Indole synthesis by conjugate addition of anilines to activated acetylenes and an unusual ligand-free copper(II)-mediated intramolecular cross-coupling

Article abstract of DOI:10.1002/chem.201202307

A versatile new synthesis of indoles was achieved by the conjugate addition of N-formyl-2-haloanilines to acetylenic sulfones, ketones, and esters followed by a copper-catalyzed intramolecular C-arylation. The conjugate addition step was conducted under e

Full text of DOI:10.1002/chem.201202307

FULL PAPER
DOI: 10.1002/chem.201202307
Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
and an Unusual Ligand-Free Copper(II)-Mediated Intramolecular Cross-
Coupling
Detian Gao and Thomas G. Back*[a]
Abstract: A versatile new synthesis of
indoles was achieved by the conjugate
addition of N-formyl-2-haloanilines to
acetylenic sulfones, ketones, and esters
followed by a copper-catalyzed intra-
molecular C-arylation. The conjugate
addition step was conducted under ex-
ceptionally mild conditions at room
temperature in basic, aqueous DMF.
Surprisingly, the C-arylation was per-
formed most effectively by employing
copper(II) acetate as the catalyst in the
absence of external ligands, without the
need for protection from air or water.
An unusual feature of this process, for
the case of acetylenic ketones, is the
ability of the initial conjugate-addition
product to serve as a ligand for the cat-
alyst, which enables it to participate in
the catalysis of its further transforma-
tion to the final indole product. Mecha-
nistic studies, including EPR experi-
ments, indicated that copper(II) is re-
duced to the active copper(I) species
by the formate ion that is produced by
the base-catalyzed hydrolysis of DMF.
This process also served to recycle any
copper(II) that was produced by the
adventitious oxidation of copper(I),
thereby preventing deactivation of the
catalyst. Several examples of reactions
involving acetylenic sulfones attached
to a modified Merrifield resin demon-
strated the feasibility of solid-phase
synthesis of indoles by using this proto-
col, and tricyclic products were ob-
tained in one pot by employing acety-
lenic sulfones that contain chloroalkyl
substituents.
Keywords: acetylenes · anilines ·
copper · cross-coupling · cyclization ·
indoles
Introduction
ortho-iodoanilines and dienyl sulfones or sulfides. Similarly,
the preparation of 4-quinolones[9] from ortho-iodoanilines
and acetylenic sulfones[10] was accomplished by a palladium-
catalyzed carbonylation, followed by intramolecular acyla-
tion (Scheme 1). These results prompted us to investigate an
approach based on the conjugate addition of ortho-iodoani-
The indole moiety is both widespread in nature and one of
the most privileged structures among synthetic medicinal
compounds.[1] The importance of indoles has prompted the
discovery of many approaches to their synthesis, including
the classical methods developed by the groups of Fischer,
Madelung, Reissert, Nenitzescu, and Bischler that continue
to find frequent application.[2] More recently, a variety of
palladium- and other transition-metal-catalyzed processes
that typically proceed under milder conditions and accom-
modate more functionally diverse products, as well as an ex-
panded range of starting materials, have been reported.[3]
Several synthetic routes to indoles based on catalysis with
various copper–ligand complexes are also known.[4] Other
À
modern approaches have utilized oxidative C H activation
methods,[3n,o,4b] microwave techniques,[5] and synthesis on
solid supports.[6]
Several years ago, we reported the palladium-catalyzed
synthesis of related carbazoles[7,8] from readily available
[a] D. Gao, Prof. Dr. T. G. Back
Department of Chemistry, University of Calgary
Calgary, AB, T2N 1N4 (Canada)
Fax : (+1)403-289-9488
E-mail: tgback@ucalgary.ca
Scheme 1. Synthesis of carbazoles and quinolones from unsaturated sul-
fones. DDQ=2,3-dichloro-5,6-dicyanobenzoquinone, LiHMDS=lithium
hexamethyldisilazide, Ts=para-toluenesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202307.
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lines to acetylenic sulfones followed by intramolecular palla-
dium-catalyzed C-arylation to afford the corresponding 3-
sulfonyl-substituted indole products. However, initial experi-
ments with aniline 1a and acetylenic sulfone 2a gave poor
yields of the desired deformylated indole 4a (Scheme 2) and
copper-catalyzed intramolecular C-arylation reaction that
employs copper(II) acetate and does not require protection
from air and moisture.
Results and Discussion
Cyclizations based on acetylenic sulfones: Our initial ap-
proach to the copper-catalyzed synthesis of indoles[19] was
based on a variation of the palladium-mediated process
shown in Scheme 2, in which the addition of ortho-haloani-
lines to acetylenic sulfones was followed by intramolecular
C-arylation. The resulting 3-sulfonylindole motif is present
in a class of reverse transcriptase inhibitors with anti-HIV
activity[20] and the sulfone moiety provides a potential site
for further transformations,[21] making these products of par-
ticular interest. We had previously observed that the conju-
gate additions of a few representative anilines to acetylenic
sulfones 2 were facilitated by employing the N-formyl (or
other N-acyl) analogues 1, instead of the parent anilines, in
DMF/water (9:1) in the presence of potassium carbonate.[9]
Under these conditions, the acetylenic sulfones first isomer-
ized to their allenic counterparts 6, which then reacted read-
ily with the conjugate bases of 1 to afford allylic, instead of
the corresponding vinylic, sulfones as the principal products.
This method proved highly effective and has been used for
the preparation of adducts 3a–3q, shown in Table 1.
Some general trends were observed during these studies.
The conjugate addition reactions tolerated the presence of
both electron-donating (Table 1, entries 7 and 8) and elec-
tron-withdrawing substituents (Table 1, entries 3 and 9–17)
on the aniline, resulting in the formation of the correspond-
ing sulfonyl enamines 3 in uniformly high yields and with
comparable reaction rates (12–16 h at room temperature).
An exception occurred for the reaction in which a strongly
electron-withdrawing para-nitro group deactivated the ani-
lide 1h, resulting in the failure of its conjugate addition to
2g (Table 1, entry 18). The ortho-bromo derivative 1b react-
ed normally (Table 1, entry 2), but surprisingly, anilide 1i,
which lacks an ortho-halo substituent, failed to undergo con-
jugate addition to 2a under the normal conditions (Table 1,
entry 19). Acetylenic sulfones with simple alkyl substituents,
as well as those with ether (Table 1, entries 4 and 11), ester
(Table 1, entries 5 and 12), and halide functionalities
(Table 1, entries 13–15), were employed. When a phenyl
group was used as the aryl moiety of 2, slightly faster reac-
tions were observed compared to the corresponding para-
tolyl derivatives (Table 1, entries 16–18).
Scheme 2. Synthesis of indoles from acetylenic sulfones by Pd-catalyzed
cross-coupling.
a complex mixture of byproducts. A plausible explanation
for the formation of 4a is that the acetylenic sulfone 2a iso-
merizes in situ to its allenic counterpart,[9] followed by the
conjugate addition of aniline 1a to produce 3a. Oxidative
addition of the aryl iodide moiety of 3a to the palladium
catalyst and subsequent intramolecular attack at the metal
center by the a-position of the ambident sulfone-stabilized
anion 5 then affords the product after reductive elimination.
