Cesium carbonate-promoted hydroamidation of alkynes: Enamides, indoles and the effect of iron(III) chloride

Article abstract of DOI:10.1002/adsc.201200430

A series of enamide derivatives was prepared by a simple procedure for the hydroamidation of alkynes with amides and sulfonamides. The use of such a mild base as cesium carbonate promotes the latter transformation, and the addition of catalytic amounts of iron(III) chloride has a beneficial effect in the outcome of some of the presented hydroamidation reactions. A range of indoles was also synthesized from ortho-alkynylanilides by both complementary procedures, which proved to be useful for the construction of the indolo[1,2-c]quinazoline tetracyclic system from an ortho-(2-aminophenylalkynyl)anilide. Copyright

Full text of DOI:10.1002/adsc.201200430

FULL PAPERS
DOI: 10.1002/adsc.201200430
Cesium Carbonate-Promoted Hydroamidation of Alkynes:
Enamides, Indoles and the Effect of Iron(III) Chloride
G
Marꢀa Teresa Herrero,a Jokin Dꢀaz de Sarralde,a Raul SanMartin,a,* Laura Bravo,a
and Esther Domꢀngueza,*
a
Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country (UPV/EHU),
48940 Leioa, Spain
Fax : (+34)-946012748; phone: (+34)-946015435; e-mail: raul.sanmartin@ehu.es or esther.dominguez@ehu.es
Received: May 15, 2012; Revised: July 3, 2012; Published online: November 4, 2012
Dedicated to Professor Miguel Angel Miranda on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200430.
Abstract: A series of enamide derivatives was pre- sized from ortho-alkynylanilides by both complemen-
pared by a simple procedure for the hydroamidation tary procedures, which proved to be useful for the
of alkynes with amides and sulfonamides. The use of construction of the indolo
such a mild base as cesium carbonate promotes the clic system from an ortho-(2-aminophenylalkynyl)-
latter transformation, and the addition of catalytic anilide.
amounts of iron(III) chloride has a beneficial effect
ACHTUNGTNER[NUNG 1,2-c]quinazoline tetracy-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
in the outcome of some of the presented hydroami- Keywords: alkynes; cesium; enamides; hydroamida-
dation reactions. A range of indoles was also synthe- tion; iron
Introduction
Following our research on the development of ad-
vantageous methods for the construction of heterocy-
The abundance of enamide and enamide-like motifs clic motifs,[9] we became interested in alternative pro-
in nature,[1] synthetic drugs[2] and valuable intermedi- cedures for the hydroamidation of alkynes as a tool
ates[3] has encouraged research on new protocols for for the construction of both enamides and indoles. In
the preparation of such privileged structures. Consid- this paper we wish to present our results in this con-
ering the relatively harsh conditions required for clas- text, including the use of a very mild base and the
sic approaches[4] like reaction between carbonyl com- beneficial role played by iron catalysts for some of
pounds and amides or hydroxylamines and anhy- the reported transformations.
drides, or the limited availability of vinyl derivatives
(halides, triflates, ethers) required for metal-catalyzed
cross-coupling reactions,[5] the hydroamidation of al- Results and Discussion
kynes has appeared as a very promising method.
Indeed, different transition metal catalysts (Ru, Cu, Phenylacetylene 1a and 2-pyrrolidinone 2a were
Pd, Rh, Re, Pt, Au) have been successfully applied to chosen as model substrates and a series of reaction
such atom-economic processes.[4e,6]
conditions was applied in order to effect hydroamida-
Another privileged structure is the indole scaffold, tion leading to enamide 3a. Apart from iron salts,
a basic element for an exceedingly high number of other transition metals were avoided, and the initial
biologically active natural and synthetic products. In assays were performed by just mixing the reactants
addition to well-established conventional methodolo- with several bases in toluene, as other solvents
gies for the preparation of such valuable heterocy- (CH2Cl2, THF, CH3CN, H2O, etc.) had been discarded
cles,[7] several procedures based on the metal-cata- from a preliminary screening of reaction conditions.
lyzed addition of nitrogen nucleophiles to alkynes As shown in Table 1, the reaction proceeded smoothly
have attracted much attention due to the relatively when using Cs2CO3, a mild base commonly used in
mild conditions and high selectivities obtained.[6j,k,8]
other relevant transformations like palladium-cata-
lyzed cross-coupling reactions. Other carbonates and
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Cesium Carbonate-Promoted Hydroamidation of Alkynes
Table 1. Selected hydroamidation assays performed with phenylacetylene 1a and 2-pyrrolidinone 2a.
Entry
Conditions i[a]
Yield [%][b]
Z/E[c]
1
2
3
4
5
6
7
NaOH, PhMe, 1508C
KOtBu, PhMe, 1508C
Na2CO3, PhMe, 1508C
K3PO4, PhMe, 1508C
K2CO3, PhMe, 1508C
Cs2CO3, PhMe, 1508C
Cs2CO3, PhMe, 1208C
Cs2CO3, PhMe, 1508C
Cs2CO3, PhMe, 1508C
Cs2CO3, PhMe, 1508C
Cs2CO3, 1508C
Cs2CO3, 1508C
20
45
18
48
48
93
<5
18
91
25
50
28
17
91
91
77
93
81
81
88
40
85/15
83/17
45/55
88/12
94/6
79/21
-
97/3
74/26
95/5
94/6
74/26
94/6
77/23
66/34
51/49
72/28
71/29
47/53
64/36
91/9
8[d]
9[e]
10[d,e]
11[f,g]
12[f]
13h]
14[i]
15[i]
16
Cs2CO3, PhMe, 1508C
Cs2CO3, FeCl3·6H2O, py, PhMe, 1508C
Cs2CO3, anh. FeCl3, py, PhMe, 1508C
1b, 2b, Cs2CO3, PhMe, 1508C
1b, 2b, Cs2CO3, FeCl3·6H2O, py, PhMe, 1508C
Cs2CO3, FeBr2, py, PhMe, 1508C
Cs2CO3, FeO, py, PhMe, 1508C
Cs2CO3, Fe, py, PhMe, 1508C
K3PO4, FeCl3·6H2O, py, PhMe, 1508C
17[i]
18[i]
19[i]
20[i]
21[i]
[a]
Reaction conditions: alkyne (1 equiv.), amide (2 equiv.), base (1 equiv.), toluene (2 mLmmolÀ1 of alkyne), 1508C, 24 h
unless otherwise noted.
Yield of isolated product.
Determined by H NMR.
[b]
[c]
[d]
[e]
[f]
1
Reaction time: 2 h.
1 mLmmolÀ1 of toluene was used.
Solventless reaction.
[g]
[h]
[i]
Reaction time: 10 min.
6 mLmmolÀ1 of toluene was used.
Reaction conditions: alkyne (1 equiv.), amide (2 equiv.), iron source (10 mol%), pyridine (40 mol%), base (2 equiv.), tolu-
ene (2 mLmmolÀ1 of alkyne), 1508C, 24 h.
stronger bases were also evaluated and provided mod- salts on the observed yields and stereoselectivities
erate to negligible results (Table 1, entries 1–5 vs. 6). should be also pointed out (e.g., entries 7–13 vs. 6 and
Although the use of cesium hydroxide in the hydro- 18–21 vs. 14 and 15).
