Copper-Catalyzed anti-Markovnikov Hydroindolation of Terminal Alkynes: Regioselective Synthesis of Bis(indolyl)alkanes

Article abstract of DOI:10.1021/acs.joc.6b02058

An efficient copper-catalyzed intermolecular hydroindolation reaction of terminal aryl alkynes to expeditiously synthesize bis(indolyl)alkanes in moderate to high yields is described. The double nucleophilic addition of two molecules of indole to one mole

Full text of DOI:10.1021/acs.joc.6b02058

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Copper-catalyzed anti-Markovnikov hydroindolation of terminal
alkynes: Regioselective synthesis of bis(indolyl)alkanes
Ananya Srivastava, Shyam Sunder Patel, Nisha Chandna, and Nidhi Jain
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02058 • Publication Date (Web): 27 Oct 2016
Downloaded from http://pubs.acs.org on October 28, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Copper-catalyzed anti-Markovnikov hydroindolation of terminal alkynes:
9
Regioselective synthesis of bis(indolyl)alkanes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ananya Srivastava, Shyam Sunder Patel, Nisha Chandna and Nidhi Jain*
Department of Chemistry, Indian Institute of Technology, Delhi
Email: njain@chemistry.iitd.ac.in
TABLE OF CONTENTS
ABSTRACT
An efficient copper-catalyzed intermolecular hydroindolation reaction of terminal aryl alkynes to
expeditiously synthesize bis(indolyl)alkanes in moderate to high yields is described. The double
nucleophilic addition of two molecules of indole to one molecule of alkyne occurs in a tandem
manner through an anti-Markovnikov pathway. Various arenes and alkynes allow for this
transformation. Preliminary mechanistic study sheds light on the observed regioselectivity
involving a Cu-vinylidene complex, and 3-styryl-1H-indole as probable intermediates.
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 24
1
2
3
4
Key words: copper catalyst, anti-Markovnikov addition, bis(indolyl)alkanes
5
6
7
INTRODUCTION
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(indolyl)alkanes are structurally important compounds, and are key synthetic intermediates
for many natural products and pharmaceutical drugs (Figure 1).1 In view of their immense
biological significance, numerous methods for their preparation have developed over the years. In
general, the synthesis of bis(indolyl)alkane derivatives has been reported using Lewis or protic
acid mediated reaction of indoles with aldehydes,2 ketones,3 amino acids,4 tertiary enamides,5 and
phenylacetaldehyde6 as the alkyl source. The use of amino acids for installation of alkyl group
involves an iron catalyzed decarboxylative-deaminative protocol, making the process expensive,
and non-atom-economic. Further, preparation of enamides or substituted aryl acetaldehydes
requires elaborate synthetic procedures.
Figure 1. Examples of biologically active bisindoles.
In this context, catalytic hydroindolation using alkynes as cheap and easily available substrates
constitutes a potentially powerful, direct atom-economic approach for bis(indolyl)alkane
synthesis. Although progress has been made in the hydroindolation processes, the control of
regioselectivity during addition of indoles to terminal alkynes still poses a challenge. The
electronic imbalance of the triple bond in transition metal-alkyne complex is ascribed to govern
the specificity of the attack of indoles on to internal C-atom of unactivated terminal alkynes,
ACS Paragon Plus Environment
2

Page 3 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
resulting in Markovnikov’s adducts. Thus, while the Markovnikov addition of indoles on both
activated and unactivated terminal alkynes has been extensively studied via a variety of transition
metal catalysts such as Pt,7 Ag,8 Au,9 Ga,10 In11 and Ru12; a general protocol for anti-Markovnikov
hydroindolation on unactivated alkynes is less investigated. To create an electronic bias in the C-
C triple bond, and facilitate indole addition at the terminal carbon of the alkyne; alkynes are
activated with electron withdrawing groups such as ester,13 amide,14 sulfone15 etc. and Pd, Hg, or
Cu salts are used as catalysts (Scheme 1A). In two separate reports from the groups of Echavarren16
and Barluenga,17 Au catalysis has been used for achieving intramolecular hydroindolation or a
hydroxyl “directing group” assisted strategy has been employed for intermolecular
hydroindolation of terminal alkynes through an anti-Markovnikov route.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. An overview of previous methods for anti-Markovnikov hydroindolation vs. our
approach.
With unactivated terminal alkynes, however, the only report on a direct intermolecular anti-
Markovnikov addition of indoles has been by Wang et al.18 who have demonstrated a rhenium
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 24
1
2
3
4
5
6
7
8
9
catalyzed synthetic protocol in toluene as the solvent (Scheme 1B). Interestingly, they have
reported that under neat conditions, the regioselectivity of the reaction is reoriented towards
Markovnikov addition with phenylacetylenes as substrates. Further, the scope of the reaction is
restricted to N-alkyl or N-benzyl indoles, and does not support free N-H indoles. Challenged by
the scarcity of effective anti-Markovnikov hydroindolation methods for terminal aryl alkynes,
coupled with our ongoing interest in developing operationally simple metal mediated reactions,19
we investigated a copper catalyzed route to achieve the same. Herein, we demonstrate a valuable
and economical approach to C3-hydroindolation of unactivated terminal aryl alkynes using copper
salt as catalyst.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
We initiated our studies with the reaction of indole (1a) and phenylacetylene (2a) as model
substrates using CuBr as catalyst in toluene as the solvent. Pleasantly as desired, the anti-
Markovnikov product 3,3'-(2-phenylethane-1,1-diyl)bis(1H-indole) (3a) was isolated in 42% yield
(Table 1, entry 1). It is important to point out that no copper catalyst has previously been reported
for such transformation. Taking this forward, we optimized the reaction with respect to catalyst,
solvent, oxidant, time and temperature (Table 1). Different copper salts were screened (Table 1,
entries 1-5); and CuBr2 was found to be the most effective giving 3a in 71% yield (Table 1, entry
2) along with unreacted 1a. Other copper salts such as Cu(OAc)2, CuI, and Cu(OTf)2 failed to
promote the reaction (Table 1, entries 3-5). Notably, 3a was formed as a single product when
CuBr2 was used as catalyst, though the yield reduced to 62% on decreasing CuBr2 to 15 mol%
(Table 1, entry 2). Effect of solvents on the reaction was investigated next. It was found that
replacing toluene with 1,4-dioxane or 1,2-dichloroethane (DCE) decreased the yield, while DMF
inhibited the reaction completely (Table 1, entries 6-8).
ACS Paragon Plus Environment
4

