Facile synthesis of 2-arylmethylindoles and 2-vinylic indoles through palladium-catalyzed heteroannulations of 2-(2-propynyl)aniline and 2-(2-propynyl)tosylanilide

Article abstract of DOI:10.1039/c3ob41961d

A facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction of 2-(2-propynyl)aniline or 2-(2-propynyl) tosylanilide with aryl iodides in the presence of Pd(OAc)₂, PPh ₃, and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the presence of Pd(OAc)₂ and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic indoles which possess exclusive E-stereochemistry in the side chain double bond. Operational simplicity, compatibility of the various functional groups, and ease of product formation are the hallmarks of these methods. A mechanism has been proposed to explain the product formation.

Full text of DOI:10.1039/c3ob41961d

Volume 12 Number 5 7 February 2014 Pages 711–856
Organic &
Biomolecular
Chemistry
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ISSN 1477-0520
PAPER
Chinmay Chowdhury et al.
Facile synthesis of 2-arylmethylindoles and 2-vinylic indoles through
palladium-catalyzed heteroannulations of 2-(2-propynyl)aniline and
2-(2-propynyl)tosylanilide

Organic &
Biomolecular Chemistry
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PAPER
Facile synthesis of 2-arylmethylindoles and
2-vinylic indoles through palladium-catalyzed
heteroannulations of 2-(2-propynyl)aniline and
2-(2-propynyl)tosylanilide†‡
Cite this: Org. Biomol. Chem., 2014,
12, 741
Bimolendu Das, Priyanka Kundu and Chinmay Chowdhury*
A facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction
of 2-(2-propynyl)aniline or 2-(2-propynyl)tosylanilide with aryl iodides in the presence of Pd(OAc)2, PPh3,
and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the
presence of Pd(OAc)2 and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic
indoles which possess exclusive E-stereochemistry in the side chain double bond. Operational simplicity,
compatibility of the various functional groups, and ease of product formation are the hallmarks of these
methods. A mechanism has been proposed to explain the product formation.
Received 27th September 2013,
Accepted 26th November 2013
DOI: 10.1039/c3ob41961d
www.rsc.org/obc
luzindole8a (compound 1, Fig. 1), 2-(3-chlorobenzyl)-5-hydroxy-
1H-benzo[g]indole-3-carboxylate8b (compound 2, Fig. 1) and
Introduction
Indoles, prevalent in many natural products1a,b and pharma- 5-substituted 2-naphthylmethylindole8c (compound 3, Fig. 1)
ceuticals,1c are considered as one of the most important
heterocyclic motifs. This class of compounds is also recog-
nized as a privileged structure in medicinal chemistry.2
Because of their profound importance, intensive investigations
into the reactivity and the synthesis of indoles have been
carried out for more than a century and the interest is still
continuing. These studies have resulted in the development of
many conventional named and transition metal catalyzed reac-
tions for the synthesis of indoles over the years.3 However,
access to C2 functionalized indoles is relatively difficult compared
to C3 substituted indoles because of the higher nucleophilicity
at C3. Though C2 functionalizations of indoles are realized via
organometallations,4 the applications of this procedure have
been limited due to the low tolerance of the functional groups.
Alternatively, a number of efficient and mild methods for the
synthesis of C2 substituted indoles have been advanced pri-
marily by the use of palladium catalyzed heteroannulation of
2-alkynylanilines5 or by direct C–H activation6 of indoles.
However, synthetic methods7 for 2-arylmethylindoles, which
serve as core structures of potent bioactive agents like
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4,
Raja S. C. Mullick Road, Kolkata-700032, India. E-mail: chinmay@iicb.res.in
†This paper is dedicated to Dr Basudeb Achari, a former scientist of this
division.
‡Electronic supplementary information (ESI) available: Experimental procedures,
characterisation data and NMR spectra. CCDC 939088. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3ob41961d
Fig. 1 Some biologically important indole derivatives.
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and as useful synthons to access other heterocycles,8a,c,9 are which was supposed to react with electron-deficient olefins
limited in number. Additionally, the majority of these pro- leading to the formation of 2-vinylic indoles (Scheme 1b, path
cedures start with indole as a substrate and use multistep reac- B). As an extension of this study, we were therefore interested
tions,7a,c toxic reagents (i.e., organotin,7b PPA7d), or difficultly to explore the applicability of this methodology to synthesize
accessible intermediates.7e Therefore, the development of such molecules. Indeed the N-tosylated derivative 7b was
facile and straightforward methods for the direct synthesis of found to react with electron-withdrawing alkenes in place of
2-arylmethylindole starting from simple substrates continues aryl iodides 8 under palladium catalysis, resulting in the syn-
to be of considerable interest.
thesis of 2-vinylic indoles.
Among other useful 2-substituted indole derivatives, 2-
To the best of our knowledge, there is only one report19 in
vinylic indoles are used as valuable building blocks in the syn- which compound 7b undergoes Ru-catalyzed 6-endo-dig and
thesis of biologically active compounds comprising indole 5-exo-dig cyclizations affording N-tosyl-1,4-dihydroquinoline
alkaloids, carbazoles and carbolines.10 Besides, this structural and N-tosyl-2-methyl-indole, respectively, whereas there is no
motif is present as a key component in medicinally important report about the synthesis of indoles utilizing 7a as a sub-
compounds such as fluvastatin11a,b (compound 4, Fig. 1) and strate. This is the first report on the palladium-catalyzed cycli-
SB-242784 11c (compound 5, Fig. 1). A 2-vinyl indole moiety is zations (5-exo-dig) of 7a and 7b to synthesize 2-substituted
also found in many bioactive alkaloids including flinderoles12 indoles as described in Scheme 1b. Herein, we disclose the
(compounds 6, Fig. 1) having potent antimalarial activities. results obtained so far in these directions.