An intramolecular Heck reaction on the allyl–sulfone
moiety of 3a would also generate the product 4a. Various
combinations of other ligands, bases, solvents, additives, and
temperatures failed to improve these results. The low yield
of the process and the high cost of palladium catalysts
prompted us to search for cheaper and more efficient alter-
native routes that are based on copper catalysts.
Since the early discoveries of the groups of Ullmann,[11]
Goldberg,[12] and Hurtley,[13] copper-catalyzed N-, O-, and C-
arylations have been widely studied and exploited in organic
synthesis.[14] Although copper powder was employed in the
earliest examples of these processes,[11–13] copper(I) catalysts
that are coordinated to appropriate ligands[14e,k,15] have typi-
cally been employed in more recent applications in which
the judicious choice of ligand can increase the reaction rate,
decrease the required catalyst loading, and permit the use of
lower temperatures. Ligands can also improve the solubility
of the catalyst, regulate chemoselectivity between N- and O-
arylations,[16] modulate disproportionation processes of
copper species in various oxidation states,[17] and facilitate
We also observed that the products 3 were obtained as
mixtures of isomers, as evident from the complexity of their
NMR spectra. More detailed analysis of the NMR spectra
of the representative product 3q revealed that duplicate sig-
nals that were present at room temperature coalesced when
the compound was heated to 398 K in [D6]DMSO. The origi-
nal spectrum was regenerated when the sample was cooled
back to room temperature. Furthermore, ROESY spectra of
3e and 3q showed correlations between the vinyl and
the formation of copperACHTUNRGTNE(NUG III) intermediates during oxidative
addition of the aryl halide.[18] In many cases, bidentate N,N,
O,O, or mixed N,O ligands have proven particularly useful.
Oxidation by air and deactivation of the copper(I) catalyst
is typically avoided by the use of inert atmospheres.
We now report a highly effective protocol and mechanistic
studies for indole synthesis based on an unusual, ligand-free,
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Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
FULL PAPER
Table 1. Preparation of sulfonyl enamines 3 and their cyclization to indoles 4 or 14.[a,b]
zation of the representative sul-
fonyl enamine 3 f with cop-
per(I) iodide in polar aprotic
solvents in the presence of
sodium hydride or cesium car-
bonate. When hexamethylphos-
phoramide (HMPA)/NaH was
employed with 1.2 equivalents
of copper(I) iodide, heating at a
temperature of 1508C for 16 h
was required to provide the cor-
responding indole 4 f in 61%
yield (Scheme 5).[23] Deformyla-
tion also occurred during the
course of the reaction. Under
the same conditions, the use of
DMSO provided the product in
only 17% yield, whereas the
use of DMF/Cs2CO3 resulted in
completion of the reaction after
only 5 h at the reduced temper-
ature of 1258C and a 67%yield
of the isolated product (4 f).
The latter conditions were
therefore chosen for further op-
timization, as summarized in
Table 2.
Entry
1
2
X
R[c]
R’
Ar
3[d]
(Yield [%])
4 or 14[d]
ACHTUNGTRENUN(NG Yield [%])
U
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
1b
1c
1a
1a
1a
1d
1e
1 f
1c
1c
1c
1 f
1 f
1c
1g
1 f
1h
1i
2a
2a
2a
2b
2c
2d
2d
2d
2d
2d
2b
2c
2e
2 f
2 f
2g
2g
2g
2a
I
Br
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
H
H
nPr
nPr
nPr
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
Ph
3a (81)
3b (81)
3c (92)
3d (81)
3e (78)
3 f (83)
3g (80)
3h (81)
3i (84)
3j (88)
3k (80)
3l (87)
3m (88)
3n (81)
3o (79)
3p (86)
3q (90)
–
4a (66%)
–
p-CO2Me
H
H
4c (81)
4d (78)
4e (75)
4 f (73)
4g (89)
4h (81)
4i (77)
4j (78)
4k (80)
4l (82)
14m[e] (55)
14n[f] (60)
14o[f] (61)
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
H
ACHTUNGTRENNUNG
p-Me
o,p-diMe
p-CN
p-CO2Me
p-CO2Me
p-CO2Me
p-CN
p-CN
p-CO2Me
m-Cl
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Et
Et
Et
nPr
p-CN
p-NO2
H
Ph
Ph
p-tolyl
4q (82)
–
–
I
H
–
[a] Conditions for the conjugate addition reactions: mixtures of 1 (1.0 equiv), 2 (1.5–2.0 equiv), and K2CO3
(1.0 equiv) in DMF/H2O (9:1) were stirred at room temperature for 12–16 h. [b] Conditions for the cyclization
reactions: mixtures of 3 (1.0 equiv), CuACHTNUTRGNE(UNG OAc)2 (0.3 equiv), and Cs2CO3 (2.0–2.2 equiv) in DMF were heated at
1258C for 3–5 h. [c] The descriptors o and p refer to substituents ortho and para to the amide moiety; m refers
to substituents meta to the amide moiety and para to the halogen X. [d] Isolated yields are reported. [e] n=1.
[f] n=2.
Table 2 reveals that decreas-
ing the amount of copper(I)
iodide to 0.5 equivalents result-
ed in an incomplete reaction,
even after 36 h, with an accom-
formyl protons (d=6.0 and 8.5 ppm, respectively) of their
major isomers. These spectra (see the Supporting Informa-
tion) support the conclusion that the products are formed as
mixtures of amide rotamers that rapidly interconvert at high
temperatures, whereas the conjugate additions are stereose-
lective, affording predominantly the E isomers of the prod-
ucts. The similarity of the NMR spectra of 3e and 3q to the
spectra of other members of this series of compounds sug-
Scheme 3. Conjugate additions to allenic sulfones.
gests that they have analogous structures. The E configura-
tion is consistent with the prior formation of allenes 6 from
2, which is then followed by attack of the anilide anion at
the less hindered face (trans to the substituent R’) of 6
(Scheme 3).
The terminal acetylenic sulfone 7 and the phenyl deriva-
tive 8 lack g-hydrogen atoms and therefore cannot isomerize
to the corresponding allenic sulfones. Nevertheless, both
compounds smoothly underwent conjugate addition with
anilide 1a to provide the vinyl sulfone derivatives 9 and 10,
respectively (Scheme 4). The E configuration of 9 was infer-
red from the coupling constants of the major and minor ro-
tamers: Jtrans =13.5 and 13.0 Hz, respectively.[22]
Scheme 4. Conjugate additions of 1a to acetylenic sulfones 7 and 8.
panying decrease in the yield (compare entries 1 and 2 in
Table 2). Other copper(I) catalysts provided no improve-
ment (Table 2, entries 3–6), and the use of copper powder
resulted in the eventual decomposition of the starting mate-
Because most copper-mediated arylations have been con-
ducted with copper(I) catalysts, we first attempted the cycli-
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T. G. Back and D. Gao
(DABCO), l-proline, sarcosine, glycine, and 1,2-ethanediol.
Only glycine provided a slightly improved yield of 81%,
whereas use of the other ligands resulted in comparable or
decreased yields. The advantages of a ligand-free protocol
appeared to outweigh the modest improvement in yield ob-
tained with the use of glycine and so the conditions shown
in Table 2, entry 11 were chosen for application in the reac-
tions of other conjugate addition products 3.
Scheme 5. Cyclization of 3 f with CuI.