Page 5 of 24
The Journal of Organic Chemistry
1
2
3
4
Table 1. Optimization table for reaction of 1a and 2a.a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry catalyst
additive
solvent
toluene
toluene
toluene
toluene
toluene
dioxane
DMF
yield%
42
1.
CuBr
-
2.
CuBr2
Cu(OAc)2
CuI
-
71, 0b, 62c
Traces
Traces
3.
-
4.
-
d
5.
Cu(OTf)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
-
-
6.
-
22
d
7.
-
-
8.
-
DCE
28
9.
-
neat
72, 57e
35
10.
11.
12.
13.
14.
15.
16.
17.
18.
DIB
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
neat
BQ
64
Oxone
traces
traces
K2S2O8
d
TBHP
-
d
1,10-Phenanthroline
-
d
K2CO3
AcOH
-
-
40
52f, 30g
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst (20 mol%), additive (0.5 mmol) in
solvent (2 mL) for 24 h at 90 ºC, breaction in absence of catalyst, c15 mol% CuBr2, no conversion
d
was detected, e1.0 mmol of 2a, freaction time was 18 h, greaction was run at 120 oC.
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 24
1
2
3
4
5
6
7
8
9
Notably, the reaction was equally facile under neat conditions (Table 1, entry 9). It is noteworthy
to mention that in this case, the regioselectivity was preserved in sharp contrast to the previous
report with Re wherein regiodivergence was observed in toluene and neat conditions. Further,
decreasing the amount of alkyne to 1 equiv. reduced the yield to 57% (Table 1, entry 9) suggesting
that the reaction performs best with an excess of alkyne. Addition of oxidants such as
benzoquinone (BQ), diacetoxyiodobenzene (DIB), oxone, K2S2O8 and t-butylhydroperoxide
(TBHP) proved detrimental to the reaction, and reduced the yield drastically (Table 1, entries 10-
14). Addition of ligand, base, or acid did not help the reaction either, and diminished conversions
were seen (Table 1, entries 15-17). Increasing the reaction time from 24 h to 36 h did not bring
about higher conversions, whereas reducing it to 18 h decreased the yield to 52% (Table 1,
entry18). Further, elevating the reaction temperature to 120 oC worsened the yield presumably due
to the decomposition of 3a (Table 1, entry 18). Hence, the best optimized conditions for the
reaction were found to be with 1.5 equiv. of 2a, 20 mol% CuBr2 at 90 oC for 24 h (Table 1, entry
9). To the best of our knowledge, this protocol is the first successful demonstration of copper
catalyzed intermolecular anti-Markovnikov addition of indoles to unactivated terminal alkynes
without any directing group.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The scope of this reaction with respect to indoles and alkynes was tested, and the results are
summarized in Table 2. When the substituent in the 5-position on the indole was electron donating,
it had little effect on the reaction, and gave the corresponding bisindolylalkane derivatives in
moderate to good yields (3a-3k). In contrast, electron withdrawing nitro or ester groups at 5-
position of indole rendered it unreactive, and the reaction did not occur under these conditions. It
is noteworthy to mention that the bromo group on indole remained intact after the reaction, thus
providing an easy handle for further synthetic elaborations (3c). 2-methyl indole was found to be
ACS Paragon Plus Environment
6

Page 7 of 24
The Journal of Organic Chemistry
1
2
3
4
Table 2. Anti-Markovnikov addition of indoles to phenylacetylenes.a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), CuBr2 (20 mol%) for 24 h at 90 ºC.
inert under the optimized conditions probably due to steric effects. The diversity in phenyl
acetylene derivatives was also explored. Reaction with phenyl acetylene bearing substitutents such
as methyl, tert-butyl, n-pentyl, and fluoro on the phenyl ring was carried out, and the corresponding
products were obtained in good yields (3d-3k). The reaction was tolerated by the heterocyclic
alkyne, 3-thienylacetylene, and the desired product 3l was isolated in 56% yield. Interestingly,
Markovnikov’s product (3m) was formed when indole was reacted with 4-methoxy
phenylacetylene derivative due to a strong +R effect. Furthermore, when the properties on the
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 24
1
2
3
4
5
6
7
8
9
nitrogen were altered, as in 1-methyl indole; the reaction did not occur at all, suggesting that free
N-H proton was a requisite for the reaction. Further, with alkyl substituted acetylene such as n-
hexyne, a mixture of two unidentified products was isolated, though the desired product was not
obtained.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Further, the synthetic utility of the developed protocol was established by carrying out a gram scale
reaction. Starting from 2g of 1a, 3a was isolated in 67% yield (Scheme 2) demonstrating the
practical potential of this method for rapid and efficient construction of bis(indolyl)alkanes.
Scheme 2. Practical synthesis of 3a on gram scale.
Next, to study the kinetics of the reaction, a cross-over reaction was performed by mixing 1a, 2a
and its deuterated analog 2a’(Scheme 3a). The LC-MS spectrum (see supporting information) of
the reaction mixture revealed a KH/KD ratio of 1.94 indicating that secondary isotope effects
prevail, and that the formation of copper acetylide (I) is not the rate-determining step. Further, to
identify the position of D-incorporation in 3a’, a reaction of 1a and 2a’ was placed (Scheme 3b).
1H NMR analysis of 3a’ showed that 24% of D-atom resided at the original terminal carbon of
alkyne 2a’, while 18% of D-atom was installed at the benzylic carbon in 3a’. The deuterium
scrambling in the product revealed the reaction to follow a non-concerted pathway.
ACS Paragon Plus Environment
8

