A robust, well-defined homogeneous silver(I) catalyst for mild intramolecular hydroamination of 2-ethynylanilines leading to indoles

Article abstract of DOI:10.1002/ejoc.201301368

A highly efficient, chemically stable and well-defined homogeneous silver(I) catalyst is reported for the room temperature, intramolecular hydroamination of 2-alkynylanilines leading to indole derivatives. Copyright

Full text of DOI:10.1002/ejoc.201301368

FULL PAPER
DOI: 10.1002/ejoc.201301368
A Robust, Well-Defined Homogeneous Silver(I) Catalyst for Mild
Intramolecular Hydroamination of 2-Ethynylanilines Leading to Indoles
James McNulty*[a] and Kunal Keskar[a]
Keywords: Homogeneous catalysis / Silver catalysis / Alkynes / Hydroamination
A highly efficient, chemically stable and well-defined homo-
geneous silver(I) catalyst is reported for the room tempera-
ture, intramolecular hydroamination of 2-alkynylanilines
leading to indole derivatives.
tected 2-ethynylanilines (1a, Table 1) has emerged as a valu-
Introduction
able route to functionalized indoles and this process has
been reported to be catalyzed by Cu salts,[3a,3b] Et2Zn,[3c]
The development of transition metal-catalyzed alkene
and alkyne hydroamination reactions has continued to
transform the synthesis of aliphatic and heterocyclic amines
over the last decade.[1] Initial work on non-Michael-type
hydroamination reactions focused on the use of base-cata-
lyzed approaches to higher amines. However, these pro-
cesses involve the use of strong base often under forcing
thermal conditions and are limited in scope.[2] A wide range
of both Lewis acidic and late transition metal homogeneous
and heterogeneous catalysts[1] have now been developed to
effect hydroamination reactions. In particular, late transi-
tion metal complexes of both d8 and d10 electronic configu-
ration are employed. Despite these improvements, many
processes require thermal conditions and substrate scope is
still largely limited to activated olefins and intramolecular
hydroamination processes.
,[3e]
ZnBr2
Hg(OAc)2,[3d] and RhI species.[3f] Conditions to
effect this cyclization are often harsh requiring high tem-
peratures and the addition of base is required along with
the catalyst to perform reaction at room temperature.[3b] No
Table 1. Silver salt-promoted intramolecular hydroamination.
Although heterogeneous and homogeneous catalytic pro-
cesses based on CuI, AuI, AuIII, Pd0, PdII, ZnII and HgII
have been developed to effect hydroamination reactions,[1,3]
very few reports on the use of AgI catalysts[4] have ap-
peared. Consequently, the development of AgI catalytic sys-
tems was recently termed “somewhat neglected” with some
understatement.[1b] The homogeneous silver(I) situation
contrasts sharply with the use of homogeneous ligated
gold(I) complexes, applications of which have expanded
greatly in recent years. Despite the expected lower π-acidity
of isoelectronic silver(I) species, the ready availability and
significantly lower cost of precursor silver salts are motiva-
ting factors in our current research program aimed at iden-
tifying robust, useful homogeneous silver(I) catalysts. As a
case in point, the intramolecular hydroamination of N-pro-
[a] Department of Chemistry and Chemical Biology, McMaster
University,
1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada
E-mail: jmcnult@mcmaster.ca
http://www.chemistry.mcmaster.ca/mcnulty/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301368
[a] Reactions run with complexes A–C rendered inferior results
with some Ag0 precipitation.
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Hydroamination of 2-Ethynylanilines Leading to Indoles
Scheme 1. Postulated reactivity for homogeneous silver(I)-promoted alkyne hydroamination.
reports on the homogeneous catalysis of this reaction using corresponding indole adducts in 83% and 94% conversions,
silver(I) species have been reported. One example of a case respectively. Notably, the use of silver salts containing
involving an unprotected aniline was reported using hetero- weakly coordinating anions here proved ineffective, in con-
geneous silver(I) triflate,[4a] whereas the intramolecular hy- trast to the intramolecular hydroamination reported on 6-
droamination of 6-amino-1-hexyne to its cyclic imine deriv- amino-1-hexyne.[4j] Although a clear explanation for the di-
ative was reported using silver tetrafluoroborate and a chotomy of these heterogeneously catalyzed reactions is not
homogeneous triphos-ligated silver(I) catalyst.[4i] This reac- obvious, we note that these reactions were conducted in
tion, pioneered by Müller and co-workers, serves as the acetonitrile on a different substrate containing a free amine.
