prashar,
A.; Sudgen, D. J. Med. Chem. 2007, 50, 6436–6440. (d) Le Borgne, M.;
Marchand, P.; Nourrisson, M. R.; Loquet, D.; Palzer, M.; Le Baut, G.; Hartmann,
R. W. J. Enzym. Inhib. Med. Ch. 2007, 22, 667–676. (e) Olgen, S.; Kilic, Z.;
Ada, A. O.; Coban, T. J. Enzym. Inhib. Med. Ch. 2007, 22, 457–462. (f) Radwan,
M. A. A.; Ragab, E. A.; Sabry, N. M.; El-Shenawy, S. M. Bioorg. Med. Chem.
2007, 15, 3832–3841. (g) Zheng, M.; Zheng, M.; Ye, D.; Gend, Y.; Qiu, S.;
Luo, X.; Chen, K.; Liu, H.; Jiang, H. Bioorg. Med. Chem. Lett. 2007, 17, 2414–
2420. (h) Husain, K.; Abid, M.; Azam, A. Eur. J. Med. Chem. 2007, 42, 1300–
1308. (i) Sung, W. S.; Lee, D. G. Biol. Pharm. Bull. 2007, 30, 1865–1869. (j)
La Regina, G.; Coluccia, A.; Piscitelli, F.; Bergamini, A.; Sinistro, A.; Cavazza,
A.; Maga, G.; Samuele, A.; Zanoli, S.; Novellino, E.; Artico, M.; Silvestri, R.
J. Med. Chem. 2007, 50, 5034–5038. (k) Basset, J.; Romero, M.; Castillo, R.;
Pujol, M. D. Drug. Future 2007, 32, 108–109. (l) Bakir, F.; Kher, S.; Pannala,
M.; Wilson, N.; Nguyen, W.; Sircar, I.; Takedomi, K.; Fukushima, C.; Zapf, J.;
Xu, K.; Zhang, S. H.; Liu, J.; Morera, L.; Schneider, L.; Sakurai, N.; Jack, R.;
Cheng, J.-F. Bioorg. Med. Chem. Lett. 2007, 17, 3473–3479.
J. Org. Chem. Vol. 73, No. 13, 2008 4975

Gabriele et al.
solution of EtMgBr thus obtained was transferred under nitrogen
to a dropping funnel and was added dropwise to a solution of
1-hexyne (2.2 g, 26.8 mmol) in anhydrous THF (7.0 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, then it was
maintained at 50 °C for 2 h and used as such at the same
temperature for the next step. 1-(2-Aminophenyl)ethanone 1 (1.2
g, 8.9 mmol) was dissolved under nitrogen in anhydrous THF (7.0
mL) and then added dropwise to the solution of the 1-hexynyl-
magnesium bromide in THF (prepared as described above) under
nitrogen. After stirring at 50 °C for 1 h, the mixture was cooled to
room temperature. Saturated NH4Cl was added with stirring to
achieve weakly acidic pH. After additional stirring at room
temperature for 15 min, AcOEt (ca. 20 mL) was added and phases
were separated. The aqueous phase was extracted with AcOEt (3
× 30 mL), and the collected organic layers were washed with brine
to ca. neutral pH and eventually dried over Na2SO4. After filtration,
the solvent was evaporated and crude 2-(2-aminophenyl)oct-3-yn-
2-ol 6 was diluted with MeOH and transferred into a volumetric
flask (50 mL). To 7.0 mL of the solution (formally deriving from
1.25 mml of 1) were added 55.5 mL of MeOH (to adjust the
substrate concentration to 0.02 mmol/mL of MeOH), and the
resulting solution was transferred to a 250 mL autoclave, previously
loaded with PdI2 (9.0 mg, 2.5 × 10-2 mmol) and KI (41.5 mg,
0.25 mmol). The autoclave was sealed and, while the mixture was
stirred, the autoclave was pressurized with CO (64 atm) and air
(up to 80 atm). After being stirred at 100 °C for 2 h, the autoclave
was cooled, degassed, and opened. The solvent was evaporated,
and products 23 and 24 were separated by column chromatography
on silica gel using 99:1 hexane-acetone as eluent (order of elution:
23, 24).
(12) For a review on recent developments in the synthesis of quinolines,
see: (a) Kouznetsov, V. V.; Me´ndez, L. Y. V.; Go´mez, C. M. M. Curr. Org.