Page 9 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Kinetic hydrogen isotope effect.
Furthermore, the reaction of indole was carried out using a mixture of two different alkynes,
deuterated phenyl acetylene (2a’) and 4-methyl phenyl acetylene under optimized conditions
(Scheme 4). The LC-MS spectrum (see supporting information) of the reaction mixture revealed
formation of four different products with and without deuterium incorporation in varied ratios. The
results were in accordance with the K.H.I.E studies reinforcing the observation that Cu-vinylidene
formation is reversible, and provides a source of H+ by H/D scrambling.
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Cross-over experiments demonstrating H/D scrambling
To understand the reaction mechanism, several control experiments were carried out (Scheme 5).
First, we performed a reaction of 1a and 2a in the presence of 20 mol% CuBr2 and 1 equiv. of
butylated hydroxytoluene (BHT) at 90 oC for 24 h. 3a was isolated in 72% yield, suggesting that
the reaction did not follow a free-radical pathway (Scheme 5(I)). Next, to identify the reaction
intermediate, (E)-3-styryl-1H-indole (4a) was synthesized from 1a using a reported procedure, and
subsequently treated with another molecule of 1a under aforementioned conditions (Scheme 5(II)).
With CuBr2 as the catalyst, 3a was obtained in 63% yield, suggesting 4a to be the most probable
intermediate formed during the reaction. However, no conversions were seen in the absence of
CuBr2, confirming its necessity in the second hydroindolation step. Involvement of the N-lone pair
in the mechanism was probed by invoking the C−H activation onto substituted N-
methyl/ethyl/phenylindole (5), wherein the reaction failed to yield the desired product 6 in all cases
(Scheme 5(IIIa)). This control reaction confirmed that free NH of indole was crucial for the
indolation reaction.20 Next, the reaction of 1a with 4b (5-styryl-1H-indole) was carried out under
ACS Paragon Plus Environment
10

Page 11 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the optimized conditions. While 4a reacted with 1a to yield the expected product 3a with excellent
regioselectivity, no traces of the desired product 5-(1-(1H-indol-3-yl)-2-phenylethyl)-1H-indole
(7) were seen (Scheme 5(IIIb)). Furthermore, when (E)-1-methyl-3-styryl-1H-indole (8) was
treated with 1a, the corresponding product 3-(1-(1H-indol-3-yl)-2-phenylethyl)-1-methyl-1H-
indole (9) was not formed, reinforcing yet again the role of N-lone pair in the second indolation
step (Scheme 5(IIIc)).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 24
1
2
3
4
Scheme 5. Preliminary mechanistic studies.
5
6
7
8
9
On the basis of above experimental results, a plausible mechanism is proposed (Scheme 6). We
hypothesize that in the first step, coordination of copper with alkyne affords the Cu-acetylide
intermediate I. This is followed by a nucleophilic attack of 1a at the Cu terminal of I to yield an
intermediate II which transforms to Cu-vinylidene21 intermediate III. Subsequently, the vinyl
group of III undergoes a migratory insertion into the indole carbon to form intermediate IV.22 The
evidence in favour of formation of III and IV comes from the GC−MS analysis of the reaction
mixture taken after 1 h of reaction time, which shows the molecular ion peak at 281.1
corresponding to the mass of Cu olefin complexes (see the Supporting Information). Protonolysis
of IV can yield the intermediate product 4a. Eventually, the second hydroindolation of IV followed
by protonolysis leads to the formation of the anti-Markovnikov product 3a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
12

Page 13 of 24
The Journal of Organic Chemistry
1
2
3
4
Scheme 6. Proposed mechanism.
5
6
7
Conclusions
8
9
In summary, we have developed efficient and economical catalytic conditions for a regioselective
anti-Markovnikov C3-hydroindolation of terminal aryl alkynes to access bis(indolyl)alkanes. The
protocol tolerates a variety of indoles and alkynes, which have not been easily accessible through
existing synthetic methods. Another noteworthy feature is that the methodology works for the
more challenging free N-H indoles. The demonstrable applicability of this direct hydroindolation
to the rapid synthesis of pharmaceutical agents from easily available substrates is a practical merit.
The involvement of Cu-vinylidene complex, and 3-styryl-1H-indole as key reaction intermediates
is proposed through preliminary mechanistic studies.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION:
Reagent information:
All reactions were carried out under an air atmosphere pressure in oven-dried round bottom flasks.
Reagents were purchased at the highest commercial quality and used without further purification,
unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried
out on a 0.25 mm silica gel plates (60F254) and visualized under UV illumination at 254 nm.
Further visualization was achieved by iodine vapour adsorbed on silica gel depending on the
product type. Organic extracts were dried over anhydrous sodium sulfate. Solvents were removed
in a rotary evaporator under reduced pressure. Column chromatography was performed on silica
gel 100200 mesh using a mixture of hexane and ethyl acetate as eluent.
Analytical information:
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 24
1
2
3
4
1
All isolated compounds were characterized by H NMR, 13C{1H} NMR, and HRMS. NMR
5
6
7
8
spectra for all the samples were measured in deuterochloroform (CDCl3) and dimethylsufoxide-
d6 (DMSO-d6). 1H and 13C{1H}NMR spectra were recorded at ambient temperature on 300 MHZ
and 75 MHz spectrometer using tetramethylsilane (TMS) as internal reference. The chemical shifts
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
are quoted in δ units, parts per million (ppm) up field from the signal of internal TMS. H NMR
data is represented as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), integration and coupling constant(s) J in Hertz (Hz). High resolution mass
spectra (HRMS) were recorded on a Mass spectrometer using electrospray ionization-time of flight
(ESI-TOF) reflectron experiments.
General procedure for synthesis of compounds (3a-n):
CuBr2 (22.3 mg, 0.1 mmol, 20 mol %), indole 1a (58.5 mg, 0.5 mmol, 1.0 equiv.) and
phenylacetylene 2a (76.5 mg, 0.75 mmol, 1.5 equiv.) were added to an oven-dried reaction vessel.
The reaction mixture was stirred in an oil bath at 90 °C for 24 h. After completion of the reaction
(as indicated by TLC), the reaction mixture was cooled to room temperature, diluted with
ethylacetate (5 mL), and water was added. This mixture was extracted with ethylacetate and the
combined organic layers were put together and dried upon Na2SO4. Solvents were removed under
reduced pressure, and the crude was purified by column chromatography on silica gel to afford 3a
in 72% yield.
Reaction mechanism investigation:
(i)
Free Radical/Ionic Mechanism:
CuBr2 (22.3 mg, 0.1 mmol, 20 mol %), 1a (58.5 mg, 0.5 mmol, 1.0 equiv.), butylated
hydroxytoluene (BHT) (110.0 mg, 0.5 mmol, 1.0 equiv.) and 2a (76.5 mg, 0.75 mmol, 1.5 equiv.)
were added to an oven-dried reaction vessel. The reaction mixture was stirred in an oil bath at 90
ACS Paragon Plus Environment
14