A
Accordingly, a number of alkynes 1 and amides 2
and azoles has been reported,[10] this is the first exam- was reacted by the optimized hydroamidation proce-
ple of intermolecular addition of an amide to phenyl- dure promoted only by Cs2CO3 (Method A) and by
acetylene promoted by cesium carbonate.
Surprisingly, the addition of catalytic amounts of ic amounts of FeCl3 (Method B), and the results are
iron(III) salts and pyridine almost equaled the ob- compared in Table 1. Both methods provided accepta-
that based on the combination of Cs2CO3 with catalyt-
ACHTUNGTRENNUNG
served yields for the same reaction in some cases (en- ble to good yields not only from amides but also from
tries 14 and 15 vs. 6). Intrigued by this unexpected sulfonamides, thus displaying two valid alternatives
result, other substrates like 1b and 2b and different for the synthesis of enamides without the requirement
iron sources [Fe(0), Fe(II)] were also assayed and of precious metal catalysts. As mentioned before, the
again good yields were obtained (e.g., entry 16 vs. addition of catalytic amounts of ironACTHUNTGRNEUNG(III) chloride and
17).[11] We therefore assumed a synergistic effect of pyridine had a beneficial effect in some cases (en-
Cs2CO3 and FeCl3·6H2O that resulted to be substrate tries 2, 5, 6, and 8–12) but a clear trend could not be
dependent. The influence of factors like reaction established. It can therefore be suggested that the
time, temperature, dilution and the presence of iron iron species plays a coordinating role (thus activating
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Marꢀa Teresa Herrero et al.
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Table 2. Synthesis of enamides 3 by hydroamidation of alkynes 1 with amide derivatives 2.[a]
Entry
1
Alkyne 1
Amide 2
Enamide 3
Yield [%],[b] Z/E[c]
A: 93 (79/21)
B: 91 (77/23)
A: 77 (51/49)
B: 93 (72/28)
2
A: 62 (73/27)
B: 48 (79/21))
3
4
A: 67 (94/6)
B: 61 (92/8)
A: 39 (30/70)
5
6
B: 79 (62/38)[d]
A: 53 (92/08)
B: 75 (89/11)
A: 81 (87/13)
B: 77 (76/24)
7
A: 72 (78/22)
B: 92 (66/34)
8
9
A: 67 (78/22)
B: 89 (84/16)
A: 60 (7/93)
B: 64 (21/79)
10
11
A: 55 (79/21)
B: 66 (86/14)
A: 58 (91/9)
B: 70 (82/18)
12
[a]
Method A: 1 (1 equiv.), 2 (2 equiv.), Cs2CO3 (1 equiv.), PhMe (2 mLmmolÀ1 of 1), 1508C, 24 h. Method B: 1 (1 equiv.), 2
(2 equiv.), FeCl3·6H2O (10 mol%), py (40 mol%), Cs2CO3 (2 equiv.), PhMe (2 mLmmolÀ1 of 1), 1508C, 24 h.
Yield of isolated product.
[b]
[c]
[d]
1
Determined by H NMR.
DMF (2 mLmmolÀ1 of 1) was used instead of PhMe.
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Cesium Carbonate-Promoted Hydroamidation of Alkynes
Table 3. Synthesis of indoles 5 by Cs2CO3-mediated intramo-
lecular hydroamidation of ortho-alkynilanilides 4.[a]
the triple bond for nucleophilic attack) similar to
other transition metals already employed for this
transformation.[6] However, the significantly lower
price and toxicity of this metal source should be
pointed out. A related example on such a facilitating
effect or promotion by iron salts has been recently re-
ported in an iodine-mediated cyclization of alkynyl-
ACHTUNGTRENNUNG
anilines leading to 3-sulfenylindoles.[12] With regard to
Entry R1
R2
R3 R4
Me H
R5
H
5 (yield
[%])[b]
Method A, this is the first report on the intermolecu-
lar hydroamidation of alkynes in the absence of tran-
sition metal catalysts. The presence of infinitesimal
amounts of such precious metals was also examined
in both intermolecular and intramolecular versions of
the presented procedures and will be discussed in
detail later. The activation of triple bonds solely
mediated by bases has been described in an elegant
intramolecular approach to 3-alkylideneisoindolin-
1
H
H
5a (96)
2[c]
3[d]
4[c]
5[c]
6[c]
7[c]
8[c]
9[c]
H
H
CN
CN
CN
CN
H
Ph
H
COPh 5b (84)
COPh 5c (82)
Ph
Ph
n-Pr
n-Pr
Ph
Ph Ph
Me Ph
Me n-Pr
Ph n-Pr COPh 5f (87)
Ph Ph
Me n-Pr
Ph
Ph Ph
Ph n-Pr COPh 5k (83)
H
H
5d (95)
5e (87)
COPh 5g (88)
5h (75)
CO2Me n-Pr
H
ACHTUNGTRENNUNGones mediated by phosphazene base P4-t-Bu or
CO2Me H
H
COPh 5i (64)
COPh 5j (79)
DBU,[13] but in our case the difference observed be-
tween cesium carbonate and other bases (Table 2, en-
tries 1–6) is significant.
10[d] CO2Me Ph
11[d] CO2Me n-Pr
12[c]
H
Ph COPh 5l (59)
Cesium salts have a superior solubility in aprotic
solvents, a lower degree of solvation and ion-pairing
in comparison with other alkali salts. These proper-
ties, combined with the large ionic radius, low charge
density and high polarizibility exhibited by the cesium
cation, are involved in what is termed the “cesium
effect”.[14] Therefore we proposed that a relatively
“naked” cesium cation and the well-balanced strength
of cesium carbonate are responsible for its superior
behavior in the presented intramolecular hydroamida-
tion of arylacetylenes. In addition, although more re-
search should be carried out in this direction, the ex-
cellent result obtained from non-terminal alkyne 1d
suggests a simple, convenient route to trisubstituted
enamides.
[a]
Reaction conditions: Cs2CO3 (2 equiv.), toluene
(6 mLmmolÀ1 of 4), 1508C, 24 h.
Yield of isolated product.
Reaction time: 4 h.
Reaction time: 16 h.
[b]
[c]
[d]
Table 4. Intramolecular hydroamidation of ortho-alkynylani-
lides 4 mediated by Cs2CO3 and FeCl3·6H2O.[a]
The successful protocols for the access of enamides
3 were then applied to the intramolecular version of
this reaction, the cyclization of ortho-alkynylanilides
4.
Due to the easy monitoring of the reaction by TLC,
it was possible to choose between both procedures (A
or B) just by a glance at the chromatogram, and only
in one questionable case it was necessary to isolate
the cyclized product 5p from both reaction conditions
(see Table 4, entry 4).