Chem. 2005, 9, 141–161. For more recent examples, see reference 7 and: (b)
Zhang, Z. H.; Tan, J. J.; Wang, Z. Y. Org. Lett. 2008, 10, 173–175. (c) Shaabani,
A.; Rahmati, A.; Badri, Z. Catal. Commun. 2008, 9, 13–16. (d) Sandelier, M. J.;
DeShong, P. Org. Lett. 2007, 9, 3209–3212. (e) Yang, D. Q.; Jiang, K. L.; Li,
J. N.; Xu, F. Tetrahedron 2007, 63, 7654–7658. (f) Abdou, W. M.; Kamel, A. A.
Synth. Commun. 2007, 37, 3945–3960. (g) Kuninobu, Y.; Inoue, Y.; Takai, K.
Chem. Lett. 2007, 36, 1422–1423. (h) Hogan, A. M. L.; O’Shea, D. F. J. Org.
Chem. 2007, 72, 9557–9571. (i) Kikuchi, S.; Iwai, M.; Kukuzawa, S. I. Synlett
2007, 2639–2642. (j) Arcadi, A.; Bianchi, G.; Inesi, A.; Marinelli, F.; Rossi, L.
Synlett 2007, 1031–1036. (k) Degtyarenko, A. S.; Tolmachev, A. A.; Volovenko,
Y. M.; Tverdokhlebov, A. V. Synthesis 2007, 3891–3895. (l) Kumar, K. H.;
Perumal, P. T. Tetrahedron 2007, 63, 9531–9535. (m) Kumar, S.; Saini, A.;
Sandhu, J. S. Synth. Commun. 2007, 37, 4071–4078. (n) Pasha, M. A.;
Mahammed, K. A.; Jayashankara, V. P. Synth. Commun. 2007, 37, 4319–4326.
(o) Hogan, A.-M. L.; O’Shea, D. F. J. Org. Chem. 2007, 72, 9557–9571. (p)
Austin, M.; Egan, O. J.; Tully, R.; Pratt, A. C. Org. Biomol. Chem. 2007, 5,
3778–3786. (q) Kidwai, M.; Barisal, V. Lett. Org. Chem. 2007, 4, 519–523. (r)
Al-Awadi, N. A.; Abdethamid, I. A.; Al-Etaibi, A. M.; Elnagdi, M. H. Synlett
2007, 2205–2208. (s) Cho, C. S.; Re, W. X. J. Organomet. Chem. 2007, 692,
4182–4186. (t) Goswami, S.; Jana, S.; Hazra, A.; Adak, A. K. J. Heterocycl.
Chem. 2007, 44, 1191–1194. (u) Baruah, B.; Deb, M. L.; Bhuyan, P. J. Synlett
2007, 1873–1876. (v) Boyd, D. R.; Sharma, N. D.; Loke, P. L.; Malone, J. F.;
McRoberts, W. C.; Hamilton, J. T. G. Org. Biomol. Chem. 2007, 5, 2983–2991.
(w) Mierde, H. V.; Ledoux, N.; Allaert, B.; Van Der Voort, P.; Drozdzak, R.;
De Vos, D.; Verpoort, F. New J. Chem. 2007, 31, 1572–1574. (x) Das, B.;
Damodar, K.; Chowdhury, N.; Kumar, R. A. J. Mol. Catal. A:Chem. 2007, 274,
148–152. (y) Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.;
Verron, J.; Masciadri, R. Tetrahedron 2007, 63, 2811–2823. (z) Sandalier, M. J.;
DeShong, P. Org. Lett. 2007, 9, 3209–3212. (aa) Zolfigol, M. A.; Salehi, P.;
Ghaderi, A.; Shiri, M. Catal. Commun. 2007, 8, 1214–1218. (bb) Shaabani, A.;
Soleimani, E.; Badri, Z. Synth. Commun. 2007, 37, 629–635. (cc) Liu, X. Y.;
Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645–2648. (dd) Zhao,
Y. L.; Zhang, W.; Wang, S.; Liu, Q. J. Org. Chem. 2007, 72, 4985–4988. (ee)
Das, B.; Damodar, K.; Chowdhury, N.; Suneel, K. Chem. Lett. 2007, 36, 796–
797. (ff) Zhang, L.; Wu, J. AdV. Synth. Catal. 2007, 349, 1047–1051. (gg) Some,
S.; Ray, J. K.; Banwell, M. G.; Jones, M. T. Tetrahedron Lett. 2007, 48, 3609–
3612.