Though metal13a–e or acid13f,g catalyzed alkenations have prom-
ised to be appealing strategies for the direct functionalization
of indoles, these usually result in selective formation of the C3
alkenylated products. In contrast, methodologies for the
Results and discussion
At the outset, the reaction conditions were optimized by con-
ducting a series of reactions between 2-(2-propynyl)aniline (7a)
and methyl 4-iodobenzoate (8a) through variation of palladium
catalyst, base, temperature, solvent, etc. Selected results are
presented in Table 1. We employed our recently reported7g
reaction conditions [PdCl2/PPh3, K2CO3, TBAB, 85 °C] for the
synthesis of product 9a. This furnished the product, but only
to the extent of 25% (entry 1, Table 1). Replacement of K2CO3
by weaker bases (Et3N/i-Pr2NH) led to the isolation of product
9a with low (15–22%) yields (entries 2–3, Table 1). Though the
use of a stronger base like Cs2CO3 improved the yield of 9a to
specific C2 alkenylation of indoles have been restricted to few
reports.14 In the past, the syntheses were mainly achieved by
the Wittig reaction of 2-formyl indoles10b,15 along with some
other miscellaneous methods including the hetero-Cope
rearrangement.16 Therefore, the development of more efficient
reactions employing suitably designed building blocks,
whereby formation of indole and subsequent C2 alkenylation
takes place in one pot under mild reaction conditions, rep-
resents an attractive but difficult to realize option.10f,17
In continuation of our interest in palladium catalyzed reac-
tions,18 we recently reported7g a two-step approach for the syn-
thesis of 2-arylmethylindoles starting from 1-((2-tosylamino)-
phenyl)-prop-2-yn-1-ol (Scheme 1a). We speculated that if this
starting compound is replaced by 2-(2-propynyl)aniline (7a) or
the N-tosyl derivative 7b for reaction with aryl iodides 8 using
a palladium catalyst, the synthesis of 2-arylmethylindoles 9
can be realized in a single step (Scheme 1b, path A). The goal
was indeed realized through employment of the appropriate
palladium catalyst and other reaction conditions. This reaction
was expected to proceed via a vinyl palladium intermediate
Table 1 Optimization of reaction conditions for the synthesis of 9aa
Yieldsc (%)
Entry
Catalystb
Base
Time [h]
9a
9b
1d
2
PdCl2
PdCl2
PdCl2
PdCl2
K2CO3
Et3N
i-Pr2NH
Cs2CO3
DBU
DBU
DBU
0.75
4
7
0.25
1
0.75
12
25
15
22
51
84
85
0
0
65
0
10
5
3
0
3e
4d
5
PdCl2
6
Pd(OAc)2
Pd(OAc)2
Pd–C
7e, f
8
DBU
DBU
4
1.5
13
47
66
18
9
Pd(PPh3)4
a Reaction conditions: 7a (0.42 mmol), 8a (0.38 mmol), Pd-cat.
(5 mol%), PPh3 (22 mol%, except entry 9), base (0.76 mmol, 2 equiv.) in
dry DMF (5 mL). b PPh3 used as a co-catalyst for entries 1–8. c Isolated
compound. d Bu4NBr (10 mol%) used. e Acetylene 7a recovered 31% and
51% for entries 3 and 7, respectively. f Reaction was carried out at rt.
Scheme 1 Envisaged route for the synthesis of 2-substituted indoles in
one pot.
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Table 2 Synthesis of 2-arylmethylindoles 9a
51%, it also gave rise to the formation (10%) of the self
cyclized product of 7a (entry 4, Table 1). Pleasingly, the
employment of DBU significantly improved the yield of 9a to
84% (entry 5, Table 1). Replacing PdCl2 by Pd(OAc)2 provided a
comparable yield (85%), while the time period was reduced to
45 min only (entry 6, Table 1). In contrast, when this reaction
was carried out at rt (30 °C), no formation of 9a was observed
(entry 7, Table 1). Further, replacement of the catalyst by Pd/C
dropped the yield of 9a to 13% and produced the side product
10a predominantly (entry 8, Table 1), while the use of
Pd(PPh3)4 afforded (Table 1, entry 9) 9a with moderate yield
(47%) in addition to product 10a (18%). Even the use of the
“Sonogashira catalyst” [Pd(PPh3)2Cl2 and CuI] and Et3N (base)
failed to effect the formation of 9a or C-arylation at the termi-
nal acetylene of 7a, except for giving rise to an uncharacter-
ized compound to a small extent. Among the solvents tested,
DMF was found to be superior compared to others (results not
shown). Thus, the reaction conditions of entry 6 of Table 1
were considered for further exploration.
Entryb Acetylene 7 Iodide 8; Ar =
Time [h] Yieldc (%) 9
1
2
3
4
5
7a
7a
7a
7a
7a
0.75
2.0
9a (85)
9b (55)
9c (79)
9d (69)
9e (49)
1.25
1.25
1.25
Using the optimized reaction conditions, we then extended
the scope of the procedure to the acetylenic substrates 7a–b
and a range of iodides 8a–j (Table 2). To our delight, iodides
8b–e possessing different electron withdrawing groups (F, CF3,
Br, and NO2) were found to react smoothly with 7a and afford
the corresponding indole derivatives 9b–e with moderate to
good yields (Table 2, entries 2–5). Furthermore, unsubstituted
aryl and heteroaryl iodides (8f and 8g–h) could also participate
in this reaction, leading to the products 9f and 9g–h, respect-
ively, with good yields (Table 2, entries 6–8). However, when
iodide 8i having an electron donating group (OMe) was
employed as a coupling agent, only tar formation was
observed. Gratifyingly, employment of the tosylated substrate
7b solved the problem, yielding the targeted product 9i albeit
in moderate (58%) yield (Table 2, entry 9). Substrate 7b was
also found to undergo reactions with other iodides (8a, 8j) pos-
sessing an electron-withdrawing or electron-donating group,
furnishing the expected product in good yields (Table 2,
entries 10 and 11). To our surprise, no trace of any 2-aryl-
methylidene-indoline (intermediate D of Scheme 2, vide infra)
product, the precursor intermediate of product 9, was observed
in any case unlike our previous study.7g
6
7
7a
7a
0.75
1.5
9f (62)
9g (60)
8
7a
1.5
9h (71)
9
7b
7b
7b
0.75
0.75
1.0
9i (58)
9j (70)
9k (64)
10
11
a Reaction conditions: 7 (0.42 mmol), 8 (0.38 mmol), Pd(OAc)2 (5 mol%),
PPh3 (22 mol%), DBU (0.76 mmol, 2 equiv.) in dry DMF (5 mL) under
argon at 85 °C. b For entries 1–8, a self-cyclized product of 7a was
obtained in 1–3% yield, whereas a self-cyclized product of 7b was
formed in 20%, 15%, 17% yield for entries 9, 10, 11, respectively.