Entry R1 R2
R3 R4
R5
5
(yield
[%])[b]
1[c]
H
H
Ph
H
COPh 5m
(87)
5n (88)
2[c]
3[d]
4
H
n-Pr
Me n-Pr
Me
H
H
H
H
5o (80)
CF3
H
Me H
5p (93)
85[e]
As shown in Table 3, a number of indole derivatives
5a–l was prepared by the cesium carbonate-promoted
cyclization of anilides 4 (Method A). Substrates bear-
ing terminal and non-terminal alkyne moieties (alkyl,
aryl) were cyclized in good yields, and interestingly,
the use of N-benzoylated anilides provided N-benzoy-
lated indoles 5b, c, 5f, g and 5i–l, whereas free (NH)
indoles 5a, 5d, e and 5h were obtained from N-acety-
lated anilides. The reaction conditions were optimized
at a higher dilution (6 mLmmolÀ1) probably on the
basis of the intramolecular nature of the reaction.
5
6[f]
Cl
Cl
Me
Me
COMe 5q (56)
H 5r (55)
[a]
Reaction conditions: FeCl3·6H2O (10 mol%), py
(40 mol%), Cs2CO3 (2 equiv.), toluene (8 mLmmolÀ1 of
4), 1508C, 24 h.
[b]
[c]
[d]
[e]
[f]
Yield of isolated product.
Toluene: 1 mLmmolÀ1
.
4 equiv. of Cs2CO3 were used.
Yield from Method A.
3 equiv. of Cs2CO3 were used.
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Marꢀa Teresa Herrero et al.
FULL PAPERS
Scheme 1. Synthesis of anilide 4c.
As mentioned above, the intramolecular cyclization
of 2-ethynylaniline derivatives in the presence of tran-
sition metal catalysts to provide indoles has been de- Scheme 2. One-pot double cyclization promoted by the
scribed,[8] in some cases base-promoted cyclizations
system Cs2CO3/FeCl3·6H2O/py.
have been reported,[10,15,16] but as far as we know, this
is the first report on the use of a mild base such as
cesium carbonate as the sole promoter of the reac- pathway is depicted in Scheme 2, showing that intra-
tion.
molecular hydroamidation occurred preferentially
Another set of substrates 4m–s reacted preferential- over hydroamination, followed by a nucleophilic addi-
ly by the iron-assisted protocol (Method B) and the tion and cyclodehydration. In addition to their elec-
corresponding results are displayed in Table 4. The troluminiscent properties,[18] indolo
ACTHNUTRGNEUNG[1,2-c]quinazolines
presence of functionalities (R2 =2-acetoxyethyl, 2-hy- have received attention due to a remarkable activity
droxyethyl) that might lead to conjugated vinyl against resistant bacterial (Gram-positive and Gram-
groups promoted a simultaneous elimination to 2-vi- negative) and pathogenic fungal strains,[19] and have
nylindoles 5o and 5r which was not observed from been found to promote inhibition of protein NS5A of
R2 =3-hydroxypropyl (Table 4, entries 3, 6 vs. 5) and hepatitis C virus.[20] Several elegant approaches to this
in this particular case N-acetylated indole 5q was tetracyclic system, the core of the alkaloid Hinckden-
formed.
tine A,[19a] have been reported in the last years,[18–21]
Considering that most of the ortho-alkynylanilides including (i) a sequential gold-catalyzed 5-endo-dig-
4 had been prepared by a route involving Sonogashira cyclization followed by a POCl3-promoted condensa-
coupling of ortho-haloanilines,[11] and taking into ac- tion,[21a] (ii) an initial Fisher indole cyclization from
count the existing reports on palladium- or copper- the phenylhydrazone of 2-aminophenyl ethyl ketone
catalyzed hydroamidation and hydroamination reac- followed by reaction with acyl chlorides,[21b] (iii) a pal-
tions,[6e–l,8a–h] anilide 4c was prepared by a palladium- ladium-catalyzed reaction of bis(ortho-trifluoroacet-
free approach based on nucleophilic substitution on
ACHTUNGTRENaNGNU midophenyl)acetylene with aryl or vinyl halides and
ortho-fluoronitrobenzene (Scheme 1), and cyclization triflates,[21c] and (iv) a two-step sequence consisting of
to 5c (Method A) provided the same yield (82%) addition/elimination between N-phenyltrifluoroaceti-
from both the latter alkyne and that prepared by a So- midoyl chlorides with indoles and a palladium-cata-
nogashira-based protocol. The content of the palladi- lyzed cyclization of the so-formed 1-(N-arylimino)in-
um and copper traces was measured (ICP-MS) in the doles.[21d] Although far from optimized, the presented
starting anilide 4c and in all the reagents involved procedure provides a new, advantageous entry to the
(Cs2CO3) and found to be below 6·10À4 mol% and valuable indolo
9·10À3 mol%, respectively. With regard to the inter-
ACHTUNGTRENNUNG
AHCTUNGTRENGN(UN III) as
molecular version, the aforementioned metal traces a Lewis acid catalyst in the nucleophilic addition of
were in all cases bellow 2·10À4 mol%. Considering the arylamine moiety to the acetyl moiety and cyclo-
previous reports on copper-catalyzed hydroamidation dehydration, Scheme 2 displays an activation effect of
reactions,[6j–l] the presence of infinitesimal amounts of the alkyne by iron complementary to that effected by
copper in the iron source of Method B (FeCl3·6H2O) the key cesium source. Such assistance could be relat-
was also carefully measured (1.4·10À4 mol%) in order ed to that reported by Li, Zhang and colleagues in
to discard this possibility. Therefore, although the co- the iodine-mediated electrophilic annulation of alk-
participation of copper traces[17] in the reported hy-
ynylanilines[12] or the hydroaryloxylation of 2-propar-
ACHTUNGTRENNUNG
droamidations cannot be ruled out, this possibility is gylphenols and naphthols displayed by Li and cow-
unlikely due to the extremely low amounts of copper orkers.[22] Moreover, as suggested by Prim and Cam-
present in the reaction mixture.
pagne,[8a] the role of iron
ACTHNGUTERNN(UG III) might be beyond a mere
We should also point out the result from anilide 4s reoxidant for the palladium catalyst in the intramolec-
(R2 =2-aminophenyl), which provided indoloquinazo- ular hydroamination of alkynylanilines performed in
line 6 by a double cyclization. A tentative mechanistic the presence of the bimetallic system FeCl3:PdCl2.
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Cesium Carbonate-Promoted Hydroamidation of Alkynes
2.26 (m, 2H, E isomer), 1.85–2.00 ( m, 2H, Z isomer);
13C NMR (75.4 MHz, CDCl3): d (data for Z isomer)=175.56
136.3, 129.2, 127.8, 126.6, 123.9, 113.8, 48.1, 30.4, 18.9; d
(data for E isomer)=173.4, 136.4, 128.9, 126.9, 125.7, 123.6,
111.8, 45.3, 31.3, 17.5; HR-MS: m/z=187.0995, calcd. for
C12H13NO: 187.0997.