(14) For recent reviews on the synthesis of indoles, see: (a) Patil, S.; Patil,
R. Curr. Org. Synth. 2007, 4, 201–222. (b) Patil, S.; Boulamwini, J. K. Curr.
Org. Synth. 2006, 3, 477–498. (c) Kuethe, J. T. Chimia 2006, 60, 543–553. (d)
Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875–2911. (e) 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. (f) Cacchi, S.; Fabrizi, G.
Chem. ReV. 2005, 105, 2873–2920. (g) 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. (h) For more recent examples, see Bratulescu, G.
Tetrahedron Lett. 2008, 49, 984–986. (i) Arcadi, A.; Bianchi, G.; Inesi, A.;
Marinelli, F.; Rossi, L. Eur. J. Org. Chem. 2008, 783–787. (j) Shore, G.; Morin,
S.; Mallik, D.; Organ, M. G. Chem. Eur. J. 2008, 14, 1351–1356. (k) Ackermann,
L.; Sandmann, R.; Villar, A.; Kaspar, L. T. Tetrahedron 2008, 64, 769–777. (l)
Main, C. A.; Petersson, H. M.; Rahman, S. S.; Hartley, R. C. Tetrahedron 2008,
64, 901–914. (m) Fang, Y. Q.; Lautens, M. J. Org. Chem. 2008, 73, 538–549.
(n) Leogane, O.; Lebel, H. Angew. Chem., Int. Ed. 2008, 47, 350–352. (o) Stoll,
A. H.; Knochel, P. Org. Lett. 2008, 10, 113–116. (p) Nakamura, I.; Mizushima,
Y.; Yamagishi, U. Tetrahedron 2007, 63, 8670–8676. (q) Palimkar, S. S.; More,
V. S.; Kumar, P. H.; Srinivasan, K. V. Tetrahedron 2007, 63, 12786–12790. (r)
Silva, L. F.; Craveiro, M. V.; Gambardella, M. T. P. Synthesis 2007, 3851–
3857. (s) Terrasson, V.; Michaux, J.; Gaucher, A.; Wehbe, J.; Marque, S.; Prim,
D.; Campagne, J.-M. Eur. J. Org. Chem. 2007, 5332–5335. (t) Fletcher, A. J.;
Bax, M. N.; Willis, M. C. Chem. Commun. 2007, 4764–4766. (u) Oskooie, H. A.;
Heravi, M. M.; Behbahani, F. K. Molecules 2007, 12, 1438–1446. (v) Yadav,
J. S.; Reddy, B. V. S.; Reddy, Y. J. Tetrahedron Lett. 2007, 48, 7034–7037. (w)
Sayyed, I. A.; Alex, K.; Tillack, A.; Schwarz, N.; Michalik, D.; Beller, M. Eur.
J. Org. Chem. 2007, 4525–4528. (x) Tanimori, S.; Kirihatali, M. Eur. J. Org.
Chem. 2007, 3977–3980. (y) Ambrogio, I.; Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F. Synlett 2007, 1775–1779. (z) Whitney, S.; Grigg, R.; Derrick, A.;
Keep, A. Org. Lett. 2007, 9, 3299–3302. (aa) Fuwa, H.; Sasaki, M. Org. Lett.
2007, 9, 3347–3350. (bb) Tang, S.; Xie, Y. X.; Li, J. H.; Wang, N. X. Synthesis
2007, 1841–1847. (cc) Androsov, D. A.; Neckers, D. C. J. Org. Chem. 2007,
72, 5368–5373. (dd) Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 2214–
2218. (ee) Saito, A.; Kanno, A.; Hanzawa, Y. Angew. Chem., Int. Ed. 2007, 46,
3931–3933. (ff) Tokuyama, H.; Makido, T.; Han-Ya, Y.; Fukuyama, T.