Page 15 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
°C for 24 h. After completion of the reaction (as indicated by TLC), the reaction mixture was
cooled down to room temperature, diluted with ethylacetate (5 mL), and water was added. This
mixture was extracted with ethylacetate and the combined organic layers were put together and
dried upon Na2SO4. Solvents were removed under reduced pressure, and the crude was purified by
column chromatography on silica gel to afford 3a in 70% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ii) Synthesis of proposed intermediate 3-Styryl-1 H-indole (4a):23
4a was prepared according to the reported procedure.23 Palladium acetate (0.1 equiv.) was added
to a mixture of styrene (1.0 equiv.), copper (II) acetate (1.8 equiv.), and indole (2.0 equiv.) in
DMF: DMSO (9:1, 0.4M), and the contents were stirred at 70 ˚C. After stirring at 70 ˚C for 18 h,
the reaction mixture was cooled to room temperature, partitioned between water and ethyl acetate,
and then filtered through a plug of celite. The layers were separated; the organic layer was washed
with aqueous saturated brine solution, dried over Na2SO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography afforded 4a.
Procedure for hydroindolation of 4a:
CuBr2 (22.3 mg, 0.1 mmol, 20 mol %), 1a (58.5 mg, 0.5 mmol, 1.0 equiv.), and 4a (109.5 mg,
0.5 mmol, 1.0 equiv.) were added to an oven-dried reaction vessel. The contents were stirred in
preheated oil bath at 90 °C for 24 h. After completion of the reaction (as indicated by TLC), the
reaction mixture was cooled down to room temperature, diluted with ethylacetate (5 mL), and
water was added. This mixture was extracted with ethylacetate and the combined organic layers
were put together and dried upon Na2SO4. Solvents were removed under reduced pressure, and the
crude was purified by column chromatography on silica gel to afford 3a in 63% yield. It was found
that no reaction occurred in the absence of CuBr2.
(iii) Role of N-lone pair:
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 24
1
2
3
4
Procedure for preparation of N-alkylindoles 5 and 8:24
5
6
7
8
N-alkylindoles were prepared from the corresponding commercially available N-H indoles
according to the known procedure.24 To a solution of indole (10 mmol ) in 15 mL DMF, NaH
(60%, 11 mmol) was added in portions at 0 ℃. The resulting solution was stirred for 30 min., and
then MeI (12 mmol) was added dropwise. The contents were stirred for 10 min, quenched with
saturated NH4Cl, and extracted with Et2O (3 × 50 mL). The combined organic layers were washed
with H2O (5 × 10 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated
under vacuum. The crude product was purified by flash column chromatography on silica gel to
afford N-alkyl indole.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure for synthesis of compound 6:
CuBr2 (20 mol %), 5 (0.5 mmol, 1.0 equiv.) and 2a (0.75 mmol, 1.5 equiv.) were added to an
oven-dried reaction vessel. The contents were stirred in an oil bath at 90 °C for 24 h. After 24 h,
no distinguish peak for compound 6 was observed by GC and starting materials were recovered
by column chromatography.
Procedure for synthesis of 5-Styryl-1H-indole (4b):25
4b was synthesized according to a reported procedure.25 To an oven dried Schlenk tube charged
with a magnetic stir bar, Pd(OAc)2 (22.5 mg, 0.10 mmol, 0.05 equiv.), tri(o-tolyl)phosphine (60.9
mg, 0.20 mmol, 0.10 equiv.), 5-bromo-1H-indole (393 mg, 2.0 mmol, 1.0 equiv.), styrene (287
µL, 2.5 mmol, 1.25 equiv.), and triethylamine (NEt3, 2.0 mL) were added. The mixture was
degassed using three vacuum/N2 back-fill cycles, and heated at 100 °C for 24 h. Upon cooling to
room temperature, the mixture was filtered through a plug of silica/sand/celite using acetone as the
eluent. The acetone was concentrated in vacuo, and purification by flash chromatography with a
mixture of EtOAc:hexanes afforded 4b.
ACS Paragon Plus Environment
16