most comprehensive study on late transition metal-cata- Our attention immediately became focused on the homo-
lyzed 5-endo-dig hydroamination processes.[4i,4j] The use of geneous ligated silver(I) species (Table 1, catalyst D shown).
silver(I) salts or complexes in hydroamination and other This hydroamination reaction was far superior and seen to
areas of catalysis has “lagged behind”[5] other coinage met- proceed at a much faster rate (vide infra), fully generating
als for several reasons. The facile precipitation of silver desired indole within 20 min (Table 1, Entry 8). Catalyst D
metal under many conditions and the rapid precipitation of
silver halides in the presence of common halide counter-
anions serve to limit the scope of silver(I) species in cataly-
sis. We recently reported the first examples of silver(I)-cata-
lyzed Huisgen cycloaddition reactions involving the use of
homogeneous silver(I) species to initiate the necessary alk-
yne activation. We prepared silver(I) acetate complexes A–
D (Scheme 1) from the corresponding 2-dialkylphosphino-
N,N-diisopropyl benzamides. The hemilabile ligand was
found to play a pivotal role in effecting this cycloaddition
through polarization effects on reaction intermediates dur-
ing the catalytic cycle.[6b]
On this basis of this π-acid reactivity, we postulated reac-
tivity along the lines outlined in Scheme 1 that might lead
to homogeneous silver-promoted alkyne hydroamination.
In this paper we describe the success of this protocol and
development of a very robust and efficient homogeneous
catalyst for the intramolecular hydroamination reaction of
2-ethynylaniline derivatives. This protocol is carried out at
room temperature and does not require the use of any basic
additives. This readily enabled the construction of a mini-
library of indole derivatives, including a sensitive and prob-
lematic[3c] silylated indole derivative (vinylsilane).
The base reaction of the N-tosyl-2-ethynylaniline 1a is
shown atop Table 1. A range of heterogeneous silver salts
were first screened under standard thermal hydroamination
conditions in toluene at 100 °C. The reactions were initially
Figure 1. Ligand optimization (top) identifying complex D as opti-
mal (100% conversion after 2.5 h; all reactions stopped after 2.5 h)
performed in deuterated toluene to allow simple monitoring
and kinetic data (bottom) for complexes A, D (three concentra-
tions) and comparison with the heterogeneous AgOAc promoted
1
by H-NMR spectroscopy. The use of silver oxide (Table 1,
Entry 5) and silver acetate (Table 1, Entry 7) alone provided reaction, room temp. in MeOH.
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J. McNulty, K. Keskar
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was found to possess superior stability relative to complexes The reactions were conducted in dry methanol or DMF
A, B and C. Figure 1 of the Supporting Information shows (shown in Table 2) at room temperature using only 1.0 mol-
the actual reactions with silver acetate after 30 min (a) and % catalyst D. No additional base was required to effect high
12 h (b) performed in toluene at 100 °C as well as the reac- conversions in all cases investigated. The reaction allows
tion with catalyst D (c) also after 12 h in toluene at 100 °C. conversion of both electron rich, electron deficient aromatic
Absolutely no silver metal precipitation was observed in the systems to the corresponding 2-substituted indole derivative
homogeneous reaction promoted by complex D, in contrast in high yields. In order to challenge the sensitivity of the
to the heterogeneous silver salt-promoted versions. In ad- new catalytic process, we prepared trimethylsilyl-alkyne 1o.
dition to catalyst thermal stability, we noted also that com- We were delighted to find the homogeneous silver-catalyzed
plexes A–D are non-hydrated or solvated; they are readily reaction in DMF permitted smooth hydroamination lead-
soluble in most organic solvents and show no silver chloride ing to the sensitive product 2-(trimethylsilyl)indole 2o,
deposition when shaken with brine. Similar stability was which could be isolated in very high yield for the first ti-
noted during the Huisgen catalytic process described me.[3c] This result is illustrative of the mild and chemoselec-
above.[6] The hydroamination reaction was investigated at tive π-acidity of these catalysts as trimethylsilyl-function-
or, near room temperature in various other solvents. De- alized alkynes normally proceed quickly to the desilylated
spite the homogeneous nature of these reactions, no conver- silver acetylides in the presence of silver salts.[7]
sion was observed in standard organic solvents such as tol-
uene, dioxane, cyclohexane and dichloromethane at room
temperature or at 50 °C after 15 min. However, to our de-
light, the reaction with 10.0 mol-% catalyst was found to
be successful in dipolar solvents methanol, acetonitrile and
dimethylformamide (DMF) at 50 °C, leading to Ͼ 95%
conversion in 15 min. The reaction performed in methanol
Scheme 2. General method for preparation of aminoalkynes.