c Isolated product.
The structures of products 9 were determined by spectro-
scopic (1H and 13C NMR, IR and Mass) and analytical data
(vide experimental). In addition, the structure of product 9c
was also confirmed by X-ray diffraction analysis (for details,
see ESI†).
Based on our observation and known palladium chemistry,
we propose a plausible reaction mechanism to explain the
product formation (Scheme 2). In the first step, Pd(0) gener-
20
ated in situ from the reaction of Pd(OAc)2 and PPh3 under-
goes oxidative addition with aryl iodide 8 resulting in the
formation of the species ArPdIII (A). Species A acting like a
Lewis acid then activates the triple bond of the acetylenic sub-
strate 7, thereby triggering an intramolecular nucleophilic
attack by the proximal amine group (as shown in species B) to
form the trans-amino palladated21 intermediate C. Finally, Scheme 2 Plausible mechanism for the formation of products 9.
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reductive elimination of palladium from species C regenerates vinyl moiety conjugated with the carbonyl group, furnishing
Pd(0) and concurrently produces a transient intermediate D22 the product 12i with 58% yield (entry 9, Table 3). As can be
which immediately undergoes in situ rearrangement via a seen from Table 3, the reaction works with a variety of alkenes
1,3-hydrogen shift to furnish product 9.
containing ester, amide, nitrile, and sulfone moieties under
After scrutinizing the reactivity of alkynes 7a–b toward aryl the reaction conditions. Exclusive E-stereoselectivity in the
iodide 8, we became interested to replace the latter by an elec- vinylic group of products 12 was observed consistently;
tron-deficient alkene 11, which might participate in the palla- besides, the reactions are highly atom economic in nature.
dium-catalyzed cascade heterocyclization/Heck-type coupling However, despite numerous attempts, amine 7a did not react
reactions23 with alkyne 7, resulting in the formation of 2-vinyl- with any of the alkenes; among the alkene substrates, the elec-
indoles 12 in one pot. Toward this endeavor, experiments tron-rich ones failed to react with either 7a or 7b. This obser-
were carried out with variation of the reaction parameters such vation is in accordance with the literature reports25 that
as catalyst, oxidant, solvent, temperature, etc. for the model amines linked to electron withdrawing substituents and elec-
conversion of 4-[N-(tosyl)-indol-2-yl]-but-3-enoic acid methyl tron-deficient alkenes are preferred reactants in these types of
ester (12a), a product produced by reacting acetylene 7b with cascade reactions.
methyl acrylate (11a). Gratifyingly, we succeeded in developing
The structures of the products 12 were characterized by
an optimized reaction condition employing 10 mol% Pd(OAc)2 spectroscopic (NMR, IR, Mass) and analytical data (vide
and 2 equiv. of NaI in dry THF under oxygen pressure experimental).
(balloon);24 this afforded the desired product 12a in 60% yield
The outcome of this reaction may be rationalized by a
(Table 3, entry 1). We then decided to explore the scope of the plausible reaction mechanism (Scheme 3). Initially the palla-
reaction with variation in electron-deficient alkenes 11 dium reagent [likely to be PdI2 formed in situ from Pd(OAc)2
(Table 3). Employment of alkene 11b having a bulky cyclohexyl and NaI], acting like a Lewis acid, activates the triple bond (in
group in the ester moiety led to the formation of product 12b species A′), which subsequently undergoes intramolecular
(Table 3, entry 2) with moderate yield (43%). The yield went nucleophilic attack by the neighboring nitrogen of the sulpho-
down further to 34% when benzyl acrylate 11c was submitted namide group via a trans-aminopalladation21 pathway to form
to this reaction (Table 3, entry 3). In contrast, the acrylamides a vinyl-palladium species B′. The insertion of alkene 11 into
11d, 11e and 11f proved quite effective in this reaction species B′ thereafter results in the formation of intermediate
affording (Table 3, entries 4, 5 and 6) the corresponding pro- C′.23,25b,26 However, unlike the reported25a,c protonolysis of the
ducts 12d, 12e and 12f in good yields (60–62%). Even acrylo- carbon–palladium bond of intermediate species C′ in the pres-
nitrile (11g) reacted with equal ease to yield (63%) the ence of excess halide, β-hydride elimination (–HPdX) preferen-
corresponding product 12g (Table 3, entry 7), but vinyl sulfone tially takes place in the present case generating the plausible
11h furnished the corresponding product 12h in only moder- intermediate product D′, which is immediately converted into
ate yield (Table 3, entry 8). Interestingly, when acrylate 11i the stable product 12 via isomerization to a conjugated aro-
having a pendant allyl group was used as the reaction partner, matic system.27 The HPdX species generated may then be con-
the acetylene 7b was found to react chemoselectively with the verted via extrusion of HX to Pd(0), which is likely reconverted
by oxygen to the active catalytic species Pd(II).23a,28 Alterna-
tively, Pd(0) to Pd(II) oxidation to give PdI2 may be promoted
by I2 which is formed in situ from the oxidation of an iodide
Table 3 Synthesis of 2-vinylic indoles 12a
ion under an oxygen atmosphere.29
Entry
Alkene 11; EWG =
Time (h)
12b
Yieldc (%)
1
2
3
4
5
6
7
8
9
11a; CO2Me
11b; CO2cyclohexyl
11c; CO2Bn
16
17
22
17
20
17
18
22
24
12a
12b
12c
12d
12e
12f
12g
12h
12i
60
43
34
60
62
62
63
38
58
11d; CONH2
11e; CONMe2
11f; CO-morpholinyl
11g; CN
11h; SO2Me
11i; CO2(CH2)2CO2allyl
a Reaction conditions: 7b (0.35 mmol), 11 (2.10 mmol), Pd(OAc)2
(10 mol%) and NaI (2 equiv.) in dry THF (5 mL) under oxygen pressure
(balloon) at rt. b No other significant side product was observed,
indicating the propensity of starting materials to undergo substantial
degradation under the reaction conditions. c Isolated product.