Page 17 of 24
The Journal of Organic Chemistry
1
2
3
4
Procedure for hydroindolation of 4b:
5
6
7
8
CuBr2 (22.3 mg, 0.1 mmol, 20 mol %), 1a (58.5 mg, 0.5 mmol, 1.0 equiv.), and 4b (109.5 mg,
0.5 mmol, 1.0 equiv.) were added to an oven-dried reaction vessel. The reaction mixture was stirred
in preheated oil bath at 90 °C for 24 h. After 24 h, no distinguish peak for compound 7 was
observed by GC and starting materials were recovered by column chromatography.
(iv) Procedure for deuterio-1-phenyl acetylene (2a’):26
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
An oven dried 10mL round bottomed flask was charged with phenyl acetylene (1 equiv.) and
potassium carbonate (1.5 equiv.) in MeCN (2 mL). This was allowed to stir under an atmosphere
of N2 for 30 minutes. To this D2O (500 μL, ~50 equiv.) was added and left to stir for 1 h. The
resulting crude reaction mixture was diluted with DCM (5 mL) and transferred to a separating
funnel. The organic layer was separated and dried with Na2SO4, filtered and solvent removed
under reduced pressure.
1H NMR of 2a’ (300 MHz, CDCl3): δ 7.49 (m, 2H), 7.33 (m, 3H), 3.05 (s, 0.09 H).
3,3'-(deuterio-2-phenylethane-1,1-diyl)bis(1H-indole) (3a’):
White viscous liquid, Hexane/EtOAc = 17/3, 0.5 mmol scale, yield 118 mg, 70%; 1H NMR (300
MHz, CDCl3): δ 7.78 (s, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.17 (m, 7H),
7.00 (t, J = 8.1 Hz, 2H), 6.89 (s, 2H), 4.78 (t, J = 7.2 Hz, 0.76H), 3.53 (d, J = 7.2 Hz, 1.63H);
13C{1H}NMR (75 MHz, CDCl3): δ 141.3, 136.6, 129.0, 127.9, 127.0, 125.7, 121.9, 121.7, 119.7,
119.5, 119.1, 111.1, 41.7, 36.3.
Characterization data:
3,3’-(2-phenylethane-1,1-diyl)bis(1H-indole) (3a):27
White viscous liquid, Hexane/EtOAc = 17/3, 0.5 mmol scale, yield 120 mg, 72%; 1H NMR
(400 MHz, CDCl3): δ 7.81 (s, 2H), 7.58 (d, J = 10.8 Hz, 2H), 7.31 (d, J = 10.8 Hz, 2H), 7.19-
7.09 (m, 7H), 7.06-7.0 (m, 2H), 6.92 (d, J = 2.8 Hz, 2H), 4.81 (t, J = 9.6 Hz, 1H), 3.54 (d, J
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 24
1
2
3
4
5
6
7
8
= 9.6 Hz, 2H); 13C{1H}NMR (75 MHz, CDCl3): δ 141.3, 136.6, 129.0, 127.9, 127.0, 125.7,
121.9, 121.7, 119.7, 119.5, 119.1, 111.1, 41.8, 36.3; HRMS (ESI/TOF-Q) m/z: [M +Na]+
Calcd for C24H20N2Na 359.1518; Found 359.1524.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3,3’-(2-phenylethane-1,1-diyl)bis(5-methoxy-1H-indole) (3b):
1
Brown viscous liquid, Hexane/EtOAc = 4/1, yield 150 mg, 76%; H NMR (400 MHz,
CDCl3): δ 7.78 (s, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.17-7.08 (m, 5H), 6.94 (dd, J1 = 2.4 Hz, J2
= 13.4 Hz, 4H), 6.79 (dd, J1 = 0.4 Hz, J2 = 10 Hz , 2H), 4.67 (t, J = 7.2 Hz, 1H), 3.73 (s, 6H),
3.50 (d, J = 7.2 Hz, 2H);13C{1H}NMR (75 MHz, CDCl3): δ 153.6, 141.3, 131.8, 129.1, 128.2,
127.9, 127.5, 125.8, 122.8, 119.2, 111.7, 101.9, 55.9, 41.7, 36.3; HRMS (ESI/TOF-Q) m/z:
[M+Na]+ Calcd for C26H24N2O2Na 419.1729; Found 419.1717.
3,3’-(2-phenylethane-1,1-diyl)bis(5-bromo-1H-indole) (3c):
Dark brown viscous liquid, Hexane/EtOAc = 17/3, yield 164 mg, 67%; 1H NMR (300 MHz,
CDCl3): δ 7.97 (s, 2H), 7.56 (s, 2H), 7.24-7.29 (m, 4H), 7.15 (d, J = 6.0 Hz, 3H), 7.03 (d, J =
6.6 Hz, 2H), 6.96 (s, 2H), 4.64 (t, J = 7.8 Hz, 1H), 3.40 (d, J = 7.5 Hz, 2H); 13C{1H}NMR
(75 MHz, CDCl3): δ 140.6, 135.2, 128.9, 128.6, 128.4, 128.1 126.0, 124.8, 123.1, 122.1,
118.7, 112.6, 112.5, 41.5, 36.2; LRMS (ESI/TOF-Q) m/z: [M-Br+Na]+ Calcd for
C24H19BrN2Na 437.06; Found 437.19.
3,3’-(2-(p-tolyl)ethane-1,1-diyl)bis(1H-indole) (3d):
1
White viscous liquid, Hexane/EtOAc = 17/3, yield 124 mg, 71%; H NMR (400 MHz,
CDCl3): δ 7.87 (s, 2H), 7.58 (d, J = 8 Hz, 2H), 7.32 (d, J = 8 Hz, 2H), 7.16-7.12 (m, 3H),
7.04-7.02 (m, 5H), 7.01-6.94 (m, 2H), 4.78 (t, J = 8.1 Hz, 1H), 3.51 (d, J = 7.2 Hz, 2H), 2.26
(s, 2H); 13C{1H}NMR (75 MHz, CDCl3): δ 138.2, 136.6, 135.1, 128.8, 128.6, 127.0, 121.9,
121.7, 119.7, 119.5, 119.0, 111.1, 41.2, 36.3, 21.0; HRMS (ESI/TOF-Q) m/z: [M + Na]+
Calcd for C25H22N2Na 373.1675; Found 373.1671.
ACS Paragon Plus Environment
18