proved very efficient even at room temperature, giving
Ͼ 99% conversion in 2.5 h. A catalyst screen identified
complex D as the most active homogeneous catalyst for the
We envision a catalytic cycle along the lines of that pos-
cyclization (Figure 1, top). Reactions in DMF and acetoni- tulated in Figure 2. Loss of acetate from the catalyst precur-
trile were also efficient at 22 °C, providing full conversion sor leads to the electrophilic 14-electron species I which te-
within 1.5–2.5 h.
thers to the alkyne leading to II and reversibly to the ortho-
The catalyst loading could also be lowered to 1.0 mol-% amino substituent, suggesting a key role for the hemilabile
in DMF or methanol, leading to full conversions in about ligand II to III. A standard pathway for the heterogeneous
13 h and 20 h respectively, demonstrating a significant rate ligand-free cycle is outlined proceeding directly from II to
effect on catalyst concentration. Kinetic data of the cycliza- V, for which the data (Table 1) show this to be relatively
tion reaction carried out in methanol using catalyst A slow. The mechanism for ligand accelerated catalysis follows
(10.0 mol-%), catalyst D at three different concentrations the cycle through intermediates II, III, IV and V. Loss of
(5, 10 and 20 mol-%) and the heterogeneous silver acetate- the weak amide donor from II opens a more electrophilic
promoted cyclization (10.0 mol-%) are shown in Figure 1, site for coordination of the amine. Re-coordination of the
bottom. The data show a clear rate acceleration for the amide (W = weak donor) in III leads to polarization of
homogeneous versions of the reaction as well as demon- the silver-nitrogen bond (III to IV) initiating the cyclization
strating the pronounced ligand accelerating effect compar- leading to organosilver intermediate V through a stepwise
ing complexes A and D. The initial rate of reaction was process. Final proto-demetalation yields the indole deriva-
precisely doubled employing catalyst D at 10.0 and tive and regenerated active catalyst.
20.0 mol-% demonstrating the reaction to be first order in
Interestingly, the only prior report detailing homogen-
catalyst concentration (see Figure 2 of the Supporting In- eous silver(I)-catalyzed hydroamination, of 6-amino-1-
formation), a result in accord with previous intramolecular hexyne leading to the cyclic imine derivative, resulted in
hydroamination reactions promoted with rare-earth met- poor (26% yield) conversion to the cyclized product using
al[1b] and copper(I) catalysts.[4j] The reaction performed in a triphos-ligated silver complex. The use of bidentate li-
methanol was also advantageous in terms of work-up as gands was described as giving rise to even worse outcomes
the product indole often precipitates during the course of (5% yield).[4i] The reaction was observed to be most ef-
reaction. All subsequent experiments were conducted in ficient using silver tetrafluoroborate alone (44–56%
either dry methanol or DMF.
yield),[4i] a process that also results in silver metal deposi-
The scope of the silver-promoted hydroamination was in- tion. This situation contrasts sharply with the present re-
vestigated employing starting materials 1a–o, which were sults using hemilabile silver acetate complex D. The com-
prepared from commercially available substituted 2-iodoan- plex is very stable and catalytically active, allowing high
ilines, following a two-step Sonogashira and N-tosylation conversion rates of 2-alkynyl anilines to indoles at room
protocol (Scheme 2). The reaction conditions developed for temperature in methanol as described (Table 2). Finally, al-
substrate 1a using catalyst D proved to be very general and though the homogeneous silver-mediated hydroamination
Table 2 summarizes the scope of variations investigated. reported here leads to N-tosyl protected indoles, we note
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Hydroamination of 2-Ethynylanilines Leading to Indoles
Table 2. Scope of the homogeneous intramolecular hydroamination of 2-alkynylanlines promoted with 1 mol-% complex D at room temp.
that N-tosyl-indole derivatives can be readily deprotected loadings (1.0 mol-%) of catalyst and are conveniently con-
using tetrabutyl ammonium fluoride under mild conditions, ducted at room temperature in methanol or DMF. The re-
in contrast to aliphatic tosylamines.[8]
actions were shown to be first order in catalyst and a
In conclusion, we describe the first examples of homo- mechanism was postulated highlighting the role of the hem-
geneous intramolecular hydroamination of 2-alkynylanil- ilabile ligand in promoting the cyclization. In addition, the
ines employing well-defined silver(I) catalysts leading to enhanced thermal and chemical stability of these silver(I)
substituted indoles. The reactions are promoted with low complexes makes them ideal to probe chemical reactivity
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J. McNulty, K. Keskar
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Figure 2. Postulated catalytic cycle for the hemilabile ligand accelerated intramolecular hydroamination promoted by complex D.