Scheme 3 Plausible mechanism for the synthesis of products 12.
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2-(4-(Trifluoromethyl)benzyl)-1H-indole (9c). Brown solid
Conclusion
(82.6 mg, 79% yield); mp 72 °C; IR (KBr) 3386, 3060, 1616,
In conclusion, we have succeeded in developing an efficient 1456, 1417, 1326, 1298, 1172, 1107, 1066 cm−1 1H NMR
;
and facile method for the general synthesis of 2-arylmethyl- (CDCl3, 300 MHz) δH 7.78 (brs, 1H), 7.58–7.54 (m, 3H), 7.36 (d,
indoles 9 via palladium-catalyzed cyclocondensation of aryl J = 7.8 Hz, 2H), 7.28–7.25 (m, 1H), 7.16–7.05 (m, 2H), 6.32 (d,
iodides with 2-(2-propynyl)aniline or 2-(2-propynyl)tosylani- J = 1.2 Hz, 1H), 4.18 (s, 2H); 13C NMR (CDCl3, 75 MHz)
lide. 2-(2-Propynyl)tosylanilide reacted successfully even with δC 142.6, 136.5, 136.3, 129.1, 128.5, 126.0, 122.4, 125.6 (q, J =
electron deficient alkenes at room temperature in the presence 3.7 Hz), 121.7, 120.1, 119.9, 110.6, 101.6, 34.5; HRMS (EI+)
of Pd(OAc)2 and sodium iodide under oxygen, providing easy calcd for C16H12F3N [M]+ 275.09218, found 275.09052.
access to 2-vinylic indoles 12 displaying exclusive E-stereo-
2-(4-Bromobenzyl)-1H-indole (9d).7d Pale yellow solid
chemistry in the side chain double bond. This reaction proto- (75.0 mg, 69% yield); mp 130–132 °C; 1H NMR (CDCl3,
col is highly atom economic in nature. All the reactions 300 MHz) δH 7.74 (brs, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.43 (d, J =
proceeded through selective 5-exo-dig cyclizations of the acety- 8.1 Hz, 2H), 7.25–7.23 (m, 1H), 7.14–7.05 (m, 4H), 6.29 (s, 1H),
lenic substrates. Operational simplicity, compatibility with 4.06 (s, 2H); 13C NMR (CDCl3, 75 MHz) δC 137.5, 137.0, 136.2,
various functional groups, and ease of product formation are 131.7, 130.5, 128.5, 121.5, 120.6, 120.0, 119.8, 110.5, 101.3,
the hallmarks of the methods. We believe that this straightfor- 34.1; HRMS (EI+) calcd for C15H12BrN [M]+ 285.01531, found
ward and flexible synthetic approach has the potential to be 285.01370.
useful in organic and medicinal chemistry as well.
2-(2-Methyl-4-nitrobenzyl)-1H-indole (9e). Orange solid
(49.5 mg, 49% yield); mp 104–106 °C; IR (KBr) 3411,
1539, 1519, 1508, 1454 cm−1 1H NMR (CDCl3, 300 MHz)
;
δH 8.06–7.99 (m, 2H), 7.81 (brs, 1H), 7.52 (d, J = 7.5 Hz, 1H),
7.31–7.25 (m, 2H), 7.17–7.06 (m, 2H), 6.21 (d, J = 1.2 Hz, 1H),
4.18 (s, 2H), 2.40 (s, 3H); 13C NMR (CDCl3, 75 MHz) δC 146.8,
Experimental section
General procedure for the synthesis of 2-arylmethylindoles 9
A mixture of Pd(OAc)2 (4.2 mg, 0.019 mmol, 5 mol%) and PPh3 144.3, 138.5, 136.2, 135.0, 130.1, 128.5, 125.1, 121.7, 121.3,
(21.7 mg, 0.083 mmol, 22 mol%) in dry DMF (5 mL) was 120.1, 120.0, 110.53, 101.8, 32.5, 19.6; HRMS (EI+) calcd for
stirred at room temperature for 5 min under an argon atmos- C16H14N2O2 [M]+ 266.10553, found 266.10468.
phere. Aryl iodide 8 (0.38 mmol) and DBU (113 µL, 0.76 mmol)
2-Benzyl-1H-indole (9f).7f Colorless solid (48.8 mg, 62%
1
were successively added to the reaction mixture which was yield); mp 78–79 °C; H NMR (CDCl3, 300 MHz) δH 7.78 (brs,
stirred for another 5 min at rt. Acetylene 7 (0.42 mmol) in dry 1H), 7.56–7.53 (m, 1H), 7.35–7.31 (m, 2H), 7.27–7.24 (m, 4H),
DMF (2 mL) was added slowly to the reaction mixture at 85 °C 7.14–7.04 (m, 2H), 6.33 (s, 1H), 4.14 (s, 2H); 13C NMR (CDCl3,
over a period of 30 min and heating was then continued until 75 MHz) δC 138.5, 137.8, 136.2, 128.8, 128.7, 126.7, 121.3,
completion of the reaction (TLC). The solvent was removed 120.0, 119.7, 110.4, 101.1, 34.7; HRMS (EI+) calcd for
in vacuo; the residue was mixed with water (10 mL) and then C15H13N [M]+ 207.10480, found 207.10410.