Conclusions
To sum up, a new and operationally simple procedure
for the synthesis of enamides has been presented. The
yields from this method, based on the use of cesium
carbonate as the reaction promoter, can be improved
in some cases by the addition of catalytic amounts of
N-[3,5-Bis(trifluoromethyl)-phenyl]-N,4-dimethylbenzene-
sulfonamide (3b): yield: 77%; data from a mixture of Z/E=
72/28; yellow powder; 1H NMR (300 MHz, CDCl3): d=
7.75–7.63 (m, 8H, E isomer), 7.38 (s, 2H, Z isomer), 7.75–
7.63 (m, 8H, Z isomer), 7.35–7.31 (m, 5H, Z isomer), 6.56
(d, J=9.1 Hz, 1H, Z isomer), 6.00 (d, J=9.0 Hz, 1H, (Z
isomer) 5.86 (d, J=14.6 Hz, 1H, E isomer), 3.03 (s, 3H, E
isomer), 2.71 (s, 3H, Z isomer), 2.45 (s, 3H, Z isomer), 2.42
(s, 3H, E isomer); 13C NMR (75.4 MHz, CDCl3): d (data for
Z isomer)=144.5, 137.1, 133.9 , 131.3 (q, J=33 Hz), 129.9,
128.5–128.6 (m), 127.2, 123.3 (q, J=273 Hz), 120.8 (m),
116.3, 107.3, 36.6, 21.5; d (data for E isomer)=144.4, 138.7,
134.4, 131.9 (q, J=33 Hz), 130.1, 127.0, 125.1–125.0 (m),
123.0 (q, J=273 Hz), 119.4 (m), 116.2, 107.3, 32.1, 21.4; IR
(neat): n=1642 (C=O) and 1616 (C=C) cmÀ1; MS: m/z
(%)=423 (M+, 52), 268 (57), 267 (26), 248 (70), 227 (40),
199 (59), 91 (100), 42 (41); HR-MS: m/z=423.0730, calcd.
for C18H15F6O2S: 423.0728.
ironACHTUNGTRENNUNG(III) chloride and pyridine. Both procedures have
been successfully applied to the synthesis of a number
of enamide derivatives by an intermolecular hydroa-
midation of terminal and non-terminal alkynes, and
the scope of the procedures has been extended to the
intramolecular cyclization of ortho-alkynilanilides,
thus providing a series of indoles. Finally, the valuable
indoloACHTUNGTRENNUNG[1,2-c]quinazoline system was obtained by
a double cyclization when the same protocol was ap-
plied to an ortho-(2-aminophenylalkynyl)anilide.
Experimental Section
General Procedures
N-(2-Phenylethenyl)-2-piperidinone (3c):[24] yield: 62%;
data from a mixture of Z/E=73/27; orange oil; 1H NMR
(300 MHz, CDCl3): d=8.16 (d, J=15.3, 1H, E isomer),
7.11–7.43 ( m, 10H, Harom), 6.79 (d, J=9.4, 1H, Z isomer),
6.10 (d, J=9.4, 1H, Z isomer), 5.97 (d, J=15.1, 1H, E
isomer), 3.56 (t, J=6.2, 2H, E isomer), 3.20 (t, J=5.8, 2H,
Z isomer), 2.51 (m, 4H), 1.96–1.99 ( m, 2H, E isomer),
1.89–1.75 (m, 4H), 1.64–1.72 (m, 2H, Z isomer); 13C NMR
(75.4 MHz, CDCl3): d (data for Z isomer)=170.8, 135.7,
128.9, 128.5, 128.2, 127.2, 119.7, 48.8, 32.2, 23.0, 20.9, 20.5; d
( data for E isomer)=168.7, 128.6, 127.1, 126.4, 125.8, 110.8,
45.3, 33.0, 22.6, 20.5; IR (neat): n=1636 (C=O) cmÀ1; MS:
m/z (%)=201 (M+, 100), 172 (29), 130 (33); HR-MS: m/z=
201.1152, calcd. for C13H15NO: 201.1154.
All reagents were purchased and used as received except
1
when indicated. H and 13C NMR spectra were recorded on
a
Bruker AC-300 instrument (300 MHz for 1H and
75.4 MHz for 13C) at 208C. Chemical shifts (d) are given in
ppm downfield from Me4Si and are referenced as internal
standard to the residual solvent (unless indicated) CDCl3
(d=7.26 for H and d=77.00 for 13C). Coupling constants, J,
1
are reported in hertz (Hz). Melting points were determined
in a capillary tube and are uncorrected. TLC was carried
out on SiO2 (silica gel 60 F254, Merck), and the spots were
located with UV light. Flash chromatography was carried
out on SiO2 (silica gel 60, Merck, 230–400 mesh ASTM). IR
spectra were recorded on a Jasco FT/IR-4100 infrared spec-
trophotometer, and only noteworthy absorptions are report-
ed in cmÀ1. Drying of organic extracts during work-up of re-
actions was performed over anhydrous Na2SO4. Evaporation
of solvents was accomplished with a Bꢂchi rotatory evapora-
tor. RMS and HR-MS were measured using a Waters GCT
mass spectrometer.
N-(2-Phenylethenyl)-2-azepanone (3d):[25] yield: 67%;
data from a mixture of Z/E=94/6; orange oil; 1H NMR
(300 MHz, CDCl3): d=7.94 (d, J=15.1, 1H, E isomer),
7.39–7.12 (m, 10H, Z and E isomer), 6.74 (d, J=9.4, Z
isomer), 6.00 (d, J=9.3, 1H, Z isomer), 3.65–3.63 (m. 2H, E
isomer), 3.30–3.22 (2H, m, 4H, Z isomer), 2.81–2.46 (m,
4H, Z and E isomer), 1.69–1.57 (m, 8H, Z and E isomer),
1.46–1.40 (m, 4H, Z and E isomer); 13C NMR (75.4 MHz,
CDCl3): d (data for Z isomer)=176.5, 135.6, 129.6 128.5,
128.3, 127.2, 118.4, 50.9, 37.2, 29.7, 28.8, 23.3; IR (neat): n=
1639 (C=O) and 1659 (C=C) cmÀ1; MS: m/z (%)=215 (M+,
100), 132 (32), 130 (31), 96 (36); HR-MS: m/z=215.1310,
calcd. for C14H17NO: 215.1310.
Synthesis of Enamides 3; Method A
A screw-capped tube was charged with alkyne 1 (0.5 mmol),
amide 2 (1.0 mmol), Cs2CO3 (1.0 mmol) and toluene (1 mL).
The reaction mixture was heated to 1508C for 24 h, allowed
to cool to room tenperature and the resulting mixture was
extracted with CH2Cl2 (3ꢃ5 mL). The combined organic
layers were dried over anhydrous sodium sulfate and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography to afford the correspond-
ing compound.