Heterocycles 2007, 72, 191–197. (gg) Attanasi, O. A.; Favi, G.; Filippone, P.;
Lillini, S.; Mantellini, F.; Spinelli, D.; Stenta, M. AdV. Synth. Catal. 2007, 349,
907–915. (hh) Kamikawa, K.; Kinoshita, S.; Furusyo, M.; Takemoto, S.;
Matsuzaka, H.; Uemura, M. J. Org. Chem. 2007, 72, 3394–3402. (ii) Sanz, R.;
Escribano, J.; Pedrosa, M. R.; Aguado, R.; Arnaiz, F. J. AdV. Synth. Catal. 2007,
349, 713–718. (jj) Simoneau, C. A.; Strohl, A. M.; Ganem, B. Tetrahedron Lett.
2007, 48, 1809–1811. (kk) Nielsen, S. D.; Ruhland, T.; Rasmussen, L. K. Synlett
2007, 443–446. (ll) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F.
Angew. Chem., Int. Ed. 2007, 46, 1529–1532. (mm) Xu, D. Q.; Yang, W.-L.;
Luo, S.-P.; Wang, B.-T.; Wu, M.; Xu, Z.-Y. Eur. J. Org. Chem. 2007, 1007–
1012. (nn) Della Rosa, C.; Kneeteman, M.; Mancini, P. Tetrahedron Lett. 2007,
48, 1435–1438.
(13) To our knowledge, this is the first method of synthesis of quinolin-3-
carboxylic esters by carbonylation of acyclic precursors. For representative
already known syntheses of these compounds by cyclization of acyclic precursors,
see: (a) Ho¨glund, I. P. J.; Silver, S.; Engstro¨m, M. T.; Salo, H.; Tauber, A.;
Kyyro¨nen, H.-K.; Saarenketo, P.; Hoffre´n, A.-M.; Kokko, K.; Pohjanoksa, K.;
Sallinen, J.; Savola, J.-M.; Wurster, S.; Kallatsa, O. A. J. Med. Chem. 2006, 49,
6351–6363. (b) Bi, Y.; Stoy, P.; Adam, L.; He, B.; Krupinski, J.; Normandin,
D.; Pongrac, R.; Seliger, L.; Watson, A.; Macor, J. E. Bioorg. Med. Chem. Lett.
2004, 14, 1577–1580. (c) Wu, J.; Xia, H.-G.; Gao, K. Org. Biomol. Chem. 2006,
4, 126–129. (d) Jia, C.-S.; Zhang, Z.; Tu, S.-J.; Wang, G.-W. Org. Biomol. Chem.
2006, 4, 104–110. (e) Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P.; Rao, R.;
Srinivasa; Nagaiah, K. Synthesis 2004, 2381–2385. (f) Wu, J.; Zhang, L.; Diao,
T.-N. Synlett 2005, 2653–2657. (g) Arumugam, P.; Karthikeyan, G.; Atchudan,
R.; Muralidharan, D.; Perumal, P. T. Chem. Lett. 2005, 34, 314–315. (h)
Karthikeyan, G.; Perumal, P. T. J. Heterocycl. Chem. 2004, 41, 1039–1042. (i)
De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 1647–1650. (j) Palimkar,
S. S.; Siddiqui, S. A.; Danial, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem.
2003, 68, 9371–9378. (k) O’Dell, D. K.; Nicholas, K. M. J. Org. Chem. 2003,
68, 6427–6430. (l) Boschelli, D. H.; Powell, D.; Golas, J. M.; Boschelli, F.
Bioorg. Med. Chem. Lett. 2003, 13, 2977–2980. (m) Zask, A.; Gu, Y.; Albright,
J. D.; Du, X.; Hogan, M.; Levin, J. I.; Chen, J. M.; Killar, L. M.;.; Sung, A.;
DiJoseph, J. F.; Sharr, M. A.; Roth, C. E.; Skala, S.; Jin, G.; Cowling, R.; Mohler,
K. M.; Barone, D.; Black, R.; March, C.; Skotnicki, J. S. Bioorg. Med. Chem.
Lett. 2003, 13, 1487–1490. (n) Patteux, C.; Levacher, V.; Dupas, G. Org. Lett.
2003, 5, 3061–3064. (o) Kim, J. N.; Chung, Y. M.; Im, Y. J. Tetrahedron Lett.
2002, 43, 6209–6212. (p) Cappelli, A.; Anzini, M.; Vomero, S.; Mennuni, L.;
Makovec, F.; Doucet, E.; Hamon, M.; Menziani, M. C.; Benedetti, P. G.; De;
Giorgi, G.; Ghelardini, C.; Collina, S. Bioorg. Med. Chem. 2002, 10, 779–802.