The cyclization of other sulfonyl enamines 3 to the corre-
sponding indoles 4 under the optimized conditions are sum-
marized in Table 1. It is noteworthy that all of these reac-
tions were performed by heating the reaction mixture in re-
agent-grade DMF[24a] without protection from air. In gener-
al, it can be seen that the conjugate addition products 3 that
contain ortho-iodo substituents gave the corresponding in-
doles 4 in good to high yield, whereas the cyclization reac-
tion failed for the bromo analogue 3b (Table 1, entry 2).
Under the basic conditions required for the cyclization, hy-
drolysis of the N-formyl group occurred in all of the exam-
ples shown in Table 1.[24b] When aliquots of the reaction mix-
ture of 3 f (Table 1, entry 6) were removed at various times
and analyzed by MALDI mass spectrometry, or worked up
and subjected to NMR analysis, there was no evidence for
the presence of the deformylated derivative of 3 f (see 11 in
Scheme 6). This suggests that rapid deformylation occurred
after the cyclization step, in which the indole anion pro-
duced by alkaline hydrolysis of 12 is stabilized by the 3-sul-
fonyl substituent, which provides a better leaving group
(Scheme 6).
Table 2. Catalysts for the cyclization of 3 f to 4 f.[a,b]
Entry
Catalyst
G
Time [h]
Yield [%][c]
1
2
3
4
5
6
7
8
9
CuI
CuI
1.2
0.5
0.3
0.3
1.2
0.3
0.3
1.2
0.3
1.2
0.3
0.2
5
36
20
3
5
6
4
7
4
2.5
3
67
40
55
31
61
CuCl
CuBr
CuCN
Cu2O
Cu
17
dec[d]
43
CuCl2
CuSO4
dec[d]
69
10
11
12
Cu
Cu(OAc)2
Cu(OAc)2
A
N
73
59
A
6
[a] The reactions were monitored by TLC until consumption of 3 f was
indicated. [b] Reaction conditions: mixtures of 3 f (1.0 equiv), the cata-
lyst, and Cs2CO3 (2.2 equiv) in DMF were heated at 1258C for the indi-
cated time. [c] Isolated yields are reported. [d] dec indicates that the
starting material decomposed and none of the product 4 f was isolated.
rial (Table 2, entry 7). When our survey was extended to
copper(II) chloride and sulfate (Table 2, entries 8 and 9),
these also proved unsatisfactory. Finally, we were pleased to
observe that the use of a substoichiometric amount of the
copper(II) acetate catalyst (0.3 equiv, 30 mol%) provided a
rapid reaction rate and an improved yield of 73% (Table 2,
entry 11). Reduction of the catalyst loading to 0.2 equiva-
lents reduced the reaction rate and decreased the yield con-
siderably (Table 2, entry 12). Attempts to further optimize
the results shown in Table 2, entry 11, by lowering the tem-
perature to 1008C or by changing the base to sodium hy-
dride, sodium or potassium carbonate, sodium hydroxide, or
sodium acetate, resulted in no further improvement.
The observation that copper(II) acetate was completely
ineffective when DMF was replaced by HMPA proved rele-
vant in our subsequent attempts to elucidate the mechanism
(see later). Other solvents that were investigated included
1,4-dioxane, THF, isopropanol, toluene, acetonitrile, water,
and triethylamine (as both solvent and base), but all proved
to be inferior to DMF or resulted in complete failure of the
reaction. The optimal reaction conditions, shown in Table 2,
entry 11, were also explored in the presence of 0.6 equiva-
lents of various ligands, including ethylene-1,2-diamine, its
N,N,N’,N’-tetramethyl derivative, trans-1,2-diaminocyclohex-
Scheme 6. Cyclization and deformylation of 3 f.
Interestingly, the ortho-iodo-meta-chloro derivative 3p,
shown in Table 1, entry 16, failed to cyclize. Instead, we ob-
served a stereoselective formyl migration (Scheme 7) that
ane,
1,10-phenanthroline,
1,4-diazabicyclo
G
Scheme 7. Transposition of the formyl group in 3p.
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Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
FULL PAPER
provided the E isomer of the product 13.[25] This was deter-
mined by the downfield shift to d=14.0 ppm for the NH
proton, which is attributed to intramolecular hydrogen
bonding with the aldehyde carbonyl group. The possibility
that hydrolysis of the N-formyl group of 3p was followed by
intermolecular C-formylation by DMF at the a-position to
the sulfone moiety was excluded by the observation that the
same product was obtained in HMPA.
The chloroalkyl-substituted sulfonyl enamines 3m–3o
(Table 1, entries 13–15) underwent a three-step sequence
under the usual reaction conditions. Copper-catalyzed intra-
molecular C-arylation was followed by deformylation and
intramolecular N-alkylation in one pot to afford the corre-
sponding products 14m–14o. This demonstrates that the
method can be successfully applied to the formation of tricy-
clic products, as well as to the simpler indoles 4.
It was also of interest to investigate the copper-catalyzed
cyclizations of adducts 9 and 10, which were obtained by
conjugate addition of 1a to 1-(para-toluenesulfonyl)ethyne
and its 2-phenyl derivative, respectively, because they
cannot form delocalized sulfone-stabilized allyl anions by a-
deprotonation or isomerize to allenes. Nevertheless, when
subjected to our standard conditions, adducts 9 and 10 gave
the corresponding indoles 15 and 16 in good yields
Scheme 9. Synthesis of indoles on solid supports.
(Scheme 8). This suggests that the C-arylation step can pro-
ceed through sulfone-stabilized vinyl anions, as well as
through allyl anions.
Cyclizations based on acetylenic ketones (ynones): In view
of the success of the above indole syntheses with acetylenic
sulfones, we also investigated the similar application of ace-
tylenic ketones 21. The same conditions as those used previ-
ously with acetylenic sulfones proved successful for both the
conjugate addition and intramolecular C-arylation steps, and
the results are shown in Table 3. While our work was in
progress, Cacchi et al.[28] reported a similar approach with
the use of aryl ynones (R’=aryl), in which the conjugate ad-
ditions of ortho-haloanilines were performed in methanol at
1208C and followed by ring closure of the resulting enami-
nones in the presence of the 1,10-phenanthroline complex
derived from copper(I) iodide. The use of N-formylanilines
in the present work avoids the need for elevated tempera-
tures in the conjugate addition step, as well as for the use of
ligands and the more oxidation-prone copper(I) catalyst in
the cyclization.
The additions of variously substituted N-formylanilines 1
to the aryl- and alkyl-substituted ynones 21a (R’=Ph) and
21b (R’=nPr) generally gave excellent yields of the corre-
sponding enaminones 22, except when nitro-substituted ani-
lines 1h and 1o were employed (Table 3, entries 14 and 15).
The products were obtained exclusively as the conjugated
enaminones, in contrast to adducts 4, in which the sulfone
moiety was located in the allylic position. Another differ-
ence compared to the acetylenic sulfone series was the com-
plete hydrolysis of the N-formyl group during the conjugate
addition step, which can be attributed to the greater stability
of the more highly conjugated anion that functions as the
leaving group during the deformylation. Only in the case of
the more hindered ortho,para-dimethyl derivative 22c
Scheme 8. Cyclization of sulfonyl enamines 9 and 10.