of δ (ppm) and coupling constants (J) are expressed in Hz. Mass
spectra were run with a Micromass Quattro Ultima spectrometer
fitted with a direct injection probe (DIP) with ionization energy set
at 70 eV and HRMS (EI) were performed using a Micromass Q-
TOF Ultima spectrometer. Thin layer chromatography (TLC) was
run using Macherey–Nagel aluminum-backed plates. Melting
points were obtained with an Electronic Research Associates Inc.
melting point apparatus corrected against an external calibrant. Sil-
ver acetate (Ͼ 99%) was purchased from Fluka. Silver trifluro-
methanesulfonate (Ͼ 98%), Silver oxide (Ͼ 99%) and Silver para-
toluenesulfonate (Ͼ 99%) were obtained from Sigma–Aldrich. Sil-
ver nitrate was obtained from International Correspondence
Schools, USA. Silver sulfate (ACS quality) was obtained from
BDH and Silver carbonate (99%) was purchased from General
Chemical Division, USA.
(π-acidity) in the area of homogeneous catalysis without
fear of silver metal or halide precipitation, problems that
have plagued the development of silver catalysis in general.
The role of these silver species in promoting Huisgen chem-
istry,[6] and now hydroamination, bodes well for the future
of silver(I) catalysis. It is our hope that use of complexes
such as D should allow this field of homogenous silver(I)
catalysis to catch-up[5] with its competing technologies and
to undergo significant advances of this previously neglect-
ed[1b] synthetic field.
Experimental Section
General: Dichloromethane was distilled from calcium hydride. Tol-
uene was distilled from sodium metal in the presence of benzo-
phenone indicator. All other solvents including dimethylformamide
General Procedure for Synthesis of (2-Phenylethynyl)aniline and N-
Tosyl-(2-phenylethynyl)aniline: (2-Phenylethynyl)aniline and N-tos-
yl-(2-phenylethynyl)aniline (1a) were prepared according to re-
(Ͼ 99%) were purchased as sure-seal bottles from Sigma–Aldrich ported procedures.[3c] Using the same procedure, other 2-substi-
1
and used as-is. H and 13C spectra were obtained with a 600 MHz
tuted ethynylanilines and corresponding N-tosyl derivatives were
Bruker NMR spectrometer. Chemical shifts are reported in units
prepared.
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Hydroamination of 2-Ethynylanilines Leading to Indoles
N-{2-[(4-Bromophenyl)ethynyl]phenyl}-4-methylbenzenesulfonamide
(1b): M.p. 99–101 °C. H NMR (600 MHz, CDCl3): δ = 7.66 (d, J
solvent was removed under vacuum. The reaction mixture was then
extracted with ethyl acetate (3 x 10 mL), washed with water, brine.
1
= 8.3 Hz, 2 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 2 The organic layer was dried with anhydrous sodium sulfate and
H), 7.37 (dd, J = 7.7, 1.3 Hz, 1 H), 7.34–7.28 (m, 3 H), 7.18 (d, J concentrated under reduced pressure. The resulting residue was
= 8.1 Hz, 2 H), 7.14 (s, 1 H), 7.07 (td, J = 7.6, 1.0 Hz, 1 H), 2.35 purified through silica gel column chromatography (2–5% ethyl
(s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 144.23, 137.71, acetate: hexanes) to afford 2a.
136.25, 133.08, 132.20, 132.02, 130.05, 129.78, 127.38, 124.80,
2-Phenyl-1-tosyl-1H-indole (2a):[9] 1H NMR (600 MHz, CDCl3): δ
= 8.31 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 7.6, 1.8 Hz, 2 H), 7.47–
123.58, 121.11, 120.58, 114.45, 95.08, 85.03, 21.69 ppm. HRMS:
calcd. for C21H16BrNO2S [M]+ 425.0085, found 425.0085.