extracted with ethyl acetate (3 × 20 mL). The combined organic
2-(Thiophen-2-ylmethyl)-1H-indole (9g). Green solid (48.6 mg,
1
extracts were washed with brine (10 mL), dried over anhydrous 60% yield); mp 70–78 °C; H NMR (CDCl3, 300 MHz) δH 7.90
Na2SO4, filtered, and concentrated under reduced pressure. (brs, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.29–7.26 (m, 1H), 7.20 (d,
The resulting crude product was purified through silica J = 4.8 Hz, 1H), 7.15–7.05 (m, 2H), 6.98–6.92 (m, 2H), 6.37 (s,
gel (100–200 mesh) column chromatography (ethyl acetate– 1H), 4.34 (s, 2H); 13C NMR (CDCl3, 75 MHz) δC 141.0, 136.8,
petroleum ether) to afford the pure product 9.
136.2, 128.6, 127.0, 125.8, 124.5, 121.5, 120.1, 119.8, 110.6,
2-(4-Carbomethoxybenzyl)-1H-indole (9a). Light brown solid 100.8, 28.9; HRMS (EI+) calcd for C13H11NS [M]+ 213.06122,
(85.6 mg, 85% yield); mp 100–102 °C; IR (KBr) 3067, 2958, found 213.05945.
2913, 1595, 1494, 1448, 1370, 1264, 1174, 1142, 1143, 1091,
2-(Pyridin-3-ylmethyl)-1H-indole (9h). Brown crystalline
1048 cm−1; H NMR (CDCl3, 300 MHz) δH 7.98 (d, J = 8.1 Hz, solid (56.1 mg, 71% yield); mp 140–142 °C; IR (KBr) 3071,
2H), 7.82 (brs, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1577, 1454, 1440, 1422 cm−1 1H NMR (CDCl3, 600 MHz)
1
;
2H), 7.27–7.25 (m, 1H), 7.15–7.05 (m, 2 H), 6.32 (s, 1H), 4.17 δH 8.53 (d, J = 1.2 Hz, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.11 (brs,
(s, 2H), 3.90 (s, 3H); 13C NMR (CDCl3, 75 MHz) δC 167.0, 143.9, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.28–7.22 (m, 2H), 7.13 (td, J =
136.7, 136.4, 130.0, 128.8, 128.7, 128.6, 121.6, 120.1, 119.9, 7.5, 1.2 Hz, 1H), 7.09–7.07 (m, 1H), 6.31 (d, J = 1.2 Hz, 1H),
110.6, 101.6, 52.1, 34.7; HRMS (EI+): Calcd for C17H15NO2 [M]+ 4.12 (s, 2H); 13C NMR (CDCl3, 75 MHz) δC 149.6, 147.9, 136.6,
265.11028, found 265.10910.
134.5, 128.4, 123.7, 121.5, 120.0, 119.7, 110.6, 101.4, 31.9;
2-(4-Fluorobenzyl)-1H-indole (9b).17b Reddish brown solid HRMS (EI+) calcd for C14H12N2 [M]+ 208.10005, found
(47.0 mg, 55% yield); mp 80–82 °C; 1H NMR (CDCl3, 300 MHz) 208.09720.
δH 7.75 (brs, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.25–6.97 (m, 7H),
6.29 (s, 1H), 4.09 (s, 2H); 13C NMR (CDCl3, 75 MHz) δC 161.7 solid (86.2 mg, 58% yield); mp 108–110 °C; IR (KBr) 2934,
(d, J = 243 Hz), 137.5, 136.2, 134.2, 130.2 (d, J = 7.5 Hz), 128.6, 1610, 1511, 1451, 1367 cm−1 1H NMR (CDCl3, 300 MHz)
2-(4-Methoxybenzyl)-1-tosyl-1H-indole (9i). Light yellow
;
121.4, 120.0, 119.8, 115.5 (d, J = 21 Hz), 110.5, 101.2, 33.9; HRMS δH 8.15 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.35
(EI+) calcd for C15H12FN [M]+ 225.09538, found 225.09486.
(d, J = 7.8 Hz, 1H), 7.28–7.20 (m, 2H), 7.17–7.11 (m, 4H), 6.83
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(d, J = 8.7 Hz, 2H), 6.08 (s, 1H), 4.28 (s, 2H), 3.80 (s, 3H), 2.33 129.6, 126.7, 126.6, 124.6, 123.9, 123.8, 120.6, 115.1, 108.9,
(s, 3H); 13C NMR (CDCl3, 75 MHz) δC 158.4, 144.6, 141.6, 73.2, 38.7, 31.6, 25.4, 23.8, 21.5; HRMS (EI+) calcd for
137.2, 136.1, 130.4, 130.0, 129.7, 129.4, 126.3, 124.0, 123.4, C25H27NO4S [M]+ 437.16608, found 437.16599.
120.2, 114.6, 113.8, 110.7, 55.3, 34.4, 21.5; HRMS (EI+) calcd
for C23H21NO3S [M]+ 391.12421, found 391.12415.