À
Several copper-catalyzed indole syntheses based on C N
bond formation have been performed on solid supports.[26]
We recently reported the use of acetylenic sulfones attached
to a modified Merrifield resin in 1,3-dipolar and other cyclo-
additions.[27] It was therefore of interest to determine wheth-
er these solid-supported materials could also be applied to
indole synthesis. As expected, the conjugate additions of N-
formylanilines 1a, 1j, and 1k to polymer-supported acety-
lenic sulfones 17a and 17b were successful under the usual
conditions, providing the corresponding sulfonyl enamines
18a–18c. This was followed by copper(II) acetate-catalyzed
cyclization to produce the corresponding indoles 19a–19c
and saponification of the ester linkers to liberate the 3-sulfo-
nylindole products 20a–20c from the support (Scheme 9).
These results confirm the feasibility of applying our solu-
tion-based protocol to the solid-phase synthesis of multisub-
stituted indoles. Both of the remaining halide substituents in
20b and 20c, as well as the sulfone moiety[21] in all three
products, provide potential sites for further modification.
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T. G. Back and D. Gao
Table 3. Preparation of enaminones 22 and their cyclization to indoles 23.[a,b]
the para-cyano group, the reac-
tion of bromide 22g failed to
produce the corresponding
indole (Table 3, entry 7), as did
the ortho-chloro derivative 22h,
even though it contained
a
para-ester substituent (Table 3,
entry 8). It is worth noting that
a second iodo substituent at the
para-position remained intact
during the cyclizations of 22j
and 22k (Table 3, entries 10
and 11, respectively). This sub-
stituent provides a site for fur-
ther transformation of the prod-
ucts by additional coupling re-
actions. Furthermore, aryl (R’=
Ph) and alkyl (R’=nPr) ketone
substituents had little effect on
the rate or yield of the cycliza-
tions (compare entries 11 and
12 to the other entries in
Table 3). The para-amino enam-
inone 22m also failed to pro-
duce the corresponding indole,
instead undergoing reductive
deiodination (Table 3, entry 13).
Entry
1
21
X
R[c]
R’
22[d]
(Yield [%])
Time
[h]
23[d,e]
ACHTUNGTRENUN(NG Yield [%])
G
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1d
1e
1c
1 f
1l
1b
1m
1k
1j
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21b
21b
21a
21a
21a
I
I
I
I
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
nPr
nPr
Ph
Ph
Ph
22a (87)
22b (81)
22c (85)[f]
22d (83)
22e (95)
22 f (88)
22g (82)
22h (90)
22i (92)
22j (91)
22k (92)
22l (87)
22m (88)
–
1.5
2
3
23a (87)
23b (86)
23c (73)[g]
23d (81)
23e (85)
23e (69)[h]
–
p-Me
o,p-diMe
p-CO2Me
p-CN
p-CN
H
p-CO2Me
p-Cl
p-I
0.6
0.25
24
24
2
0.7
0.7
0.6
0.5
3
I
Br
Br
Cl
I
I
I
I
I
I
I
–
23 f (92)
23g (85)
23h (91)
23i (76)
1j
p-I
1 f
1n
1h
1o
p-CN
p-NH2
p-NO2
m-NO2
[i]
–
–
–
–
–
–
[a] The conjugate addition reactions were conducted under the same conditions as those described in Table 1
for 16–24 h with the use of a 2:1 ratio of 21/1. [b] Conditions for the cyclizations: mixtures of 22 (0.2 mmol),
CuACHTUNGTRENNUNG(OAc)2 (0.03 mmol), and Cs2CO3 (0.2 mmol) in DMF (5 mL) were stirred at 1258C for the indicated time.
[c] The descriptors o and p refer to substituents ortho and para to the amide moiety; m refers to substituents
meta to the amide moiety and para to the halogen X. [d] Isolated yields are reported. [e] Reactions were moni-
tored by TLC until the starting materials were consumed. [f] The N-formyl group remained intact. [g] The N-
formyl derivative of the enaminone was used. [h] The reaction was carried out at 808C. [i] Reductive deiodina-
tion occurred instead of cyclization.
A
one-pot procedure was
also investigated for the conver-
(Table 3, entry 3) did the N-formyl group remain intact. The
sion of anilides 1 f and 1k to in-
enaminones were formed exclusively as the Z isomers, as in-
ferred from the downfield chemical shifts of their NH pro-
tons (ca. d=12–13 ppm), due to intramolecular hydrogen
bonding with the carbonyl oxygen atoms. Further evidence
for the Z configuration of products 22b, 22e, and 22i–22l
was obtained from their ROESY NMR spectra, in which
correlations were observed between their respective vinylic
protons (ca. d=5.3–6.0 ppm) and both the corresponding al-
lylic and homoallylic methylene protons (ca. d=2.3 and
1.5 ppm, respectively) of the n-butyl moieties (see the Sup-
porting Information). The similarity of the NMR spectra of
the other enaminones 22, listed in Table 3, to those of the
above products suggests that they too possess the Z configu-
ration.
doles 23e and 23 f, respectively, by their conjugate additions
to ynone 21a followed directly by cyclization. The conjugate
addition step with 21a proceeded smoothly in reagent grade
DMF in the presence of cesium carbonate, as shown in
Scheme 10. The final products 23e and 23 f were obtained in
moderate, but poorer, yields than those obtained in the two-
step procedure shown in entries 5 (95 and 85%) and 9 (92
and 92%, respectively) in Table 3.
The intramolecular C-arylation reactions of the enami-
nones were then performed under the same general condi-
tions as those used previously for the sulfonyl derivatives in
Table 1. The results are shown in Table 3. Enaminones con-
taining a wide variety of para substituents were accommo-
dated by this protocol. The best results were obtained with
ortho-iodo derivatives (22, X=I), which cyclized effectively
with either electron-donating or electron-withdrawing
groups present on the anilide moiety. The ortho-bromo de-
rivative 22 f, containing an electron-withdrawing para-cyano
substituent (Table 3, entry 6), reacted more slowly than its
ortho-iodo analogue 22e (Table 3, entry 5) and provided a
lower yield of indole 23e than did 22e. In the absence of
Scheme 10. One-pot indole synthesis from ynone 21a.
Cyclizations based on acetylenic esters (ynoates): The prep-
aration of indoles that have ester substituents at the 3-posi-
tion was similarly attempted from N-formylanilines 1 and
ynoates 24. The conjugate additions of ortho-haloanilines to
various b-substituted ynoates at elevated temperatures in
the presence of copper(I) iodide,[29] or at room temperature
with silver tetrafluoroborate[30] or gold salts,[31] have been
previously reported. Again, the use of the N-formylanilines
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Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
FULL PAPER
proved expedient for additions to ynoates and these process-
es proceeded at room temperature without the need for
metal additives. However, the reactions proved more com-
plex than in the previous series of activated acetylenes be-
cause three distinct types of product were identified, de-
pending on the nature of the b-substituent of the ynoate.
The results are summarized in Scheme 11 and Table 4.
Ynoates 24a and 24b lack g-hydrogen atoms and conse-
quently produced only the conjugated enaminoates 25a and
25b, respectively. The methyl-substituted derivative 24c be-
haved similarly, providing only the conjugated product 25c,
despite the availability of a g-hydrogen atom and therefore
the possibility of forming the corresponding b,g-unsaturated
ester. These products underwent deformylation during the
course of the addition reaction and were isolated as the
pure Z isomers (Scheme 11), as in the case of the products
of the conjugate additions to ynones. The Z configuration of
25a was evident from the coupling constant Jcis =8.5 Hz,
whereas both 25a and 25b showed correlations between the
two vinylic protons and between the vinylic proton and an
ortho proton of the unsubstituted phenyl group, respectively,
in their ROESY NMR spectra (see the Supporting Informa-
tion).