Page 19 of 24
The Journal of Organic Chemistry
1
2
3
4
3,3’-(2-(p-tolyl)ethane-1,1-diyl)bis(5-methoxy-1H-indole) (3e):
Pale yellow viscous liquid, Hexane/EtOAc = 4/1, yield 151 mg, 74%; 1H NMR (400 MHz,
CDCl3): δ 7.79 (s, 2H), 7.20 (d, J = 11.6 Hz, 2H ), 7.01-6.93 (m, 7H), 6.81 (dd, J1 = 11.6
Hz, J2 = 2.8 Hz, 2H), 4.66 (t, J = 10.0 Hz, 1H), 3.75 (s, 6H), 3.46 (d, J = 10 Hz, 2H), 2.25 (s,
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
3H); C{1H}NMR (75 MHz, CDCl3): δ 153.6, 138.2, 135.1, 131.8, 128.9, 128.6, 127.5,
122.7, 119.3, 111.6, 101.9, 55.9, 41.2, 36.3, 20.9; HRMS (ESI/TOF-Q) m/z: [M + K]+ Calcd
for C27H26N2O2K 449.1625; Found 449.1615.
3,3’-(2-(4-(tert-butyl)phenyl)ethane-1,1-diyl)bis(1H-indole) (3f):
Light brown viscous liquid, Hexane/EtOAc = 17/3, yield 152 mg, 78%; 1H NMR (400 MHz,
CDCl3): δ 7.83 (s, 2H), 7.52 (d, J = 8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.18-7.11 (m, 4H),
7.05 (d, J = 8 Hz, 2H), 7.00 (t, J = 7.6 Hz, 2H), 6.93 (s, 2H), 4.80 (t, J = 7.2 Hz, 1H), 3.50 (d,
J = 7.2 Hz, 2H), 1.25 (s, 9H); 13C{1H}NMR (75 MHz, CDCl3): δ 148.5, 138.2, 136.6, 128.6,
127.1, 124.9, 121.9, 121.7, 119.8, 119.7, 119.0, 111.0, 41.3, 35.9, 34.3, 31.4; HRMS
(ESI/TOF-Q) m/z: [M + H]+ Calcd for C28H29N2 393.2325; Found 393.2318.
3,3’-(2-(4-(tert-butyl)phenyl)ethane-1,1-diyl)bis(5-methoxy-1H-indole) (3g):
1
Brown viscous liquid Hexane/EtOAc = 4/1, yield 178 mg, 79%; H NMR (300 MHz,
DMSO-d6): δ 10.53 (s, 2H), 7.16-7.19 (m, 8H), 7.00 (d, J = 2.1, 2H), 6.66 (dd, J1 = 8.7 Hz,
J2 = 2.1 Hz 2H), 4.67 (t, J = 7.5 Hz, 1H), 3.68 (s, 6H), 3.44 (d, J = 7.5 Hz, 2H), 1.22 (s, 9H);
13C{1H}NMR (75 MHz, DMSO-d6): δ 153.0, 148.0, 138.8, 132.1, 128.9, 127.4, 125.0,
123.5, 118.5, 112.2, 110.8, 101.8, 55.8, 35.6, 34.4, 31.6; HRMS (ESI/TOF-Q) m/z: [M+K]+
Calcd for C30H32N2O2K 491.2087; Found 491.2095.
3,3’-(2-(4-pentylphenyl)ethane-1,1-diyl)bis(1H-indole) (3h):
1
White viscous liquid, Hexane/EtOAc = 17/3, yield 156 mg,77%; H NMR (300 MHz,
CDCl3): δ 7.80 (s, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.12 (t, J = 7.2 Hz,
2H), 6.99 (t, J = 8.1 Hz, 6H), 6.91 (s, 2H), 4.77 (t, J = 7.2 Hz, 1H), 3.49 (d, J = 7.5 Hz, 2H),
2.49 (t, J = 7.8 Hz, 2H), 1.54 (quint, J = 7.8 Hz, 2H), 1.29 (m, 4H), 0.872 (t, J = 6.6 Hz, 3H);
13C{1H}NMR (75 MHz, CDCl3): δ 140.2, 138.4, 136.6, 128.8, 128.0, 127.1, 121.9, 121.7,
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 24
1
2
3
4
5
6
119.7, 119.7, 119.0, 111.0, 41.4, 36.2, 35.5, 31.5, 31.2, 22.5, 14.0; HRMS (ESI/TOF-Q) m/z:
[M + Na]+ Calcd for C29H30N2Na 429.2301; Found 429.2299.
7
8
9
3,3’-(2-(4-pentylphenyl)ethane-1,1-diyl)bis(5-methoxy-1H-indole) (3i):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Light brown viscous liquid, Hexane/EtOAc = 4/1, yield 181 mg, 78%; 1H NMR (300 MHz,
CDCl3): δ 7.73 (s, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.03-7.17 (m, 6H), 6.90 (s, 2H), 6.79 (d, J
= 10.8 Hz, 2H), 4.66 (t, J = 7.5 Hz, 1H), 3.73 (s, 6H), 3.46 (d, J = 7.2 Hz, 2H), 2.50 (t, J = 7.5
Hz, 2H), 1.54 (quint, J = 7.8 Hz, 2H), 1.29 (m, 4H), 0.87 (t, J = 6.3 Hz, 3H); 13C{1H}NMR
(75 MHz, CDCl3): δ 153.6, 140.3, 138.4, 131.8, 128.9, 128.0, 127.5, 122.8, 119.4, 111.6,
101.9, 55.9, 41.3, 36.1, 35.5, 31.6, 31.2, 22.5, 14.0; HRMS (ESI/TOF-Q) m/z: [M + K]+
Calcd for C31H34N2O2K 505.2251; Found 505.2235.
3,3’-(2-(4-fluorophenyl)ethane-1,1-diyl)bis(1H-indole) (3j):
Dark brown viscous liquid, Hexane/EtOAc = 17/3, yield 127 mg, 72%; 1H NMR (300 MHz,
CDCl3): δ 7.80 (s, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 6.9 Hz,
2H), 6.95-7.03 (m, 4H), 6.87 (s, 2H), 6.79 (t, J = 8.7 Hz, 2H), 4.70 (t, J = 7.5 Hz, 1H), 3.48
13
1
1
(d, J = 8.7 Hz, 2H); C{ H}NMR (75 MHz, CDCl3): δ 161.2 (d, JCF = 241.8 Hz), 136.9,
136.6, 130.3 (d, 3JCF = 7.6 Hz), 126.9, 121.9, 121.8, 119.6, 119.2, 119.2, 114.6 (d, 2JCF = 20.8
Hz), 111.1, 40.9, 36.6; HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for C24H19FN2Na
377.1424; Found 377.1412.
3,3’-(2-(4-fluorophenyl)ethane-1,1-diyl)bis(5-methoxy-1H-indole) (3k):
Light brown viscous liquid, Hexane/EtOAc = 4/1, yield 155 mg, 75%; 1H NMR (300 MHz,
DMSO-d6): δ 10.56 (s, 2H), 7.22 (m, 6H), 6.99-6.93 (m, 4H), 6.68 (d, J = 8.7 Hz, 2H), 4.64
(t, J = 7.5 Hz, 1H), 3.72 (s, 6H), 3.48 (d, J = 7.5 Hz, 2H); 13C{1H}NMR (75 MHz, DMSO-
d6): δ 160.9 (d, 1JCF = 239.1 Hz), 153.1, 138.0, 137.9, 132.1, 131.0 (d, 3JCF = 7.7 Hz), 127.4,
123.5, 118.2, 114.8 (d, 2JCF = 20.7 Hz), 112.3, 110.9, 101.8, 55.8, 36.0; HRMS (ESI/TOF-
Q) m/z: [M + Na]+ Calcd for C26H23FN2O2Na 437.1635; Found 437.1655.
ACS Paragon Plus Environment
20