(q) Kobayashi, K.; Nakashima, T.; Mano, M.; Morikawa, O.; Konishi, H. Chem.
Lett. 2001, 602–603. (r) Doucet-Personeni, C.; Bentley, P. D.; Fletcher, R. J.;
Kinkaid, A.; Kryger, G.; Pirard, B.; Taylor, A.; Taylor, R.; Taylor, J.; Viner,
R.; Silman, I.; Sussman, J. L.; Greenblatt, H. M.; Lewis, T. J. Med. Chem. 2001,
44, 3203–3215. (s) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Kim, H. S. Tetrahedron
Lett. 2001, 42, 3737–3740. (t) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett.
2001, 3, 1109–1112. (u) Vitry, C.; Vasse, J.-L.; Dupas, G.; Levacher, V.;
Queguiner, G.; Bourguignon, J. Tetrahedron 2001, 57, 3087–3098.
(15) To our knowledge, this is the first method of synthesis of indol-2-acetic
esters by carbonylation of acyclic precursors. For already know syntheses of
these compounds, see: (a) Bevk, D.; Svete, J.; Stanovnik, B. J. Heterocycl. Chem.
2005, 42, 1413–1415. (b) Bellur, E.; Goerls, H.; Langer, P. J. Org. Chem. 2005,
70, 4751–4761. (c) Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem.
Soc. 2004, 126, 10246–10247. (d) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato,
A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124,
2137–2138. (e) Kuehne, M. E.; Cowen, S. D.; Xu, F.; Borman, L. S. J. Org.
Chem. 2001, 66, 5303–5316.
4976 J. Org. Chem. Vol. 73, No. 13, 2008

Carbonylation of 1-(2-Aminoaryl)-2-Yn-1-Ols
Pure 2-butyl-4-methylquinoline 23 was a yellow oil (60.3 mg,
24% based on starting 1), whose spectroscopic data agreed with
those we already reported.7 2-Butyl-4-methylquinoline-3-carboxylic
acid methyl ester 24 was a yellow oil [221.3 mg, 69% based on
starting 1-(2-aminophenyl)ethanone 1]. IR (film): ν ) 1731 (s),
1588 (m), 1456 (m), 1435 (m), 1290 (m), 1235 (s), 1161 (w), 1056
the solvent was evaporated and crude 2-(2-aminophenyl)-5,5-
dimethylhex-3-yn-2-ol 12 was diluted with MeOH and transferred
into volumetric flask (50 mL). To 7.0 mL of the solution (formally
deriving from 1.25 mml of 1) were added 55.5 mL of MeOH (to
adjust the substrate concentration to 0.02 mmol/mL of MeOH), and
the resulting solution was transferred to a 250 mL autoclave,
previously loaded with PdI2 (9.0 mg, 2.5 × 10-2 mmol) and KI
(41.5 mg, 0.25 mmol). The autoclave was sealed, purged at room
temperature several times with CO with stirring (10 atm) and
eventually pressurized at 90 atm of CO. After being stirred at 100
°C for 2 h, the autoclave was cooled, degassed, and opened. The
solvent was evaporated, and products 36 and 38 were separated by
column chromatography on silica gel using hexane-acetone from
99:1 to 95:5 (order of elution: 36, 38).
Pure 2-tert-butyl-4-methylquinoline 36 was a yellow oil (yield:
15.2 mg, 6% based on starting 1), whose spectroscopic properties
agreed with those we already reported.7 3,3-Dimethyl-2-(3-methyl-
1H-indol-2-yl)acetic acid methyl ester 38 was a yellow solid, mp
115-117 °C (yield: 244.7 mg, 75% based on starting 1). IR (KBr):
ν ) 3401 (s), 1727 (s), 1460 (w), 1340 (w), 1151 (m), 741 (m)
cm1; 1H NMR (300 MHz, CDCl3): δ ) 8.81 (s, br, 1 H), 7.56-7.48
(m, 1 H), 7.36-7.28 (m, 1 H), 7.21-7.03 (m, 2 H), 3.80 (s, 1 H),
3.69 (s, 3 H), 2.25 (s, 3 H), 1.05 (s, 9 H); 13C NMR (75 MHz,
CDCl3): δ ) 173.9, 135.2, 129.0, 128.4, 121.6, 118.9, 118.4, 110.7,
109.7, 52.3, 51.7, 36.9, 28.0, 9.2 ; GC-MS: m/z ) 259 (53) [M+],
203 (45), 202 (45), 172 (14), 171 (100), 170 (92), 144 (27), 143
(28), 142 (16), 116 (10), 115 (30); anal. calcd for C16H21NO2
(259.34): C, 74.10; H, 8.16; N, 5.40. Found C, 74.21; H, 8.14; N,
5.38.