The copper-mediated cyclizations of enaminoates 25b and
25c proceeded smoothly under the usual conditions to pro-
vide good yields of indole esters 26b and 26c, respectively,
whereas the unsubstituted derivative 25a underwent exten-
sive decomposition under the normal conditions.
However, with the use of a smaller amount of base
Scheme 11. Conjugate additions and cyclizations of ynoates.
Table 4. Preparation of esters 29 and 30 from ynoate 24d and cyclization to indoles
31.[a]
and lower temperatures the 2-pyridone 27, rather
than the expected indole, was obtained in modest
yield. This is likely due to a base-catalyzed retro-
conjugate addition that involves the regeneration of
methyl propiolate (24a) from the enaminoate 25a,
followed by the conjugate addition of a second mol-
ecule of 25a to the liberated propiolate and cycliza-
tion of the resulting intermediate 28 by proton
transfer and intramolecular acylation (Scheme 11).
In contrast to 24a–24c, reactions of the n-pentyl
derivative 24d generally gave mixtures of b,g-unsa-
turated and conjugated esters 29 and 30, respective-
ly, in which the former were the dominant products
(Table 4). Moreover, unlike 25a–25c, both 29 and
30 contained the intact N-formyl group. Although
we were unable to detect the presence of the allene
isomer of 24d in these reaction mixtures, it is likely
that the isomerization of 24d to the corresponding
allene precedes the more rapid conjugate addition
of 1 and accounts for the formation of products 29
in a manner analogous to the formation of allylic
sulfones 3 from allenes 6, as shown in Table 1 and
Scheme 3. The conjugate additions again tolerated
the presence of a variety of substituents on the ani-
Entry
1
X
R[b]
addition products[c,d]
29 and 30 (Yield [%])
cyclization product[c]
31 (Yield [%])
1
2
3
4
5
6
7
1a
1h
1l
1d
1m
1b
1g
I
I
I
I
Br
Br
I
H
p-Cl
p-I
p-Me
p-CN
H
29a (72)
29b (89)
29c (80)
29d (71)
29e (80)
29 f (77)
29g (72)
30a (9)
–
31a (80)
31b (83)
31c (83)
31d (81)
–
–
–
30c (9)
30d (7)
30e (10)
30 f (9)
–
m-Cl
[a] A molar ratio of ynoates to anilides of 2:1 was employed. [b] The descriptors o and
p refer to substituents ortho and para to the amide moiety; m refers to substituents
meta to the amide moiety and para to the halogen X. [c] Isolated yields are reported.
[d] The minor products 30 were separated from 29 by flash chromatography, but con-
tained unidentified impurities; their yields are therefore approximate.
1
line. Duplicate H and 13C NMR signals in enami-
noates 29 were consistent with the presence of amide rotam-
ers, and ROESY NMR spectroscopy of the representative
compound 29a indicated that the enone moiety in the major
rotamer had the E configuration. The minor isomers 30
could not be completely separated from unidentified impuri-
ties, but similar NMR analysis of crude 30a revealed that it
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T. G. Back and D. Gao
was principally formed as the Z isomer (see the Supporting
Information).
In the present work, we propose that two separate catalyt-
ic cycles are involved. In one, the copper catalyst shuttles
between the copper(II) and copper(I) oxidation states, and
in the second, the copper(I) species promotes the intramo-
lecular C-arylation step via the corresponding putative
The unseparated mixtures of 29 and 30 afforded high
yields of the indoles 31a–31d (Table 4, entries 1–4). As in
the case of adducts 3, which were derived from acetylenic
sulfones, deformylation occurred together with cyclization in
these examples. Unfortunately, the ortho-bromo derivatives
(Table 4, entries 5 and 6) failed to provide the corresponding
indoles and the meta-chloroenaminoate 29g also failed to
cyclize, as in the case of the meta-substituted substrate 3p
shown in Table 1, entry 16.
copperACTHNUGRTENUNG(III) intermediate.
In the first stage, the initially added copper(II) acetate is
reduced to copper(I) by the formate anion generated in situ
by the gradual base-catalyzed hydrolysis of the solvent
(DMF).[33] This is consistent with the reducing ability of the
formate ion/formic acid and with the observation that cop-
per(I) iodide functioned as the catalyst in both DMF and
HMPA solvents (Scheme 5), whereas copper(II) acetate was
only effective in the former solvent. The lack of sensitivity
of the reaction to oxygen is also consistent with this hypoth-
esis, because any adventitious oxidation of copper(I) to cop-
per(II) by air is simply followed by its reconversion to cop-
per(I) by reduction with the formate ion. On the other
hand, several reactions were conducted under inert-gas at-
mospheres and yields of the corresponding indole products
were similar to those obtained when the reaction mixtures
were exposed to air, thus ruling out the possibility that
oxygen is beneficial or necessary for the success of the reac-
tion. Further support for the proposed mechanism is based
on EPR monitoring of the signal that is due to the paramag-
netic copper(II) species.[34] Figure 1a shows the EPR spectra
of the reaction mixture of 3 f in DMF containing 0.3 equiva-
lents of copper(II) acetate under the reaction conditions
used in Table 1 after heating at 1258C for 1 min (trace A),
15 min (trace B), and 180 min (trace C). These spectra
reveal the gradual disappearance of the copper(II) signal at
around 3400 G, which is expected for the reduction of the
copper(II) species to its diamagnetic copper(I) analogue.
Furthermore, when the reaction mixture was then allowed
to stand for 1 week at room temperature while exposed to
air, the copper(II) EPR signal gradually reappeared (Fig-
ure 1b). EPR spectra of control experiments containing
neat DMF or the reaction mixture in the absence of cop-
per(II) acetate showed no trace of the signal at 3400 G. This
provides strong support for our postulated mechanism for
the interconversion of copper(I) and copper(II) under the
conditions of the intramolecular C-arylation reactions.
Mechanism: As mentioned earlier, most copper-catalyzed
arylation reactions have been performed with copper(I) cat-
alysts in the presence of ligands that often play a critical
role in the outcome of the reaction. Moreover, because cop-
per(I) species are prone to oxidation these processes often
require protection from the air. The protocol presented
herein is based on copper(II) acetate, requires no ligands,
and can be run without the exclusion of air or moisture.
These unexpected differences compared to conventional
protocols prompted a further investigation of the mecha-
nism of the cyclization.
The mechanisms of copper-catalyzed C- and heteroatom-
arylations have been widely investigated, especially for aryl
aminations, and have proven remarkably complex.[14c,18,32] In
general, the most salient features involve the addition of the
nucleophile to a suitably ligated copper(I) species, followed
by the oxidative addition of the aryl halide substrate to pro-
duce a putative copperACTHNUTRGNE(NUG III) intermediate. Reductive elimina-
tion then provides the desired product (Scheme 12, path B).
The reason why the presence of ligands for the copper
catalyst in our cyclization reactions produced little or no
benefit, in contrast to the crucial role they play in numerous
other copper(I)-mediated reactions (see above), became
clear when the cyclization of enaminone 22e was stopped in
its early stages, after the initial blue colour had changed to a
very dark brown (ca. 1 h at room temperature). The brown
intermediate was isolated by silica gel flash chromatography
and proved to be both water- and air-stable. It was assigned
the structure 32 on the basis of spectroscopic data and X-ray
crystallography,[35] which indicated that the bidentate start-
ing enaminone had formed a 2:1 complex with copper(II).