Page 21 of 24
The Journal of Organic Chemistry
1
2
3
4
3,3’-(2-(thiophen-2-yl)ethane-1,1-diyl)bis(1H-indole) (3l):
Light brown viscous liquid, Hexane/EtOAc = 4/1, Yield 95 mg, 56%; 1H NMR (300 MHz,
DMSO-d6): δ 10.70 (s, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.31 (m, 1H),7.26 (m, 2H), 7.21 (s,
2H), 7.08 (s, 1H), 6.98 (t, J = 8.1 Hz, 2H), 6.91 (d, J = 4.8 Hz, 1H), 6.86 (t, J = 7.8 Hz, 2H),
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
4.74 (t, J = 7.8 Hz, 1H), 3.50 (d, J = 7.5 Hz, 2H); C{1H}NMR (75 MHz, DMSO-d6): δ
150.8, 137.4, 129.1, 126.4, 125.2, 123.2, 123.1, 121.2, 120.9, 120.8, 118.3, 111.9, 41.2;
HRMS (ESI/TOF-Q) m/z: [M + H]+ Calcd for C22H19N2S 343.1263 ; Found 343.1264.
3,3’-(1-(4-methoxyphenyl)ethane-1,1-diyl)bis(1H-indole) (3m):
Brown solid, Hexane/EtOAc = 4/1, yield 139 mg, 76%; 1H NMR (300 MHz, CDCl3): δ 7.85
(s, 2H), 7.35 (m, 6H), 7.14 (t, J = 7.2 Hz, 2H), 6.94 (t, J = 7.8 Hz, 2H), 6.79 (d, J = 9.0 Hz,
2H), 6.61 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H); 13C{1H}NMR (75 MHz, CDCl3): δ 157.5, 140.3,
137.1, 129.1, 126.4, 125.0, 123.3, 122.1, 121.5, 118.9, 113.0, 111.1, 55.2, 43.1, 28.8; HRMS
(ESI/TOF-Q) m/z: [M + Na]+ Calcd for C25H22N2ONa 389.1624; Found 389.1622. HRMS
(ESI/TOF-Q) m/z: [M + H]+ Calcd for C25H23N2O+ 367.1805; Found 367.1807.
3-styryl-1H-indole (4a):
1
Light brown viscous liquid, Hexane/EtOAc = 19/1, 2 mmol scale, yield 262 mg, 60%; H
NMR (300 MHz, DMSO-d6): δ 11.37 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.58 (d,
J = 7.2 Hz, 2H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (s, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.21-7.09 (m,
4H); 13C{1H}NMR (75 MHz, DMSO-d6): δ 139.0, 137.5, 129.1, 126.7, 126.5, 125.9, 125.6,
123.7, 123.0, 122.2, 120.3, 120.1, 114.1, 112.4.
(E)-5-styryl-1H-indole (4b):
1
Yellow viscous liquid, Hexane/EtOAc = 19/1, 2 mmol scale, yield 315 mg, 72%; H NMR
(300 MHz, CDCl3): δ 8.06 (s, 1H), 7.75 (s, 1H), 7.52 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 8.7 Hz,
1H), 7.34 (t, J = 7.8 Hz, 3H), 7.24 (m, 2H), 7.15 (m, 1H), 7.07 (d, J = 16.2 Hz, 1H), 6.54 (s,
1H); 13C{1H}NMR (75 MHz, CDCl3): δ 138.1, 135.6, 130.1, 129.6, 128.6, 128.3, 127.0,
126.3, 126.1, 124.8, 120.7, 119.5, 111.3, 103.0.
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 24
1
2
3
4
5
6
7
8
9
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, Delhi-
110016; E-mail: njain@chemistry.iitd.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank Council of Scientific and Industrial Research (CSIR), India 02(0180)/14/EMR-
II for financially supporting this work, and providing the fellowship to NC. We acknowledge DST-
FIST for funding the ESI-HRMS facility at IIT Delhi. AS and SSP thank CSIR for their graduate
fellowships.
Supporting Information
1
Copies of H NMR, 13C{1H}NMR and HR-MS for all the synthesized compounds, GC-MS
spectrum of III/IV and LC-MS spectra for determination of KH/KD and cross-over experiment for
determination of scrambling of H/D has been included. This material is available free of charge
via the internet at http://pubs.acs.org.
REFERENCES
1. Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250-
2293.
ACS Paragon Plus Environment
22