7.39 (m, 4 H), 7.39–7.33 (m, 1 H), 7.29–7.24 (m, 4 H), 7.04 (d, J =
8.0 Hz, 2 H), 6.54 (s, 1 H), 2.29 (s, 3 H) ppm. 13C NMR (151 MHz,
N-{2-[(3-Chlorophenyl)ethynyl]phenyl}-4-methylbenzenesulfon-
1
CDCl3): δ = 144.66, 142.29, 138.43, 134.84, 132.57, 130.70, 130.49,
129.34, 128.79, 127.64, 126.95, 124.92, 124.45, 120.82, 116.82,
113.74, 21.67 ppm.
amide (1c): H NMR (600 MHz, CDCl3): δ = 7.66 (d, J = 8.3 Hz,
2 H), 7.63 (d, J = 8.2 Hz, 1 H), 7.40 (d, J = 1.6 Hz, 1 H), 7.37 (dt,
J = 7.7, 1.8 Hz, 2 H), 7.36–7.30 (m, 3 H), 7.19 (d, J = 8.0 Hz, 2
H), 7.11 (s, 1 H), 7.10–7.06 (m, 1 H), 2.35 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 144.26, 137.78, 136.31, 134.55, 132.31,
131.54, 130.16, 129.93, 129.82, 129.45, 127.36, 124.89, 123.85,
120.92, 114.42, 94.50, 85.02, 21.69 ppm. HRMS: calcd. for
C21H16ClNO2S [M]+ 381.0581, found 381.0590.
2-(4-Bromophenyl)-1-tosyl-1H-indole (2b): M.p. 142–144 °C. 1H
NMR (600 MHz, CDCl3): δ = 8.30 (d, J = 8.4 Hz, 1 H), 7.59–7.52
(m, 2 H), 7.44 (d, J = 7.7 Hz, 1 H), 7.40–7.36 (m, 3 H), 7.29–7.24
(m, 3 H), 7.05 (d, J = 8.1 Hz, 2 H), 6.54 (s, 1 H), 2.29 (s, 3 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 144.87, 141.00, 138.52, 134.64,
131.89, 131.51, 130.92, 130.59, 129.43, 126.88, 125.23, 124.63,
123.22, 120.94, 116.87, 114.19, 21.68 ppm. HRMS: calcd. for
C21H16BrNO2S [M]+ 425.0083, found 425.0085.
2-(3-Chlorophenyl)-1-tosyl-1H-indole (2c): M.p. 47–50 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.30 (d, J = 8.4 Hz, 1 H), 7.45 (d, J =
7.7 Hz, 1 H), 7.44–7.42 (m, 1 H), 7.42–7.38 (m, 2 H), 7.32–7.24 (m,
2 H), 7.28 (dd, J = 7.9, 2.2 Hz, 3 H), 7.07 (d, J = 8.4 Hz, 2 H),
6.57 (s, 1 H), 2.30 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ
= 144.93, 140.55, 138.49, 134.71, 134.26, 133.56, 130.43, 130.07,
129.46, 128.92, 128.89, 128.81, 126.92, 125.31, 124.58, 121.03,
116.78, 114.30, 21.68 ppm. HRMS: calcd. for C21H16ClNO2S
[M]+ 381.0599, found 381.0590.
N-[4,5-Dimethyl-2-(phenylethynyl)phenyl]-4-methylbenzenesulfon-
amide (1d): M.p. 170–172 °C. 1H NMR (600 MHz, CDCl3): δ =
7.51 (d, J = 8.2 Hz, 2 H), 7.37–7.29 (m, 3 H), 7.25 (dd, J = 8.3,
2.3 Hz, 2 H), 7.07 (d, J = 21.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H),
6.36 (s, 1 H), 2.51 (s, 3 H), 2.29 (s, 3 H), 2.23 (s, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 143.58, 138.22, 137.17, 136.89,
133.11, 132.66, 131.62, 130.67, 129.51, 128.66, 128.34, 127.64,
122.76, 121.53, 93.89, 85.67, 21.58, 20.90, 19.63 ppm. HRMS:
calcd. for C23H21NO2S [M]+ 375.1300, found 375.1293.
N-{2-[(2-Chlorophenyl)ethynyl]phenyl}-4-methylbenzenesulfon-
1
amide (1e): M.p. 91–94 °C. H NMR (600 MHz, CDCl3): δ = 7.72
(d, J = 8.4 Hz, 2 H), 7.69 (d, J = 8.5 Hz, 2 H), 7.53–7.48 (m, 2 H),
7.40 (dd, J = 7.7, 1.5 Hz, 1 H), 7.36–7.32 (m, 1 H), 7.32–7.27 (m,
2 H), 7.17–7.14 (m, 2 H), 7.05 (td, J = 7.6, 1.1 Hz, 1 H), 2.32 (s, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 144.07, 138.48, 136.27,
135.93, 132.83, 131.83, 130.23, 130.07, 129.73, 129.49, 127.52,
126.89, 124.15, 122.35, 119.18, 113.39, 93.36, 89.42, 21.66 ppm.