Thus, the starting material for the cyclization appears to
function as an effective ligand for its own catalytic transfor-
mation to the final indole product. Although it is likely that
Scheme 12. Copper-catalyzed arylation mechanisms.
This contrasts with the hypothetical path A in Scheme 12
that resembles the mechanism for palladium-catalyzed
cross-couplings, in which oxidative addition of the aryl
halide typically precedes transmetallation or reaction with
the nucleophile, as in the example shown in Scheme 2.
Moreover, there has been considerable discussion in the lit-
erature concerning the precise nature of the oxidative addi-
tion step, including the role of s-complexation, s-metathesis,
atom transfer, single-electron transfer, p-complexation, and
direct insertion.[14c,32a–c,e,h]
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Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
FULL PAPER
Scheme 13. Catalytic cycle for C-arylation of enaminone 22e.
Conclusion
A simple, two-step, copper-catalyzed process that permits
the synthesis of variously substituted indoles from readily
available N-formyl-ortho-haloanilines and acetylenes acti-
vated by sulfonyl, keto, or ester substituents has been devel-
oped. These reactions can be carried out in the absence of
added ligands and without protection from air and moisture.
In the first step, the conjugate additions of N-formylani-
lines to the activated acetylenes proceeded at room temper-
ature in DMF/water (9:1) to afford the a,b- or b,g-unsatu-
rated products as either E or Z geometrical isomers, de-
pending on the nature of the acetylenic substituents. For
cases in which the N-formyl group remained intact, the
products were also formed as mixtures of rotamers. The use
of the N-formylaniline derivatives proved to be particularly
expedient because their conjugate bases were formed under
mildly basic conditions and reacted readily with activated
acetylenes at room temperature. This avoids the need for
heating or the addition of silver or gold complexes, as re-
ported previously for reactions involving primary anilines.
In the second step, the mixtures of unseparated stereo-
and regioisomeric conjugate addition products underwent
intramolecular C-arylations in the presence of copper(II)
acetate. This remarkable process required no additional li-
gands because the conjugate addition products themselves
can, in at least some cases, function as bidentate ligands for
copper(II), thus participating in the catalysis of their own
transformation to the desired indole products. Furthermore,
the copper(II) acetate acts as a procatalyst and is reduced to
copper(I) in situ by the formate ion, which is produced by
the gradual alkaline hydrolysis of the DMF solvent. The fail-
Figure 1. a) EPR spectra of the reaction mixture of 3 f, CuACHTNUTRGNEUNG(OAc)2, and
Cs2CO3 in DMF under the reaction conditions shown in Table 1 after
heating at 1258C for 1 min (A), 15 min (B), and 180 min (C); b) EPR
spectra of the above reaction mixture after standing for 1 week at room
temperature with exposure to air.
similar ligation of the corresponding copper(I) species con-
tinues after the reduction of 32, we were unable to isolate or
conclusively identify the expected copper(I) coordination
complex, perhaps because of its more transient nature. The
subsequent nucleophilic substitution and oxidative addition
steps to produce the corresponding copperACTHNUTRGNE(NUG III) intermediate
33 are similar to those indicated for various other intramo-
lecular O-, N-, and C-arylations.[4,14k,28,32c,f,h,36] We therefore
propose the overall mechanism shown in Scheme 13 for the
transformation of the illustrative example of 22e to indole
23e. It is reasonable to assume that similar processes ac-
count for the cyclizations of the other enaminones and en-
aminoates reported herein, although the formation and role
of copper(II) complexes of the sulfonyl enamines is less cer-
tain.
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T. G. Back and D. Gao
Typical preparation of 2:
ure of copper(II) acetate to catalyze the cyclization in
HMPA and other solvents that are incapable of creating a
reducing environment supports this conclusion. The adventi-
tious oxidation of copper(I) back to copper(II) by exposure
to air is not deleterious because formate reduction regener-
ates the required copper(I) species. EPR experiments that
were used to monitor the disappearance of copper(II) in al-
kaline DMF at elevated temperatures and its reappearance
upon exposure to air at room temperature are consistent
with this pathway. The oxidative addition of the aryl iodide
moiety to copper(I), to generate the corresponding copper-
Preparation of 1-(para-toluenesulfonyl)tetradecyne (2d): Se-Phenyl-para-
tolueneselenosulfonate[49] (3.11 g, 10.0 mmol) and 1-tetradecyne (1.94 g,
10.0 mmol) were dissolved in chloroform (25 mL) and the solution was ir-
radiated for 2.5 h under UV light (300 nm lamps). MCPBA (20 mmol)
was added and the mixture was stirred for 25 min. The solution was
washed with aqueous KOH solution, dried, and refluxed for 3 h. The
chloroform was evaporated under vacuum and the residue was purified
by flash chromatography on silica gel (hexanes/ethyl acetate, 20:1) to
provide 2d (2.42 g, 70%) as a pale-yellow solid. M.p. 39–408C; 1H NMR
(400 MHz, CDCl3): d=7.88 (d, J=8.4 Hz, 2H), 7.36 (d, J=7.9 Hz, 2H),
2.46 (s, 3H), 2.34 (t, J=7.2 Hz, 2H), 1.58–1.49 (m, 2H), 1.37–1.17 (m,
18H), 0.87 ppm (t, J=6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=
145.1, 139.5, 130.0, 127.4, 97.6, 78.6, 32.1, 29.8, 29.7, 29.5, 29.0, 28.9, 27.1,
22.8, 21.8, 19.1, 14.3 ppm; IR (film): n˜ =2203, 1327, 1154 cmÀ1; MS (CI):
m/z (%): 366 (100) [M+NH4+]; HRMS (EI): m/z calcd for C21H32O2S:
348.2123; found: 348.2136.
ACHTUNGTRENNUNG(III) intermediate, is then followed by reductive elimination
to afford the final products.
A one-pot variation of the above process was also effec-
tive, but generally produced lower overall yields. When
pendant b-chloroalkyl substituents were present on the ace-
tylene, further cyclization occurred by N-alkylation to afford
tricyclic products. Several examples of the indole synthesis
were performed on a modified Merrifield resin to successful-
ly validate the possibility of adapting the process for the
solid-phase organic synthesis (SPOS) of indoles.