(E)-Benzyl 4-(1-tosyl-1H-indol-2-yl)but-3-enoate (12c). Light
yellow amorphous solid (53.0 mg, 34% yield); 1H NMR (CDCl3,
2-(4-Carbomethoxybenzyl)-1-tosyl-1H-indole (9j). Light green 300 MHz) δH 8.17 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H),
solid (111.5 mg, 70% yield); mp 56–58 °C; IR (KBr) 2949, 1720, 7.42–7.35 (m, 6H), 7.30–7.15 (m, 3H), 7.09 (d, J = 8.1 Hz, 2H),
1604, 1444, 1368, 1280 cm−1 1H NMR (CDCl3, 300 MHz) 6.66 (s, 1H), 6.24 (dt, J = 15.3, 7.2 Hz, 1H), 5.19 (s, 2H),
;
δH 8.16 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.51 (d, 3.40–3.38 (m, 2H), 2.28 (s, 3H); 13C NMR (CDCl3, 75 MHz)
J = 8.1 Hz, 2H), 7.38 (d, J = 7.5 Hz, 1H), 7.30–7.18 (m, 4H), 7.12 δC 171.0, 144.7, 138.7, 137.1, 135.7, 135.2, 129.9, 129.6, 128.6,
(d, J = 8.1 Hz, 2H), 6.25 (s, 1H), 4.41 (s, 2H), 3.92 (s, 3H), 2.32 128.3, 128.2, 126.7, 126.6, 126.3, 125.9, 124.6, 124.4, 123.9,
(s, 3H); 13C NMR (CDCl3, 75 MHz) δC 166.9, 144.7, 143.4, 120.6, 115.1, 109.0, 66.7, 38.2, 21.5; HRMS (EI+) calcd for
139.5, 137.2, 135.9, 129.7, 129.2, 128.5, 126.2, 124.3, 123.5, C26H23NO4S [M]+ 445.13478, found 445.13467.
120.3, 114.7, 111.2, 52.0, 35.1, 21.5; HRMS (EI+) calcd for
C24H21NO4S [M]+ 419.11913, found 419.11908.
(E)-4-(1-Tosyl-1H-indol-2-yl)but-3-enamide (12d). Brown solid
(74.4 mg, 60% yield); mp 72–74 °C; IR (KBr) 3446, 1668,
2-(2,4-Dimethoxypyrimidin-5-yl)methyl-1-tosyl-1H-indole 1366 cm−1; H NMR (CDCl3, 300 MHz) δH 8.14 (d, J = 8.1 Hz,
(9k).7g Brown amorphous solid (102.9 mg, 64% yield); 1H NMR 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.31–7.21
(CDCl3, 300 MHz) δH 8.15 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.66 (m, 2H), 7.17–7.05 (m, 3H), 6.68 (s, 1H), 6.31–6.21 (m, 1H),
(d, J = 8.1 Hz, 2H), 7. 34 (d, J = 7.8 Hz, 1H), 7.29–7.16 (m, 4H), 5.80 (brs, 1H), 5.44 (brs, 1H), 3.26 (d, J = 6.6 Hz, 2H), 2.31 (s,
6.05 (s, 1H), 4.21 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H), 2.34 (s, 3H); 3H); 13C NMR (CDCl3, 75 MHz) δC 173.0, 144.9, 138.4, 137.0,
13C NMR (CDCl3, 150 MHz) δC 169.3, 164.7, 158.1, 144.7, 135.1, 129.8, 129.7, 127.0, 126.5, 124.8, 124.7, 123.9, 120.7,
139.0, 137.3, 136.1, 129.8, 129.3, 126.4, 124.2, 120.3, 123.6, 115.0, 109.2, 40.0, 21.4; HRMS (EI+) calcd for C19H18N2O3S
1
114.7, 111.7, 110.2, 54.8, 54.0, 26.2, 21.6.
[M]+ 354.10381, found 354.10376.
(E)-N,N-Dimethyl-4-(1-tosyl-1H-indol-2-yl)but-3-enamide
(12e). Yellow solid (82.9 mg, 62% yield); mp 110–112 °C; IR
General procedure for the synthesis of 2-vinylic indoles 12
;
To a well-stirred solution of Pd(OAc)2 (7.8 mg, 0.035 mmol, (KBr) 1639, 1595, 1546, 1494, 1396, 1363 cm−1 1H NMR
10 mol%) and NaI (104.3 mg, 0.70 mmol) in dry THF (6 mL) (CDCl3, 300 MHz) δH 8.14 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.1
were added successively alkene 11 (2.10 mmol) and acetylene Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.28–7.21 (m, 2H), 7.19–7.09
7b (100 mg, 0.35 mmol) and the reaction mixture was (m, 3H), 6.69 (s, 1H), 6.36–6.31 (m, 1H), 3.39 (dd, J = 6.9, 0.9
allowed to stir at room temperature under oxygen pressure Hz, 2H), 3.10 (s, 3H), 3.01 (s, 3H), 2.30 (s, 3H); 13C NMR
(balloon). After completion of the reaction (TLC), the solvent (CDCl3, 75 MHz) δC 170.4, 144.7, 138.9, 136.9, 135.2, 130.0,
was removed in vacuo; the residue was mixed with water 129.6, 127.9, 126.6, 124.5, 123.8, 123.2, 120.6, 115.0, 108.9,
(10 mL) and then extracted with ethyl acetate (3 × 20 mL). The 37.9, 37.4, 35.5, 21.5; HRMS (EI+) calcd for C21H22N2O3S [M]+
combined organic extracts were washed with brine (10 mL), 382.13511, found 382.13528.
dried over anhydrous Na2SO4, filtered, and concentrated under
(E)-1-Morpholino-4-(1-tosyl-1H-indol-2-yl)but-3-en-1-one (12f).
reduced pressure. The resulting residue was purified through Yellow amorphous solid (92.1 mg, 62% yield); 1H NMR (CDCl3,
silica gel (100–200 mesh) column chromatography (ethyl 500 MHz) δH 8.12 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H),
acetate–petroleum ether) to afford pure product 12.