HRMS: calcd. for C21H16ClNO2S [M]+ 381.0597, found 381.0590.
1
5,6-Dimethyl-2-phenyl-1-tosyl-1H-indole (2d): M.p. 146–150 °C. H
NMR (600 MHz, CDCl3): δ = 7.48 (dd, J = 7.8, 1.6 Hz, 2 H), 7.41–
7.34 (m, 3 H), 7.01 (s, 1 H), 6.97–6.90 (m, 5 H), 6.41 (s, 1 H), 2.81
(s, 3 H), 2.37 (s, 3 H), 2.30 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 146.10, 144.21, 139.15, 135.52, 134.64, 133.13, 132.89,
130.65, 129.99, 129.07, 128.51, 127.90, 127.42, 118.75, 116.69,
21.70, 21.57, 21.28 ppm. HRMS: calcd. for C23H21NO2S [M]+
375.1295, found 375.1293.
N-{2-[(4-Fluorophenyl)ethynyl]phenyl}-4-methylbenzenesulfonamide
1
(1h): H NMR (600 MHz, CDCl3): δ = 7.67 (d, J = 8.3 Hz, 1 H),
2-(2-Chlorophenyl)-1-tosyl-1H-indole (2e): M.p. 48–52 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.27 (d, J = 8.4 Hz, 1 H), 7.51 (d, J =
7.7 Hz, 1 H), 7.49–7.47 (m, 1 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.41–
7.31 (m, 4 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.11 (d, J = 8.2 Hz, 2 H),
6.63 (s, 1 H), 2.31 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ
= 144.84, 137.52, 137.35, 135.41, 135.20, 133.14, 131.74, 130.25,
129.96, 129.57, 127.10, 125.89, 125.13, 124.08, 121.14, 115.83,
113.90, 21.70 ppm. HRMS: calcd. for C21H16ClNO2S [M]+
381.0591, found 381.0590.
2-m-Tolyl-1-tosyl-1H-indole (2f):[9] 1H NMR (600 MHz, CDCl3): δ
= 8.30 (d, J = 8.4 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.37–7.33
(m, 1 H), 7.33–7.27 (m, 5 H), 7.26–7.22 (m, 2 H), 7.04 (d, J =
8.1 Hz, 2 H), 6.53 (s, 1 H), 2.42 (s, 3 H), 2.29 (s, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 144.60, 142.45, 138.39, 137.15,
134.93, 132.46, 131.19, 130.69, 129.57, 129.29, 127.57, 127.54,
127.00, 124.82, 124.38, 120.77, 116.76, 113.49, 21.66, 21.56 ppm.
7.61 (d, J = 8.2 Hz, 1 H), 7.47–7.42 (m, 1 H), 7.36 (dd, J = 7.7,
1.4 Hz, 1 H), 7.30 (td, J = 8.2, 1.5 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1
H), 7.16 (s, 1 H), 7.11–7.05 (m, 2 H), 2.35 (s, 2 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 163.09 (d, J = 251.3 Hz), 144.21 (s), 137.70
(s), 136.28 (s), 133.71 (d, J = 8.5 Hz), 132.16 (s), 129.83 (d, J =
15.3 Hz), 127.40 (s), 124.74 (s), 120.43 (s), 118.28 (s), 116.10 (d, J
= 22.2 Hz), 114.55 (s), 95.14 (s), 83.62 (s), 21.69 (s) ppm. HRMS:
calcd. for C21H16FNO2S [M]+ 365.0891, found 365.0886.
N-[5-Chloro-2-(hex-1-ynyl)phenyl]-4-methylbenzenesulfonamide
1
(1m): H NMR (600 MHz, CDCl3): δ = 7.69 (d, J = 8.3 Hz, 2 H),
7.59 (d, J = 2.0 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.21 (s, 1 H),
7.16 (d, J = 8.3 Hz, 1 H), 6.95 (dd, J = 8.3, 2.1 Hz, 1 H), 2.42 (t,
J = 7.1 Hz, 2 H), 2.39 (s, 3 H), 1.62–1.53 (m, 2 H), 1.51–1.40 (m,
2 H), 0.97 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 144.42, 138.74, 136.05, 134.67, 132.80, 129.88, 127.39, 124.44,
119.21, 113.14, 99.08, 74.66, 30.71, 22.22, 21.72, 19.37, 13.73 ppm.