Typical preparation of 3:
Preparation of (E)-N-(2-iodophenyl)-N-[(1-para-toluenesulfonyl)hex-2-en-
2-yl]formamide (3a): Acetylenic sulfone 2a (354 mg, 1.50 mmol) was
added to a mixture of anilide 1a (247 mg, 1.00 mmol) and potassium car-
bonate (138 mg, 1.00 mmol) in DMF/H2O (5 mL, 9:1) and stirred at
room temperature for 16 h. The reaction mixture was diluted with water
(50 mL) and was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried, and filtered. The residue was con-
centrated under vacuum and purified by flash chromatography (hexanes/
ethyl acetate, 8:1 to 4:1) to provide 3a (391 mg, 81%) as a yellow oil in a
64:36 mixture of rotamers. 1H NMR (300 MHz, CDCl3): major rotamer:
d=8.38 (s, 1H), 7.95–7.77 (m, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.47–7.28
(m, 4H), 7.15–6.95 (m, 1H), 5.99 (t, J=7.6 Hz, 1H), 3.69 (brs, 2H), 2.42
(s, 3H), 1.93–1.55 (m, 2H), 1.45–1.10 (m, 2H), 0.84 ppm (t, J=7.3 Hz,
3H); minor rotamer: d=8.13 (s, 1H), 5.66 (t, J=7.6 Hz), 4.19 (brs, 2H),
0.74 ppm (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) both rotamers:
d=162.5, 162.0, 145.4, 144.9, 142.7, 140.8, 140.2, 138.7, 138.1, 137.0, 136.2,
136.1, 131.5, 131.2, 130.33, 130.25, 130.2, 130.1, 129.9, 129.5, 128.6, 128.3,
125.5, 125.0, 99.8, 97.9, 54.5, 54.2, 30.1, 29.4, 22.1, 22.0, 21.7, 13.8,
13.7 ppm; IR (film): n˜ =1692, 1323, 1151 cmÀ1; MS (CI): m/z (%): 501
(100) [M+NH4+], 484 (25) [M+H+]; HRMS (EI): m/z calcd for
C20H22INO3S: 483.0729; found: 483.0744.
Experimental Section
General experimental: NMR spectra were recorded at 300 or 400 MHz
on a Bruker DMX 300, Bruker Avance II 400 or a Bruker Avance III
400 spectrometer, and mass spectra were obtained by electron impact,
chemical, or electrospray ionization, as indicated for each individual com-
pound, on a Bruker Esquire 3000, Thermo Finnigan Mat SSQ7000, Agi-
lent 6520 or a Waters GCT Premier spectrometer. Aliquots were re-
moved from the reaction mixture described in Figure 1 at the indicated
times and transferred to 0.5 mm diameter capillary tubes. EPR analysis
of these aliquots was performed at room temperature by using the fol-
lowing parameters: X-band (9.775 GHz); microwave power=10–12 mW;
modulation frequency=100 KHz; modulation amplitude=10 Gauss; scan
rate=1000 G per 5 min; time constant=82 ms.
The other sulfonyl enamines 3 that are shown in Table 1, as well as com-
pound 9, were prepared similarly. Their yields and any modifications to
the conditions are provided in Table 1 and in Scheme 4, and their charac-
terization data are listed in the Supporting Information. The crude sul-
fonyl enamines 3h, 3n, and 10 were used directly in subsequent steps
without prior purification.
All of the parent ortho-haloanilines of N-formyl-ortho-iodoanilines 1 are
commercially available, although some were prepared by standard aro-
matic bromination[37] or iodination[38] methods. N-Formylanilines 1b and
1i were purchased from commercial sources, and the other N-formylani-
lines were obtained by N-formylation of the corresponding ortho-haloani-
lines with formic acid following a literature procedure.[39] Anilide 1n was
prepared by reduction of the corresponding nitro derivative 1h with
tin(II) chloride in ethanol.[40] The products were isolated as mixtures of
rotamers.
Acetylenic sulfones 2a,[41a] 2b,[41a] 2c–f, and 8[41b] were obtained by the se-
lenosulfonation and selenoxide elimination of the corresponding acety-
lenes.[42] Sulfone 2c was kindly provided to us by Dr. H. Zhai, and 2g[43]
was prepared by the meta-chloroperoxybenzoic acid (MCPBA) oxidation
of the corresponding acetylenic sulfide, which was obtained by the gener-
al method of Kabanyane and Magee.[44] Terminal acetylenic sulfone 7
was produced by the method of Chen and Trudell.[45] Polymer-supported
acetylenic sulfones 17a and 17b were prepared as reported previously.[27]
The preparation of 2d is described below and characterization data for
the novel compounds 2e and 2 f are described in the Supporting Informa-
tion. Ynone 21b was obtained by following a general literature proce-
dure,[46] whereas ynone 21a and ynoates 24a–24d are commercially avail-
able or, in some cases, were prepared by the Sonogashira coupling of the
corresponding acyl chlorides with alkynes.[47] In general, it was expedient
to employ an excess of the activated acetylene in the conjugate addition
step. The yields in Tables 1, 3, and 4 are based on the N-formylaniline re-
actant.[48]
Typical preparation of 4:
Preparation of 2-n-butyl-3-(para-toluenesulfonyl)-1H-indole (4a): The
conjugate addition product 3a (121 mg, 0.250 mmol), CuACHTNUTRGNEUNG(OAc)2 (14 mg,
0.077 mmol), and Cs2CO3 (163 mg, 0.500 mmol) were heated in DMF
(3 mL) for 3 h at 1258C. The solvent was removed under vacuum, and
the residue was triturated with dichloromethane and filtered. The filtrate
was concentrated under vacuum and purified by silica gel chromatogra-
phy (ethyl acetate/hexanes, 1:3) to provide indole 4a (54 mg, 66%) as
pale-yellow crystals. M.p. 140–1418C (from dichloromethane/hexanes).
Preparation of 14: Indoles 14m–14o were prepared similarly under more
dilute conditions (15 mL of DMF were used). The yields of the products
3 and 14 are provided in Table 1 and those of the 2-unsubstituted and 2-
phenyl indole derivatives 15 and 16 are shown in Scheme 8. Characteriza-
tion data and copies of 1H and 13C NMR spectra of indoles 4a, 4c–4g,
4i–4l, 14m–14o, 15, and 16 are provided in the Supporting Information
of our preliminary communication.[19] The characterization data and spec-
tra of the remaining indoles 4h and 4q that are in Table 1 are described
in the accompanying Supporting Information.
Preparation of 13: Sulfonyl enamine 3p (68 mg, 0.14 mmol) was subject-
ed to the same cyclization conditions as 3a. Purification by flash chroma-
tography (ethyl acetate/hexanes, gradient) provided 13 (48 mg, 73%) as a
yellow oil. 1H NMR (400 MHz, CDCl3): d=14.02 (s, 1H), 9.96 (s, 1H),
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Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
FULL PAPER
7.92–7.85 (m, 3H), 7.61–7.50 (m, 3H), 7.28 (d, J=2.3 Hz, 1H), 6.80 (dd,
J=8.4, 2.3 Hz, 1H), 2.64–2.55 (m, 2H), 1.29–1.12 (m, 2H), 0.70 ppm (t,
J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=189.3, 172.6, 144.2,
141.1, 139.9, 137.1, 132.6, 129.2, 126.9, 126.5, 125.7, 111.0, 97.9, 31.5, 21.6,
14.2 ppm; IR (film): n˜ =3336, 1718, 1582, 1303, 1147 cmÀ1; MS (CI): m/z
(%): 490 (100) [M+H+]; HRMS (EI): m/z calcd for C18H17ClINO3S:
488.9662; found: 488.9649.
13C NMR spectra of indoles 23a, 23b, and 23d–23i were provided in the
Supporting Information of our preliminary communication.[19] Characteri-
zation data and spectra of indole 23c are provided in the accompanying
Supporting Information.