N,4-Dimethyl-N-(2-phenylethenyl)-benzenesulfonamide
(3e): yield: 39%; data from a mixture of Z/E=30/70; orange
1
oil; H NMR (300 MHz, CDCl3): d=7.68 (d, J=8.1 Hz, 2H,
Z isomer), 7.59 (d, J=8.3 Hz, 2H E isomer), 7.44 (d, J=
14.5 Hz, 1H, E isomer), 7.28 (d, J=7.9 Hz, 2H, Z isomer) ,
7.23–7.10 (m, 14H, E and Z isomer), 6.20 (d, J=9.0 Hz, 1H,
Z isomer), 5.93 (d, J=9.1 Hz, 1H, Z isomer), 5.60 (d, J=
14.3 Hz, 1H, E isomer), 2.93 (s, 3H, E isomer), 2.68 (s, 3H,
Z isomer), 2.38 (s, 3H, Z isomer), 2.33 (s, 3H, E isomer);
13C NMR (75.4 MHz, CDCl3): d (data for Z isomer)=143.9,
136.1, 134.6, 129.8, 128.7, 128.1, 127.5, 127.0, 125.5, 110.8,
N-(2-Phenylethenyl)-2-pyrrolidinone (3a):[23] yield: 93%;
data from a mixture of Z/E=79/21; orange oil; 1H NMR
(300 MHz, CDCl3): d=7.63 (d, J=14.9, 1H, E isomer),
7.12–7.40 (m, 10H), 6.79 ( d, J=9.9, 1H, Z isomer), 5.99 (d,
J=9.9, 1H, Z isomer), 5.89 (d, 1H, E isomer), 3.66 (t, J=
7.2, 2H, E isomer), 3.19 (t, J=7.1, 2H, Z isomer), 2.55 (t,
J=8.1, 2H, E isomer), 2.41 (t, J=8.0, 2H, Z isomer) 2.10–
Adv. Synth. Catal. 2012, 354, 3054 – 3064
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3059

Marꢀa Teresa Herrero et al.
FULL PAPERS
32.2, 21.5; d ( data for E isomer)=143.9, 134.8, 134.2, 129.8,
128.9, 128.2, 127.8, 127.3, 126.4, 120.9, 36.6, 21.6; IR (neat):
n=1639 (C=O) cmÀ1; MS: m/z (%)=201 (M+, 100), 172
(26), 130 (29); HR-MS: m/z=287.0977, calcd. for
C16H17NO2S: 287.0980.
Z isomer); 13C NMR (75.4 MHz, CDCl3): d (data for Z
isomer)=175.5, 137.3, 136.1, 129.8, 127.6,127.5,126.2, 123.6,
113.9, 48.0, 30.3, 21.3, 18.8; d (data for E isomer)=173.3,
138.2, 136.2„ 128.5, 127.3, 126.1, 123.4, 122.9, 111.8„ 45, 2,
31.2, 21.3, 17.4; IR (neat): n=1694 (C=O) and 1603 (C=C)
cmÀ1; MS: m/z (%)=201 (M+, 100), 146 (71), 144 (34), 31
(32); HR-MS: m/z=201.1151, calcd. for C13H15NO:
201.1154.
N-{2-[3,5-Bis(trifluoromethyl)-phenyl]-ethenyl}-2-pipepiri-
done (3j): yield: 60%; data from a mixture of Z/E=7/93;
yellow oil; 1H NMR (300 MHz, CDCl3): d=118.21 (d, J=
15.1 Hz, 1H, E isomer), 7.68–7.56 (m, 6H, Z and E isomer),
6.85 (d, J=9.4 Hz, Z isomer), 6.03 (d, J=9.5 Hz, Z isomer),
5.00 (d, J=15.1 Hz, E isomer), 3.49 (t, J=6.2 Hz, 2H, E
isomer), 3.09 (t, J=6.0 Hz, 2H, Z isomer), 2.51 (t, J=
6.5 Hz, 2H, E isomer), 2.48 (t, J=6.8 Hz, 2H, Z isomer),
1.966–1.88 (m, 2H, E isomer), 1.84–1.76 (m, 2H, Z isomer),
1.73–1.64 (m, 2H, E isomer); 13C NMR (75.4 MHz, CDCl3):
d (data for E isomer)=169.1, 139.3, 131.9 (q=33.1 Hz),
130.0, 125.4, 125.3, 123.4 (q, J=272.7 Hz), 119.6–119.5 (m),
107.8, 45.5, 36.0, 22.5, 20.3; IR (neat): n=1674 (C=O) and
1639 (C=C) cmÀ1 MS: m/z (%)=337 (M+, 100), 308 (29),
381 (31), 381 (36), 266 (41), 82 (51); HR-MS: m/z=
337.0900, calcd. for C15H13F6NO: 337.0901.
N-[2-(4-Methoxyphenyl)-ethenyl]-2-pyrrolidinone
(3f):
yield:53%; data from a mixture of Z/E=92/08; yellow oil;
1H NMR (300 MHz, CDCl3): d=7.50 d, J=14.8 Hz, 1H, E
isomer), 7.28 (d, J=8.8 Hz, 2H, E isomer), 7.11 (d, J=
8.6 Hz, 2H, Z isomer), 6.84 (d, J=8.7 Hz, 4H, Z/E isomer),
6.70 (d, J=9.8 Hz, 1H, Z isomer), 5.95 (d, J=9.7 Hz, 1H, Z
isomer), 5.85 (d, J=14.8 Hz, 1H, E isomer), 3.82 (s, 3H, Z
isomer), 3.79 (s, 3H, E isomer), 3.64 (t, J=7.2 Hz, 2H, E
isomer), 3.22 (t, 7.1 Hz, 2H, Z isomer), 2.54 (t, 8 Hz, 2H, E
isomer), 2.40 (t, 8.0 Hz, 2H, Z isomer), 220–2.10 (m, 2H, E
isomer); 13C NMR (75.4 MHz, CDCl3):
d (data for Z
isomer)=175.6, 158.5, 130.2, 128.5, 123.2, 114.2, 113.2, 55.2,
48.0, 31.3, 30.4, 18.8; IR (neat): n=1694 (C=O) and 1647
(C=C) cmÀ1; MS: m/z (%)=217 (M+, 100), 202 (27), 162
(34), 132 (29); HR-MS: m/z=217.1104, calcd. for
C13H15NO2: 217.1103.