7.40 (d, J = 7.5 Hz, 1H), 7.27–7.24 (m, 1H), 7.19 (t, J = 7.5 Hz,
(E)-Methyl-4-(1-tosyl-1H-indol-2-yl)but-3-enoate (12a). Light 1H), 7.15–7.11 (m, 3H), 6.69 (s, 1H), 6.31 (dt, J = 15.0, 6.5 Hz,
yellow solid (77.5 mg, 60% yield); mp 66–68 °C; IR (KBr) 2951, 1H), 3.70 (t, J = 4.5 Hz, 4H), 3.67–3.66 (m, 2H), 3.55 (t, J =
1737, 1595, 1443, 1369 cm−1 1H NMR (CDCl3, 300 MHz) 4.5 Hz, 2H), 3.38 (d, J = 6.5 Hz, 2H), 2.30 (s, 3H); 13C NMR
;
δH 8.17 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.41 (d, (CDCl3, 125 MHz) δC 169.1, 144.8, 138.8, 137.0, 135.3, 129.9,
J = 7.5 Hz, 1H), 7.30–7.17 (m, 3H), 7.14 (d, J = 7.8 Hz, 2H), 6.68 129.7, 127.2, 126.6, 124.6, 123.9, 123.7, 120.6, 115.1, 109.0,
(s, 1H), 6.22 (dt, J = 15.6, 7.2 Hz, 1H), 3.75 (s, 3H), 3.34 (dd, J = 66.8, 66.6, 46.2, 42.1, 37.7, 21.5; HRMS (EI+) calcd for
7.2, 1.5 Hz, 2H), 2.30 (s, 3H); 13C NMR (CDCl3, 75 MHz) C23H24N2O4S [M]+ 424.14568, found 424.14581.
δC 171.6, 144.7, 138.7, 137.1, 135.3, 129.9, 129.6, 126.7, 126.0,
124.6, 124.2, 123.9, 120.6, 115.1, 109.0, 52.0, 38.0, 21.5; HRMS solid (74.1 mg, 63% yield); mp 62–64 °C; IR (KBr) 3067, 2924,
(EI+) calcd for C20H19NO4S [M]+ 369.10348, found 369.10333. 2251, 1596, 1493, 1370 cm−1 1H NMR (CDCl3, 600 MHz) δH
(E)-4-(1-Tosyl-1H-indol-2-yl)but-3-enenitrile
(12g). Brown
;
(E)-Cyclohexyl 4-(1-tosyl-1H-indol-2-yl)but-3-enoate (12b). 8.19 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.8
Light brown amorphous solid (65.8 mg, 43% yield); 1H NMR Hz, 1H), 7.36 (d, J = 15.6 Hz, 1H), 7.33–7.30 (m, 1H), 7.23 (t, J =
(CDCl3, 300 MHz) δH 8.19 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 6.69 (s, 1H), 5.99 (dt, J =
8.1 Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.32–7.20 (m, 3H), 7.16 16.2, 6.0 Hz, 1H), 3.35 (dd, J = 6.0, 1.8 Hz, 2H), 2.32 (s, 3H);
(d, J = 7.8 Hz, 2H), 6.69 (s, 1H), 6.31–6.20 (m, 1H), 4.87–4.80 13C NMR (CDCl3, 150 MHz) δC 145.0, 137.2, 137.1, 135.3,
(m, 1H), 3.33 (d, J = 6.6 Hz, 2H), 2.32 (s, 3H), 1.92–1.84 129.8, 129.5, 126.5, 125.9, 125.2, 124.0, 120.9, 120.7, 116.9,
(m, 2H), 1.79–1.75 (m, 2H), 1.63–1.24 (m, 6H); 13C NMR 115.0, 109.6, 21.5, 20.9; HRMS (EI+) calcd for C19H16N2O2S
(CDCl3, 75 MHz) δC 170.6, 144.7, 138.9, 137.1, 135.3, 129.9, [M]+ 336.09325, found 336.09311.
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(E)-2-[3-(Methylsulfonyl)prop-1-enyl]-1-tosyl-1H-indole (12h).
Brown solid (51.8 mg, 38% yield); mp 96–98 °C; IR (KBr) 1625,
4406; (d) L. Ackermann, Org. Lett., 2005, 7, 439;
(e) B. Gabriele, R. Mancuso, G. Salerno, E. Lupinacci,
G. Ruffolo and M. Costa, J. Org. Chem., 2008, 73, 4971;
(f) B. Gabriele, L. Veltri, G. Salerno, R. Mancuso and
M. Costa, Adv. Synth. Catal., 2010, 352, 3355;
(g) B. Gabriele, L. Veltri, R. Mancuso, G. Salerno and
M. Costa, Eur. J. Org. Chem., 2012, 2549.
1369, 1299, 1174, 1131 cm−1 1H NMR (CDCl3, 600 MHz)
;
δH 8.14 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.45 (d, J =
7.2 Hz, 1H), 7.41 (d, J = 15.6 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
7.24–7.21 (m, 1H), 7.16 (d, J = 7.8 Hz, 2H), 6.79 (s, 1H),
6.26–6.21 (m, 1H), 3.95 (d, J = 7.2 Hz, 2H), 2.97 (s, 3H), 2.31 (s,
3H); 13C NMR (CDCl3, 75 MHz) δC 145.1, 137.3, 137.1, 134.9,
129.8, 129.7, 129.6, 126.5, 125.4, 124.2, 121.1, 119.2, 115.1,
110.6, 58.8, 39.6, 21.5; HRMS (EI+) calcd for C19H19NO4S2 [M]+
389.07555, found 389.07565.
6 (a) See a review article: L. Joucla and L. Djakovitch, Adv.