Typical preparation of 25:
Preparation of methyl (Z)-3-(2-iodophenylamino)prop-2-enoate (25a):[50]
A
mixture of ynoate 24a (60 mg, 0.71 mmol), anilide 1a (300 mg,
Preparation of indoles on solid supports: A mixture of polymer-support-
ed acetylenic sulfone 17a or 17b[27] (1.5 g, 0.67 mmolgÀ1) and DMF
(22.5 mL) was stirred for 30 min, and then N-formylaniline 1a (371 mg,
1.50 mmol), 1j (560 mg, 1.50 mmol), or 1k (422 mg, 1.50 mmol) and po-
tassium carbonate (138 mg, 1.00 mmol) and water (2.5 mL) were added.
In each case, the reaction mixture was stirred at room temperature for
16 h. The resins were filtered, washed with water, and then three times
alternately with each of the following solvents: dichloromethane, water,
and methanol. The resins were air dried and then dried under reduced
pressure overnight. The resulting solid-supported sulfonyl enamines 18a–
18c were stirred in DMF (25 mL) for 30 min and then copper(II) acetate
(38 mg, 0.20 mmol) and cesium carbonate (652 mg, 2.00 mmol) were
added. The mixtures were stirred at 1258C for 3 h. The resins were fil-
tered and washed with ammonium hydroxide (5%), water, and then
three times alternately with each of the following solvents: dichlorome-
thane, water and methanol. The resins were air dried and then dried
under reduced pressure overnight to afford the solid-supported indoles
19a–19c, respectively.
1.21 mmol), and potassium carbonate (417 mg, 3.02 mmol) in DMF/H2O
(5.0 mL, 9:1) was stirred at room temperature for 24 h. Another portion
of ynoate 24a (60 mg, 0.71 mmol) was added and the mixture was stirred
for a further 24 h. The solvent was removed under reduced pressure and
the resulting residue was triturated with dichloromethane and filtered.
The filtrate was concentrated and purified by flash chromatography on
silica gel (ethyl acetate/hexanes, gradient) to afford of 25a (239 mg,
65%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d=10.15 (d, J=
11.2 Hz, 1H), 7.78 (dd, J=7.9, 1.3 Hz, 1H), 7.33–7.25 (m, 1H), 7.20 (dd,
J=12.3, 8.5 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.72 (td, J=7.8, 1.3 Hz,
1H), 4.96 (d, J=8.5 Hz, 1H), 3.77 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=170.1, 142.0, 141.6, 139.9, 129.5, 123.8, 113.6, 89.3, 87.4,
51.0 ppm. The Z geometry of the enaminoate was assigned on the basis
of the coupling constant Jcis =8.5 Hz and the ROESY NMR spectrum,
which indicated a correlation between the two vinylic protons.
The preparations of enaminoates 25b, 25c,[51] and 29a–29g were per-
formed similarly, and any minor changes to the procedures are indicated
in Scheme 11 and Table 4. Products 30a, 30c, and 30d–30 f were isolated
as minor by-products of the corresponding major isomers 29. Characteri-
zation data and spectra for the major products are provided in the Sup-
porting Information. Of the minor products 30, only 30a was obtained in
a relatively pure state and its characterization data are described in the
Supporting Information.
Each of the above resins 19a–19c (1.5 g) was stirred in THF (50 mL) for
30 min, and then aqueous LiOH solution (5%, 3.0 mL, 6.3 mmol) was
added. The reaction mixtures were stirred at room temperature for 1–3 d,
then the resin was filtered and washed three times, alternatively, with
each of THF and methanol. The combined THF and methanol filtrates
were neutralized with HCl (5%) and concentrated under reduced pres-
sure. The resulting residue was triturated with dichloromethane (20 mL)
and the mixture was filtered. The filtrate was concentrated under re-
duced pressure and the resulting residue was purified by flash chromatog-
raphy on silica gel (ethyl acetate/hexanes, gradient) to provide the indole
products 20a (122 mg, 53%), 20b (195 mg, 62%), and 20c (168 mg,
63%). The characterization data and spectra of the products are provid-
ed in the Supporting Information.
Typical preparation of 26 and 31: The preparation of indoles 26b, 26c,
and 31a–31d was performed similarly to that described for sulfonyl en-
amines 3, with any minor changes indicated in Scheme 11 and Table 4.
Characterization data and copies of 1H and 13C NMR spectra of indoles
26b, 26c, and 31a–31d were provided in the Supporting Information of
our preliminary communication.[19] Characterization data and spectra for
27 are provided in the accompanying Supporting Information.
Typical preparation of 22:
Preparation
(22a):
of
(Z)-3-(2-iodophenylamino)-1-phenylhept-2-en-1-one
A
mixture of ynone 21a (140 mg, 0.750 mmol), anilide 1a
(120 mg, 0.500 mmol), and potassium carbonate (140 mg, 1.00 mmol) in
DMF/H2O (5.0 mL, 9:1) was stirred at room temperature for 12 h. An-
other portion of ynone 22a (44 mg, 0.25 mmol) was added and the mix-
ture was stirred for a further 12 h. The solvent was removed under re-
duced pressure and the resulting residue was triturated with dichlorome-
thane and filtered. The filtrate was concentrated under reduced pressure
and purified by flash chromatography on silica gel (ethyl acetate/hexanes,
1:5) to provide 22a (177 mg, 87%) as a yellow oil. 1H NMR (400 MHz,
CDCl3): d=12.93 (s, 1H), 8.01–7.96 (m, 2H), 7.94 (dd, J=7.9, 1.3 Hz,
1H), 7.52–7.42 (m, 3H), 7.39 (dd, J=7.7, 1.3 Hz, 1H), 7.26 (dd, J=7.8,
1.2 Hz, 1H), 7.01 (dt, J=7.7, 1.4 Hz, 1H), 6.01 (s, 1H), 2.31 (t, J=7.6 Hz,
2H), 1.54–1.43 (m, 2H), 1.37–1.25 (m, 2H), 0.84 ppm (t, J=7.3 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=189.3, 166.3, 141.1, 140.0, 139.6, 131.0,
128.8, 128.3, 128.1, 127.7, 127.3, 98.3, 93.3, 32.2, 30.1, 22.3, 13.7 ppm; IR
(film): n˜ =1586, 1283 cmÀ1; MS (EI): m/z (%): 405 (20) [M+], 363 (55),
278 (59), 105 (100), 77 (75); HRMS (EI): m/z calcd for C19H20INO:
405.0590; found: 405.0572.
Acknowledgements
We thank the Natural Sciences and Engineering Research Council of
Canada for financial support. D.G. thanks the Province of Alberta for a
Queen Elizabeth II scholarship. We also thank Dr. Huimin Zhai for the
preparation of acetylenic sulfone 2c and Dr. Chris Smith for assistance
with several experiments.
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Chem. Eur. J. 2012, 00, 0 – 0
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T. G. Back and D. Gao
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Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes
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Received: June 29, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

T. G. Back and D. Gao
Cross-Coupling
D. Gao, T. G. Back* ......... &&&& — &&&&
Indole Synthesis by Conjugate Addi-
tion of Anilines to Activated Acety-
lenes and an Unusual Ligand-Free
Copper(II)-Mediated Intramolecular
Cross-Coupling
No ligands required! Intramolecular
C-arylations of sulfonyl enamines,
ynones, and ynoates were promoted by
CuACHTUNRTGENUNG(OAc)2 in alkaline DMF/H2O to
provide substituted indoles without
protection from air (see scheme). The
starting material functioned as the
ligand for its own cyclization. The
process has been applied to the prepa-
ration of tricyclic products and to
indole synthesis on solid supports.
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!