Page 23 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2. a) Ji, S. -J.; Zhou, M. -F.; Gu, D. -G.; Jiang, Z. -Q.; Loh, T. -P. Eur. J. Org. Chem. 2004,
1584-1587. b) Nagarajan, R.; Perumal, P. T. Tetrahedron 2002, 58, 1229-1232. c)
Mahadevan, A.; Sard, H.; Gonzaleza, M.; McKew, J. C. Tet. Lett. 2003, 44, 4589-4591.
3. Chakrabarty, M.; Ghosh, N.; Basaka, R.; Harigaya, Y. Tet. Lett. 2002, 43, 4075-4078.
4. Xiang, J.; Wang, J.; Wang, M.; Meng, X.; Wu, A. Org. Biomol. Chem. 2015, 13, 4240-
4247.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5. Xu, H.-Y.; Zi, Y.; Xu, X.-P.; Wang, S.-Y.; Ji, S.-J. Tetrahedron 2013, 69, 1600-1605.
6. Yang, Q.; Wang, L.; Guo, T.; Yu, Z. J. Org. Chem. 2012, 77, 8355-8361.
7. Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C. -H. Chem. Eur. J. 2007, 13, 8285-8293.
8. Wang, M.-Z.; Zhou, C.-Y.; Che, C.-M. Chem. Commun. 2011, 47, 1312-1314.
9. Barluenga, J.; Fernandez, A.; Rodriguez, F.; Fananas, F. J. Chem. Eur. J. 2009, 15, 8121.
10. Yadav, J. S.; Reddy, B. V. S.; Padmavani, B.; Gupta, M. K. Tet. Lett. 2004, 45, 7577.
11. a) Tsuchimoto, T.; Nagase, Y.; Miyamura, T.; Matsubayashi, H.; Kaneko, M.; Shirakawa,
E. J. Am. Chem. Soc. 2008, 130, 15823. b) Bhaskar, G.; Saikumar, C.; Perumal, P. T. Tet.
Lett. 2010, 51, 3141.
12. a) Gao, R.; Yi, C. S. J. Org. Chem. 2010, 75, 3144. b) Cadierno, V.; Francos, J.; Gimeno,
J. Chem. Commun. 2010, 46, 4175.
13. Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Org. Lett. 2000, 2, 2927.
14. Donets, P. A.; Hecke, K. V.; Meervelt, L. V.; Van Der Eycken, E. V.; Org. Lett. 2009, 11,
3618.
15. Xie, M.-H.; Xie, F.-D.; Lin, G.-F.; Zhang, J.-H. Tet. Lett. 2010, 51, 1213.
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 24
1
2
3
4
5
6
7
8
9
16. a) Ferrer, C.; Escribano-Cuesta, A.; Echavarren, A. M. Tetrahedron 2009, 65, 9015. b)
Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem. Eur. J. 2007, 13, 1358. c) Ferrer, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17. Barluenga, J.; Fernandez, A.; Rodriguez, F.; Fananas, F. J. J. Organomet. Chem. 2009,
694, 546.
18. Xia, D.; Wang, Y.; Du, Z.; Zheng, Qi-Yu; Wang, C. Org. Lett. 2012, 14, 588.
19. a) Jha, A. K.; Jain, N. Chem. Commun. 2016, 52, 1831-1834. b) Sharma, P.; Rohilla, S.;
Jain, N. J. Org. Chem. 2015, 80, 4116-4122. c) Premi, C.; Dixit, A.; Jain, N. Org.
Lett. 2015, 17, 2598-2601.
20. Verma, A.K., Danodia, A.K., Saunthwal, R.K., Patel, M., Choudhary, D. Org. Lett. 2015,
17, 3658-3661.
21. Beckhaus, R.; Oster, J.; Wang, R. Organometallics 1998, 17, 2215-2221.
22. a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302-1315. b) Xiao, Q.; Xia, Y.; Li,
H.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2011, 50, 1114 -1117. c) Xiao, T.; Donga,
X.; Zhou, L. Org. Biomol. Chem. 2013, 11, 1490-1497.
23. Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem. Int. Ed. 2005,
44, 3125-3129.
24. Peng, J.-B.; Qi, Y.; Ma, A.-J.; Tu, Y.-Q.; Zhang, F.-M.; Wang, S.-H.; Zhang, S.-Y. Chem.
Asian J. 2013, 8, 883-887.
25. Frei, R.; Breitbach, A. S.; Blackwel, H. E. Angew. Chem. Int. Ed. 2012, 51, 5226-5229.
26. Bew, S. P.; Hiatt-Gipson, G. D.; Lovell, J. A.; Poullain, C. Org. Lett. 2012, 14, 456-459.
27. Noguchi-Yachide, T.; Tetsuhashi, M.; Aoyama, H.; Hashimoto, Y. Chem. Pharm. Bull. 2009, 57,
536-540.
ACS Paragon Plus Environment
24