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(E)-3-(Allyloxy)-3-oxopropyl 4-(1-tosyl-1H-indol-2-yl)but-3-
enoate (12i). Light brown amorphous solid (94.9 mg, 58%
1
yield); H NMR (CDCl3, 600 MHz) δH 8.16 (d, J = 8.4 Hz, 1H),
7.62 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.29–7.26 (m,
1H), 7.21–7.17 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H),
6.20 (dt, J = 15.6, 7.2 Hz, 1H), 5.93–5.88 (m, 1H), 5.31 (dd, J =
17.4, 1.5 Hz, 1H), 5.23 (dd, J = 10.6, 0.9 Hz, 1H), 4.62 (d, J =
5.4 Hz, 2H), 4.44 (t, J = 6.3 Hz, 2H), 3.33 (dd, J = 7.2, 1.2 Hz,
2H), 2.73 (t, J = 6.3 Hz, 2H), 2.30 (s, 3H); 13C NMR (CDCl3,
150 MHz) δC 170.9, 170.2, 144.7, 138.6, 137.1, 135.3, 131.8,
129.9, 129.6, 126.6, 125.7, 124.6, 124.3, 123.8, 120.6, 118.5,
115.1, 109.0, 65.5, 60.2, 37.9, 33.8, 21.5; MS (ESI+) m/z 490.07
[M + Na]+. Anal. Calcd for C25H25NO6S: C, 64.22; H, 5.39;
N, 3.00. Found: C, 64.24; H, 5.42; N, 3.02.
Acknowledgements
B.D. thanks CSIR, New Delhi, India, for a fellowship. Financial
support from the CSIR network project (CSC0108) is gratefully
acknowledged.
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Paper
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M. Kaneko and T. Sakamoto, Heterocycles, 1998, 48, 1793;
Scheme 2) which after reductive elimination of palladium
generates the (Z)-isomer of D. Finally, this newly formed
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immediately to afford the stable product 9.
(f) G. Fridkin, N. Boutard and W. D. Lubell, J. Org. Chem.,
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15 M. Eitel and U. Pindur, Synthesis, 1989, 364 and references 24 The additive sodium iodide was essential for this reaction
cited therein.
and it was found to be the best among various metal
halides screened; omission of NaI from the reaction led to
the isolation of only the self-cyclized product with substrate
7b. Furthermore, carrying out the reaction of 7b and 11a
(entry 1 of Table 3) in open air in place of oxygen balloon
resulted in 20% yield of product 12a, underlining the
importance of oxygen atmosphere for this reaction.
16 T. Balasubramanian and K. K. Balasubramanian, J. Chem.
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18 For selected examples, see: (a) C. Chowdhury, 25 (a) A. Lei and X. Lu, Org. Lett., 2000, 2, 2699;
S. Mukherjee, B. Das and B. Achari, J. Org. Chem., 2009, 74,
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B. Achari, Org. Biomol. Chem., 2011, 9, 5856; (c) K. Brahma,
(b) A. Yasuhara, Y. Takeda, N. Suzuki and T. Sakamoto,
Chem. Pharm. Bull., 2002, 50, 235; (c) Z. Shen and X. Lu,
Tetrahedron, 2006, 62, 10896.
A. Sasmal and C. Chowdhury, Org. Biomol. Chem., 2011, 9, 26 See a review article: X. Lu, Top. Catal., 2005, 35, 73.
8422; (d) K. Brahma, B. Achari and C. Chowdhury, Syn- 27 The anion formed by loss of the benzylic proton is stabil-
thesis, 2013, 545.
19 A. Varela-Fernandez, J. A. Varela and C. Saa, Adv. Synth.
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20 C. Amatore, A. Jutand and M. A. M’Barki, Organometallics,
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21 In the literature, trans-aminopalladation onto the triple
bond has been authenticated by several reports; for a rep-
resentative example, see: L. B. Wolf, K. C. M. F. Tjen,
H. T. Ten Brink, R. H. Blaauw, H. Hiemstra,
H. E. Schoemaker and F. P. J. T. Rutjes, Adv. Synth. Catal.,
2002, 344, 70.
22 Unlike our previous study (ref. 7g), we were unable to trap
the (E)-2-arylmethylidene-indoline intermediate D despite
repeated attempts. Therefore, the formation of the corres-
ponding (Z)-isomer of D via an alternative mechanistic
ized by conjugation (extended over two double bonds) to
the electron-withdrawing group (EWG). Protonation alpha
to the EWG furnishes the product with correct double
bond geometry.
28 (a) B. Gabriele, R. Mancuso and G. Salerno, Eur. J. Org.
Chem., 2012, 6825; (b) B. Gabriele, G. Salerno and
M. Costa, Top. Organomet. Chem., 2006, 18, 239;
(c) B. Gabriele and G. Salerno, Palladium(II) Iodide, in Elec-
tronic Encyclopedia of Reagents for Organic Synthesis (EROS),
ed. D. Crich, Wiley-Interscience, 2006; (d) B. Gabriele,
G. Salerno and M. Costa, Synlett, 2004, 2468;
(e) B. Gabriele, G. Salerno, M. Costa and G. P. Chiusoli,
Curr. Org. Chem., 2004, 8, 919; (f) B. Gabriele, G. Salerno,
M. Costa and G. P. Chiusoli, J. Organomet. Chem., 2003,
687, 219.
pathway may not be ruled out. Accordingly, it is assumed 29 (a) B. Gabriele, M. Costa, G. Salerno and G. P. Chiusoli, J.
that the palladium of the species ArPdI (A) makes coordi-
nation with the nitrogen of the amine moiety of substrate 7
and then undergoes ligand exchange. Thereafter, an intra-
molecular syn-palladation onto the triple bond leads to the
formation of the (Z)-isomer of the intermediate C (of
Chem. Soc., Perkin Trans. 1, 1994, 83; see also pertinent
review articles of ref. 28; (b) S. Ma, Z. Yu and Z. Gu, Chem.–
Eur. J., 2005, 11, 2351. Indeed, in our case, considerable
amount of iodine was isolated during chromatographic
separation of the crude products.
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