HRMS: calcd. for C19H20ClNO2S [M]+ 361.0905, found 361.0903.
2-p-Tolyl-1-tosyl-1H-indole (2g):[9] 1H NMR (600 MHz, CDCl3): δ
General Procedure for Intramolecular Hydroamination Reaction: = 8.30 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 7.7 Hz, 1 H), 7.40 (d, J =
(for example 2a): Into a screw cap vial containing a telfon-coated
stirring bar was added 1a (0.0020 g, 0.0057 mmol) followed by a
solution of the catalyst D (1.0 mol-%) in dimethylformamide or
methanol (0.280 mL). The reaction mixture was allowed to stir at
room temperature for 12–28 h. Upon completion of reaction (TLC)
8.0 Hz, 2 H), 7.36–7.32 (m, 1 H), 7.30–7.26 (m, 4 H), 7.26–7.22 (m,
3 H), 7.04 (d, J = 8.2 Hz, 2 H), 6.51 (s, 1 H), 2.44 (s, 3 H), 2.28 (s, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 144.59, 142.46, 138.77,
138.37, 134.83, 130.81, 130.35, 129.70, 129.31, 128.41, 126.96,
124.76, 124.41, 120.72, 116.83, 113.42, 21.66, 21.59 ppm.
Eur. J. Org. Chem. 2014, 1622–1629
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1627

J. McNulty, K. Keskar
FULL PAPER
2-(4-Fluorophenyl)-1-tosyl-1H-indole (2h): M.p. 112–115 °C. 1H
NMR (600 MHz, CDCl3): δ = 8.31 (d, J = 8.4 Hz, 1 H), 7.48–7.42
7.6 Hz, 1 H), 7.17 (d, J = 8.3 Hz, 2 H), 6.95 (s, 1 H), 2.32 (s, 3 H),
0.46 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 144.48,
(m, 3 H), 7.39–7.33 (m, 1 H), 7.28 (d, J = 7.5 Hz, 1 H), 7.26–7.24 143.15, 138.71, 136.45, 130.93, 129.81, 126.56, 125.02, 123.31,
(m, 2 H), 7.11 (t, J = 8.7 Hz, 2 H), 7.05 (d, J = 8.2 Hz, 2 H), 6.52 121.74, 121.10, 114.24, 21.65, 0.71 ppm. HRMS: calcd. for
(s, 1 H), 2.29 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
163.24 (d, J = 248.9 Hz), 144.81, 141.07, 138.38, 134.86, 132.26 (d,
J = 8.1 Hz), 130.53, 129.42, 128.58, 126.88, 125.07, 124.53, 120.84,
116.78, 114.77 (d, J = 21.8 Hz), 113.74, 21.68 ppm. HRMS: calcd.
for C21H16FNO2S [M]+ 365.0884, found 365.0886.
Methyl 2-phenyl-1-tosyl-1H-indole-5-carboxylate (2i):[10] 1H NMR
(600 MHz, CDCl3): δ = 8.36 (d, J = 8.8 Hz, 1 H), 8.17 (d, J =
1.2 Hz, 1 H), 8.04 (dd, J = 8.8, 1.7 Hz, 1 H), 7.50–7.46 (m, 2 H),
7.46–7.45 (m, 1 H), 7.44–7.39 (m, 2 H), 7.27 (d, J = 8.3 Hz, 3 H),
7.05 (d, J = 8.0 Hz, 2 H), 6.60 (s, 1 H), 3.94 (s, 3 H), 2.30 (s, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.34, 145.09, 143.45,
140.95, 134.80, 131.97, 130.59, 130.32, 129.52, 129.12, 127.71,
126.95, 126.37, 126.03, 122.98, 116.32, 113.41, 52.31, 21.69 ppm.
(1-Tosyl-1H-indol-2-yl)methanol (2j):[11] 1H NMR (600 MHz,
CDCl3): δ = 8.05 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2 H),
7.48 (d, J = 7.7 Hz, 1 H), 7.32–7.28 (m, 1 H), 7.23 (t, J = 7.5 Hz,
1 H), 7.20 (d, J = 8.3 Hz, 2 H), 6.64 (s, 1 H), 4.91 (s, 2 H), 3.31
(br. s, 1 H), 2.33 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
145.25, 140.31, 137.09, 135.64, 130.06, 129.21, 126.51, 125.06,
123.83, 121.28, 114.45, 111.28, 58.67, 21.63 ppm.