1
(w), 759 (m) cm-1; H NMR (300 MHz, CDCl3): δ ) 8.08-8.05
(m, 1 H), 8.01-7.96 (m, 1 H), 7.70 (ddd, J ) 8.3, 6.9, 1.4, 1 H),
7.53 (ddd, J ) 8.3, 6.9, 1.4, 1 H), 3.99 (s, 3 H), 2.96-2.88 (m, 2
H), 2.63 (s, 3 H), 1.85-1.72 (m, 2 H), 1.44 (sext, J ) 7.4, 2 H),
0.95 (t, J ) 7.4, 3 H); 13C NMR (75 MHz, CDCl3): δ ) 169.9,
158.3, 147.3, 141.6, 130.0, 129.5, 127.7, 126.3, 125.7, 124.0, 52.4,
37.1, 31.8, 22.9, 15.9, 13.9 ; GC-MS: m/z ) 257 (6) [M+], 242
(17), 228 (23), 226 (11), 216 (16), 215 (100), 200 (53), 198 (10),
171 (10), 167 (12), 158 (13), 157 (88), 143 (10), 115 (13); anal.
calcd for C16H19NO2 (257.33): C, 74.68; H, 7.44; N, 5.44. Found
C, 74.76; H, 7.46; N, 5.43.
Typical Procedure for the Synthesis of Indol-2-acetic Esters.
We report here as a typical procedure the preparation of 38 (Table
2, entry 17). Details for the preparation of all the other indol-2-
acetic esters 41-43, 45-47, and 50 can be found in the Supporting
Information. To a suspension of Mg turnings (700.0 mg, 28.8 mmol)
in anhydrous THF (2.0 mL), maintained under nitrogen and under
reflux, was added pure EtBr (0.5 mL) to start the formation of the
Grignard reagent. The remaining bromide was added dropwise (ca.
20 min) in THF solution (1.5 mL of EtBr in 15.0 mL of THF; total
amount of EtBr added: 2.92 g, 26.8 mmol). The mixture was then
allowed to reflux for additional 20 min. After cooling, the solution
of EtMgBr thus obtained was transferred under nitrogen to a
dropping funnel and was added dropwise to a solution of 2,2-
dimethyl-1-butyne (2.2 g, 26.8 mmol) in anhydrous THF (7.0 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, then it
was maintained at 50 °C for 2 h and used as such at the same
temperature for the next step. 1-(2-Aminophenyl)ethanone 1 (1.2
g, 8.9 mmol) was dissolved under nitrogen in anhydrous THF (7.0
mL) and then added dropwise to the solution of the alkynylmag-
nesium bromide in THF (prepared as described above) under
nitrogen. After stirring at 50 °C for 2 h, the mixture was cooled to
room temperature. Saturated NH4Cl was added with stirring to
achieve weakly acidic pH. After additional stirring at room
temperature for 15 min, AcOEt (ca. 20 mL) was added and phases
were separated. The aqueous phase was extracted with AcOEt (3
× 30 mL), and the collected organic layers were washed with brine
to ca. neutral pH and eventually dried over Na2SO4. After filtration,
Acknowledgment. This work was supported by the Ministero
dell’Universita` e della Ricerca (Progetto di Ricerca di Interesse
Nazionale PRIN 2006031888).
Supporting Information Available: General experimental
methods, preparation of starting 1-(2-aminoaryl)ketones 1-5,
general procedure for the synthesis of quinoline-3-carboxylic
esters 24-32, general procedure for the synthesis of indol-2-
acetic esters 38, 41-43, 45-47, and 50, characterization data
1
and copy of H and 13C NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8006495
J. Org. Chem. Vol. 73, No. 13, 2008 4977