N-{2-[3,5-Bis(trifluoromethyl)-phenyl]-ethenyl}-2-pyrroli-
dinone (3g): yield: 81%; data from a mixture of Z/E=87/13;
1
yellow oil; H NMR (300 MHz, CDCl3): d=7.75 (d, J=14.9,
1H, Z isomer), 7.74 (s, 4H, Z, E isomer), 7.63–7.61 (m, 2H,
Z, E isomer), 6.94 (d, J=10.0, 1H, E isomer), 5.94 (d, J=
10.0, 1H, E isomer), 5.90 (d J=15.0 Hz, 1H, Z isomer), 3.67
( t, J=7.2, 2H, Z isomer), 3.12 ( t, J=7.0, 2H, E isomer),
2.58 (t, J=8.2, 2H, Z isomer), 2.44 (t, J=8.1, 2H, E
isomer), 2.29–2.13 (m, 2H, Z isomer), 2.06–1.95 (m, 2H, E
N-[2-(3-Methylphenyl)-ethenyl]-2-pipepiridone
(3k):
yield: 55%; data from a mixture of Z/E=79/21; yellow
powder; 1H NMR (300 MHz, CDCl3): d=8.08 (d, J=
15.1 Hz, E isomer), 7.19–6.90 (m, 8H, Z and E isomer), 6.69
(d, J=9.4 Hz, 1H, Z isomer), 5.99 (d, J=9.4 Hz, Z isomer),
5.87 (d, J=15.1 Hz, 1H, E isomer), 3.47 (t, J=6.1, 2H, E
isomer), 3.14 (t, J=5.8 Hz, 2H, Z isomer), 2.47 (t, J=
7.0 Hz, 2H, E isomer), 2.44 (t, J=6.7 Hz, 2H, Z isomer),
2.26 (s, 6H, Z and E isomer), 1.89–1.84 (m, 2H, E isomer),
1.78–1.70 (m, 4H, Z and E isomer), 1.65–1.58 (m, 2H, Z
isomer); 13C NMR (75.4 MHz, CDCl3):
d (data for Z
isomer)=175.6, 138.4, 131.1 (q, J=33.4), 128.9, 126.4,125.1,
123.2 (J=272 Hz), 120.3–120.5 (m), 108.6, 45.1, 30.2, 17.5; d
(data for E isomer)=173.9, 138.8, 131.9 (q, J=33.1), 129.0,
126.5, 125.2, 123.3 (J=272 Hz), 119.5–119.7 (m), 109.7, 48.3,
31.1, 19.00; IR (neat): n=1713 (C=O) and 1644 (C=C) cmÀ1
;
isomer); 13C NMR (75.4 MHz, CDCl3):
d (data for Z
MS: m/z (%)=323 (M+, 100), 268 (99), 266 (32); HR-MS:
m/z=323.0740, calcd. for C14H11F6NO: 323.0745.
isomer)=170.8, 137.7, 135.6, 129.2, 128.7, 128.0, 128.0, 125.6,
119.9, 48.6 , 32.2, 23.0, 21.3, 20.9; d (data for E isomer)=
168.6, 138.1, 136.6, 128.4, 127.2, 126.8, 126.3, 123.0, 110.8,
45.2, 32.9, 22.5, 21.3 , 20.4; IR (neat): n=1641 (C=O) and
1660 (C=C) cmÀ1; MS: m/z (%)=215 (M+, 100)„ 132 (32),
186 (25), 144 (23); HR-MS: m/z=215.1306, calcd. for
C14H17NO: 215.1310.
N-(1-Methyl-2-phenylethenyl)-2-pyrrolidinone (3h): yield:
72%; data from a mixture of Z/E=78/22; yellow oil;
1H NMR (300 MHz, CDCl3): d=7.27–7.12
ACTHNUTRGNE(NUG m, 10H), 6.23 (s,
1H, Z isomer), 6.22 (s, 1H, E isomer), 3.65 (t, J=7.0, 2H, E
isomer), 3.23 (t, J=7.0, 2H, Z isomer), 2.45 (t, J=8.1, 2H,
Z isomer), 2.34 (t, J=8.1, 2H, Z isomer), 2.20 (s, 3H, E
isomer), 2.01 (s, 3H, Z isomer), 2.06–2.00 (m, 2H, E
isomer), 1.95–1.89 (m, 2H, E isomer); 13C NMR (75.4 MHz,
CDCl3): d (data for Z isomer)=174.9, 136.6, 136.5, 128.3,
127.7, 127.2, 126.3, 125.5, 47.4, 31.2, 18.2, 16.6; 13C NMR
(75.4 MHz, CDCl3): d (data for E isomer)=174.3, 135.6,
134.3, 129,1, 128.1, 126.3, 118.1, 49.3, 32.8, 20.5, 19.1; IR
(neat): n=1674 (C=O) cmÀ1; MS: m/z (%)=201 (M+, 100),
144 (26), 116 (30), 115 (39); HR-MS: m/z=201.1154, calcd.
for C13H15NO: 201.1154.
N-[2-(3,5-Difluorophenyl)-ethenyl]-2-pipepiridone
(3l):
yield: 58%; data from a mixture of Z/E=91/9; yellow
powder; 1H NMR (300 MHz, CDCl3): d=8.12 (d, J=
15.2 Hz, 1H, E isomer), 7.49–7.41 (m, 1H, E isomer), 7.28–
7.20 (m, 1H, Z isomer), 6.94 (d, J=9.4 Hz, 1H, Z isomer),
6.86–6.76 (m, 4H, E/Z isomer), 6.02 (d, J=15.2 Hz, 1H, E
isomer), 5.96 (d, J=9.6 Hz, 1H, Z isomer), 3.55 (t, J=
6.0 Hz, 2H, E isomer), 3.15 (t, J=5.8 Hz, 2H, Z isomer),
2.55 (d, J=6.7 Hz, 2H, E isomer), 2.50 (t, J=6.8 Hz, 2H, Z
isomer), 1.99–1.94 (m, 2H, E isomer), 1.88–1.77 (m, 4H, E
and Z isomer), 1.76–1.65 (m, 2H, Z isomer); 13C NMR
(75.4 MHz, CDCl3): d (data for Z isomer)=170.5, 162.1 (dd,
J=250, 12 Hz), 159.7 (dd, J=251, 12 Hz), 131.0–130.8 (m),
119.9 (dd, J=15, 4 Hz), 111.1 (dd, J=21, 4 Hz), 110.0 (d, J=
2 Hz), 103.8 (t, J=26 Hz), 48.7, 32.3, 23.1, 20.8; IR (neat):
n=1660 (C=O) and 1614 (C=C) cmÀ1; MS: m/z (%)=237
(M+, 100), 180 (23), 166 (26); HR-MS: m/z=237.0961,
calcd. for C13H13F2NO: 237.0965.
N-[2-(3-Methylphenyl)-ethenyl]-2-pyrrolidinone
(3i):
yield: 67%; data from a mixture of Z/E=78/22; yellow oil;
1H NMR (300 MHz, CDCl3): d=7.54 (d, J=14.9, 1H, E
isomer), 7.22–6.94 (m, 8H, E and Z isomer), 6.69 (d, J=9.9,
1H, Z isomer), 5.88 (d, J=9.9, 1H, Z isomer), 5.78 (d, J=
14.8, 1H, E isomer), 3.58 (t, J=7.2, 2H, E isomer), 3.13 (t,
J=7.0, 2H, Z isomer), 2.47 (t, J=8.1, 2H, E isomer), 2.33 (
2H, t, J=8.0, Z isomer), 2.27 (s, 3H, Z isomer), 2.25 (s, 3H,
E isomer), 2.17–2.02 (m, 2H, E isomer), 1.95–1.80 (2H, m,
3060
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3054 – 3064

Cesium Carbonate-Promoted Hydroamidation of Alkynes
8.8, 1H), 6.95 (d, J=8.6, 1H), 6.53 (s, 1H), 2.79 (t, J=7.6,
2H), 1.66 (dd, J=15.0, 7.4, 2H), 0.93 (t, J=7.3, 3H);
13C NMR (75.4 MHz, CDCl3): d=169.5, 145.2, 138.9, 134.3,
133.9, 130.0, 129.3, 129.1, 125.7, 124.8, 119.9, 114.4, 106.5,
105.6, 30.6, 22.1, 13.8; IR (neat): n=2224 (CN), 1696 (C=O)
and 1598 (C=C) cmÀ1; MS: m/z (%)=288 (13), 105 (100), 77
(38); HR-MS: m/z=288.1271, calcd. for C19H16N2O:
288.1263.