6-Chloro-2-phenyl-1-tosyl-1H-indole (2k):[10] 1H NMR (600 MHz,
CDCl3): δ = 8.35 (d, J = 1.8 Hz, 1 H), 7.48–7.43 (m, 3 H), 7.43–
7.39 (m, 2 H), 7.36 (d, J = 8.3 Hz, 1 H), 7.28–7.23 (m, 3 H), 7.07
(d, J = 8.1 Hz, 2 H), 6.50 (s, 1 H), 2.31 (s, 4 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 145.02, 142.82, 138.74, 135.19, 134.76,
132.05, 130.77, 130.56, 129.52, 129.03, 127.69, 127.01, 125.03,
121.47, 116.87, 112.97, 21.71 ppm.
2-Butyl-1-tosyl-1H-indole (2l): 1H NMR (600 MHz, CDCl3): δ =
8.16 (d, J = 8.3 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.40 (d, J =
7.5 Hz, 1 H), 7.24 (dd, J = 8.3, 1.2 Hz, 1 H), 7.21–7.19 (m, 1 H),
7.18 (d, J = 8.2 Hz, 2 H), 6.38 (s, 1 H), 2.98 (t, J = 7.7 Hz, 2 H),
2.33 (s, 3 H), 1.73 (dt, J = 15.3, 7.6 Hz, 2 H), 1.48–1.40 (m, 2 H),
0.96 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
144.70, 142.69, 137.38, 136.45, 131.03, 129.91, 126.41, 123.90,
123.58, 120.16, 114.99, 108.74, 31.13, 28.88, 22.62, 21.68,
14.07 ppm.
2-Butyl-6-chloro-1-tosyl-1H-indole (2m):[9] M.p. 95–98 °C. 1H
NMR (600 MHz, CDCl3): δ = 8.21 (d, J = 1.7 Hz, 1 H), 7.62 (d,
J = 8.4 Hz, 2 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.21 (d, J = 8.2 Hz, 2
H), 7.18 (dd, J = 8.3, 1.8 Hz, 1 H), 6.34 (d, J = 0.6 Hz, 1 H), 2.95
(t, J = 7.4 Hz, 2 H), 2.35 (s, 3 H), 1.70 (dt, J = 15.3, 7.6 Hz, 2
H), 1.49–1.36 (m, 2 H), 0.95 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 145.08, 143.39, 137.67, 136.20, 130.08,
129.81, 128.43, 126.45, 124.16, 120.81, 115.14, 108.17, 30.96, 28.77,
22.58, 21.72, 14.04 ppm. HRMS: calcd. for C19H20ClNO2S [M]+
361.0893, found 361.0903.
5-Fluoro-2-phenyl-1-tosyl-1H-indole (2n): 1H NMR (600 MHz,
CDCl3): δ = 8.26 (dd, J = 8.9, 4.5 Hz, 1 H), 7.49 (dd, J = 7.8,
1.7 Hz, 2 H), 7.47–7.40 (m, 3 H), 7.24 (d, J = 8.4 Hz, 2 H), 7.11–
7.07 (m, 2 H), 7.05 (d, J = 8.5 Hz, 2 H), 6.50 (s, 1 H), 2.30 (s, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 160.34 (d, J =
240.9 Hz), 144.89, 144.13, 134.70, 134.52, 132.19, 131.82, 130.45,
129.41, 129.07, 127.72, 126.95, 118.03 (d, J = 9.3 Hz), 113.42,
112.70 (d, J = 25.1 Hz), 106.39 (d, J = 24.0 Hz), 21.69 (s) ppm.
C18H21NO2SSi [M]+ 343.1070, found 343.1062.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra for compounds 2a–2o,
photographs of heterogeneous and homogeneous hydroamination
reaction mixtures with and without silver metal deposition and ki-
netic data on the initial rate of reaction and calculation of order
with respect to catalyst concentration.
Acknowledgments
The authors thank Natural Sciences and Engineering Research
Council of Canada (NSERC) and Cytec Canada for financial sup-
port of this work.
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1-Tosyl-2-(trimethylsilyl)-1H-indole (2o): 1H NMR (600 MHz,
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1628
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Received: September 13, 2013
Published Online: January 23, 2014
Eur. J. Org. Chem. 2014, 1622–1629
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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