Synthesis of Enamides 3; Method B
A screw-capped tube was charged with alkyne 1 (0.5 mmol),
amide
2 (1.0 mmol), FeCl3·6H2O (0.05 mmol), pyridine
(0.2 mmol), Cs2CO3 (1.0 mmol) and toluene (1 mL). The re-
action mixture was heated to 1508C for 24 h, allowed to
cool to room tenperature and the resulting mixture was ex-
tracted with CH2Cl2 (3ꢃ5 mL). The combined organic
layers were dried over anhydrous sodium sulfate and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography to afford the correspond-
ing compound.
N-(2-Phenylethenyl)-2-pyrrolidinone (3a): yield: 91%.
N-[3,5-Bis(trifluoromethyl)-phenyl]-N,4-dimethylbenzene-
sulfonamide (3b): yield: 93%.
N-(2-Phenylethenyl)-2-piperidinone (3c): yield: 48%.
N-(2-Phenylethenyl)-2-azepanone (3d): yield: 61%.
N-Phenyl-N,4-dimethylbenzenesulfonamide (3e): yield:
79%.
N-[2-(4-Methoxyphenyl)-ethenyl]-2-pyrrolidinone
yield: 75%.
N-{2-[3,5-Bis(trifluoromethyl)-phenyl]-ethenyl}-2-pyrroli-
dinone (3g): yield: 77%.
N-(1-Methyl-2-phenylethenyl)-2-pyrrolidinone (3h): yield:
92%.
N-[2-(3-Methylphenyl)-ethenyl]-2-pyrrolidinone
yield: 89%.
N-{2-[3,5-Bis(trifluoromethyl)-phenyl]-ethenyl}-2-pipepiri-
done (3j): yield: 64%.
N-[2-(3-Methylphenyl)-ethenyl]-2-pipepiridone
yield: 66%.
1-Benzoyl-2-phenyl-1H-indole-5-carbonitrile (5g): yield:
88%, brown powder; mp 150–1528C; 1H NMR (300 MHz,
CDCl3): d=7.98 (s, 1H), 7.76 (d, J=8.6, 1H), 7.59 (d, J=
7.2, 2H), 7.50 (dd, J=8.6, 1.3, 1H), 7.43 (t, J=7.6, 2H),
7.33–7.14 (m, 7H), 6.82 (s, 1H); 13C NMR (75.4 MHz,
CDCl3): d=169.6, 143.5, 139.7, 134.1, 133.6, 131.8, 130.3,
129.2, 129.1, 128.5, 128.4, 128.4, 128.3, 128.2, 127.1, 126.0,
125.6, 125.5, 125.3, 125.1, 119.8, 114.7, 111.8, 108.1, 106.3,
100.1; IR (neat): n=2223 (CN) and 1696 (C=O) cmÀ1; MS:
m/z (%)=222 (12), 218 (25), 190 (11), 105 (100); HR-MS:
m/z=322.1105, calcd. for C22H14N2O: 322.1106.
(3f):
Methyl 2-propyl-1H-indole-5-carboxylate (5h):[29] yield:
75%, brown powder.
Methyl 1-benzoyl-1H-indole-5-carboxylate (5i): yield:
64%, white powder; mp 88–908C; 1H NMR (300 MHz,
CDCl3): d=8.41 (d, J=8.7, 1H), 8.34 (s, 1H), 8.07 (d, J=
8.7, 1H), 7.62 (ddd, J=27.4, 22.9, 7.0, 5H), 7.37 (d, J=3.7,
1H), 6.68 (d, J=3.7, 1H), 3.95 (s, 3H); 13C NMR
(75.4 MHz, CDCl3): d=168.7, 167.3, 138.6, 134.0, 132.3,
130.6, 129.3, 128.8, 128.7, 126.2, 125.8, 123.2, 116.0, 108.8,
52.0; IR (neat): n=1715 (C=O) and 1600 (C=C) cmÀ1; MS:
m/z (%)=279 (18), 105 (100), HR-MS: m/z=279.0905,
calcd. for C17H13NO3: 279.0895.
(3i):
(3k):
N-[2-(3,5-Difluorophenyl)-ethenyl]-2-pipepiridone
yield: 70%.
(3l):
Methyl 1-benzoyl-2-phenyl-1H-indole-5-carboxylate (5j):
1
yield: 79%, yellow oil; H NMR (300 MHz, CDCl3): d=8.39
(s, 1H), 7.96 (dd, J=8.8, 1.6, 1H), 7.69 (d, J=8.8, 1H), 7.62
(d, J=7.1, 2H), 7.42 (t, J=7.4, 1H), 7.28 (dd, J=15.5, 7.6,
4H), 7.23–7.13 (m, 3H), 6.84 (s, 0H), 3.96 (s, 3H); 13C NMR
(75.4 MHz, CDCl3): d=169.8, 167.4, 142.5, 140.7, 134.5,
133.2, 132.4, 130.3, 128.9, 128.4, 128.3, 128.3, 127.9, 125.4,
125.0, 123.1, 113.6, 109.2, 52.1; IR (neat): n=1715 (C=O)
and 1600 (C=C) cmÀ1; MS: m/z (%)=355 (28), 190 (10), 105
(100), 77 (24); HR-MS: m/z=355.1210, calcd. for
C23H17NO3: 355.1208.
Synthesis of Indoles 5a–l; Method A
In a sealed tube, a mixture of acetamide or benzamide 4
(0.3 mmol) and Cs2CO3 (0.6 mmol) in toluene (1–
8 mLmmolÀ1) was stirred and heated at 1508C for 4–16 h.
After cooling, the crude mixture was washed with water
(10 mL) and the aqueous layer extracted with EtOAc (3ꢃ
3 mL). The combined organic extracts were dried over anhy-
drous Na2SO4 and concentrated under vacuum. The residue
was purified by flash column chromatography, providing the
indoles 5 shown below:
Methyl 1-benzoyl-2-propyl-1H-indole-5-carboxylate (5k):
1
yield: 83%, yellow oil; H NMR (300 MHz, CDCl3): d=8.22
1H-Indole (5a):[26] yield: 96%, brown powder.
1-Benzoylindole (5b):[27] yield: 84%, brown powder.
1-Benzoyl-2-phenylindole (5c):[6k] yield: 82%, green
powder.
(d, J=1.3, 1H), 7.80–7.58 (m, 4H), 7.50 (t, J=7.7, 2H), 6.87
(d, J=8.8, 1H), 6.54 (s, 1H), 3.91 (s, 3H), 2.82 (t, J=7.6,
2H), 1.82–1.58 (m, 2H), 1.04–0.87 (m, 3H); 13C NMR
(75.4 MHz, CDCl3): d=169.8, 167.5, 144.2, 139.8, 134.8,
133.5, 130.0, 129.1, 128.9, 124.3, 123.9, 122.3, 113.5, 107.4,
52.0, 30.7, 22.2, 13.8; IR (neat): n=1718 (C=O) and 1691
(C=O) cmÀ1; MS: m/z (%)=321 (14), 188 (10), 105 (100),
77 (18); HR-MS: m/z=321.1367, calcd. for C20H19NO3:
321.1365.
1-Benzoyl-1H-indole-5-carbonitrile (5d):[28] yield: 95%,
brown powder.
2-Propyl-1H-indole-5-carbonitrile (5e): yield: 87%, brown
1
powder; mp 81–838C; H NMR (300 MHz, CDCl3): d=8.43
(s, 1H), 7.85 (s, 1H), 7.35 (s, 2H), 6.31 (s, 1H), 2.76 (t, J=
7.5, 2H), 1.77 (dq, J=14.9, 7.4, 2H), 1.02 (t, J=7.3, 3H);
13C NMR (75.4 MHz, CDCl3): d=142.3, 137.6, 128.7, 125.1,
124.1, 121.0, 111.1, 102.5, 100.3, 30.2, 22.2, 13.8; IR (neat):
u=3319 (NH), 2217 (CN) and 1614 (C=C) cmÀ1; MS: m/z
(%)=184 (23), 155 (100), 101 (5); HR-MS: m/z=184.1000,
calcd. for C12H12N2: 184.1000.
1-Benzoyl-2-propyl-1H-indole-5-carbonitrile (5f): yield:
87%, yellow oil; 1H NMR (300 MHz, CDCl3): d=7.82 (s,
1H), 7.69 (t, J=8.7, 3H), 7.52 (t, J=7.6, 2H), 7.24 (d, J=
1-Benzoyl-2-vinylindole (5l): yield: 59%, brown powder;
1
mp 98–1008C; H NMR (300 MHz, CDCl3): d=8.82 (s, 1H),
8.61 (d, J=8.1, 1H), 7.94 (d, J=7.0, 2H), 7.62–7.36 (m,
7H), 7.09 (s, 1H), 6.09 (d, J=11.2, 1H), 5.72 (dd, J=44.7,
14.7, 2H); 13C NMR (75.4 MHz, CDCl3): d=165.1, 139.1,
134.9, 132.1, 131.6, 130.2, 130.0, 129.9, 129.6, 128.9, 128.9,
128.7, 128.3, 127.8, 127.0, 123.5, 119.1, 116.5, 112.1, 95.6,
85.0; IR (neat): n=1680 (C=O) and 1578 (C=C) cmÀ1; MS:
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m/z (%)=247 (39), 105 (100), 77 (41); HR-MS: m/z=
247.0999, calcd. for C17H13NO: 247.0997.
thanks the University of the Basque Country (UPV/EHU)
for a predoctoral scholarship.
Synthesis of Indoles 5m–r and 6-Methyl-9-(trifluoro-
methyl)indoloACHTUNGTRENNUNG[1,2-c]quinazoline 6; Method B
References
In a sealed tube, a mixture of acetamide or benzamide 4
(0.3 mmol), FeCl3·6H2O (10 mol%), pyridine (40 mol%)
and Cs2CO3 (0.6 mmol) in toluene (1–8 mLmmolÀ1) was
stirred and heated at 1508C for 4–16 h. After cooling, the
crude mixture was washed with water (10 mL) and the aque-
ous layer extracted with EtOAc (3ꢃ3 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and con-
centrated under vacuum. The residue was purified by flash
column chromatography, providing the indoles 5 shown
below:
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1-Benzoylindole (5m):[27] yield: 87%, brown powder.
2-Propyl-1H-indole (5n):[30] yield: 88%, brown powder.
2-Vinyl-1H-indole (5o):[31] yield: 80%, brown powder.
6-(Trifluoromethyl)-1H-indole (5p): yield: 93%, maroon
powder; mp 97–1008C; 1H NMR (300 MHz, CDCl3): d=
8.29 (s, 1H), 7.75 (d, J=8.3, 1H), 7.67 (s, 1H), 7.40 (d, J=
8.3, 1H), 7.34 (t, J=2.7, 1H), 6.65 (s, 1H); 13C NMR
(75.4 MHz, CDCl3): d=169.8, 167.4, 142.5, 140.7, 134.5,
133.2, 132.4, 130.3, 128.9, 128.4, 128.3, 128.3, 127.9, 125.4,
125.0, 123.1, 113.6, 109.2, 52.1; IR (neat): n=3403 (NH)
1571 (C=C) cmÀ1; MS: m/z (%)=355 (28), 190 (10), 105
(100), 77 (24); HR-MS: m/z=355.1210, calcd. for
C23H17NO3: 355.1208.
3-(6-Chloro-1H-indol-2-yl)-propan-1-ol (5q): yield: 56%,
1
maroon powder; mp 88–908C; H NMR (300 MHz, CDCl3):
d=8.21 (s, 1H), 7.42 (d, J=8.4, 1H), 7.26 (s, 1H), 7.04 (dd,
J=8.4, 1.8, 1H), 6.23 (d, J=1.0, 1H), 4.17 (t, J=6.3, 2H),
2.79 (t, J=7.4, 2H), 2.08 (s, 3H), 2.07–1.98 (m, 2H);
13C NMR (75.4 MHz, CDCl3): d=171.5, 139.3, 136.3, 127.3,
126.9, 120.6, 120.3, 110.4, 99.9, 63.6, 28.3, 24.6, 21.0; IR
(neat): n=3324 (OH) and 1710 (C=O) and 1616 (C=C)
cmÀ1; MS: m/z (%)=251 (59), 191 (64), 164 (100), 156 (20),
143 (12), 128 (16); HR-MS: m/z=251.0719, calcd. for
C13H14NO2Cl: 251.0713.
6-Methyl-9-(trifluoromethyl)indoloACTHNUTRGNE[NUG 1,2-c]quinazoline (6):
yield: 60%, brown powder; mp 168–1708C; 1H NMR
(300 MHz, CDCl3): d=8.35 (s, 1H), 8.06 (d, J=7.5, 1H),
7.89 (d, J=8.3, 1H), 7.76 (d, J=7.9, 1H), 7.65 (d, J=8.3,
1H), 7.58 (t, J=7.5, 1H), 7.50 (t, J=7.4, 1H), 7.24 (s, 1H),
3.17 (s, 3H); 13C NMR (75.4 MHz, CDCl3): d=147.9, 139.1,
137.5, 132.7, 130.6, 129.8, 127.3, 127.2, 123.9, 123.5, 122.9,
121.0, 120.1, 120.1, 120.1, 120.0, 119.7, 112.3, 112.2, 112.1,
112.0, 100.0, 95.3, 25.4; IR (neat): n=1616 (C=C) cmÀ1; MS:
m/z (%)=300 (100), 178 (21), 161 (11), 123 (16), 105 (13),
83 (11); HR-MS: m/z=300.0878, calcd. for C17H11N2F3:
300.0874.
Acknowledgements
This research was supported by the University of the Basque
Country/Basque Government (Projects GIC10/52/IT-370-10,
S-PC10UN10 and UFI QOSYC 11/22) and the Spanish Min-
istry of Science and Innovation (CTQ2010-20703). J.D.
3062
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Adv. Synth. Catal. 2012, 354, 3054 – 3064

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