Palladium catalyzed coupling of tosylhydrazones with aryl and heteroaryl halides in the absence of external ligands: Synthesis of substituted olefins

Article abstract of DOI:10.1021/jo301987c

Palladium catalyzed cross-coupling reaction of hydrazones with aryl halides in the absence of external ligand is reported. The versatility of this coupling reaction is demonstrated in showcasing the selectivity of coupling reaction in the presence of hydr

Full text of DOI:10.1021/jo301987c

Subscriber access provided by DALHOUSIE UNIV
Article
Palladium Catalyzed Coupling of Tosylhydrazones with Aryl & Heteroaryl
Halides in the Absence of External ligands: Synthesis of Substituted Olefins
Devi Prasan Ojha, and Kandikere Ramaiah Prabhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301987c • Publication Date (Web): 27 Nov 2012
Downloaded from http://pubs.acs.org on November 28, 2012
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 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Palladium Catalyzed Coupling of Tosylhydrazones with
Aryl & Heteroaryl Halides in the Absence of External
ligands: Synthesis of Substituted Olefins
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
Devi Prasan Ojha and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.
prabhu@orgchem.iisc.ernet.in
Telephone: +91-80-22932887; Fax: +91-80-23600529
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
Abstract
1
2
3
4
5
6
7
8
9
Palladium catalyzed cross coupling reaction of hydrazones with aryl halides in the absence of external
ligand is reported. The versatility of this coupling reaction is demonstrated in showcasing the selectivity
of coupling reaction in the presence of hydroxyl and amine functional groups. This method allows
synthesizing a variety of heterocyclic compounds, which are difficult to access from other traditional
methods and are not synthesized by employing similar coupling reactions. Application of the present
methodology is validated in tandem reaction of ketones to the corresponding substituted olefins in a
single pot experiment.
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
Introduction
Amongst the several approaches for C-C bond formation, oxidative cross-coupling reactions with a
variety of organometallic compounds are both attractive as well as useful.1 A variety of organometallic
reagents such as organocopper, magnesium, zinc, tin, silicon, and boron have been subject of intensive
research to furnish C-C bonds.2 In this respect, the metal mediated C-H functionalization provides a
potentially more efficient methodology to construct aromatic as well as heteroaromatic compounds.3
Palladium catalyzed cross-coupling reactions to provide C(sp2)-C(sp2) bonds are emerging as most
prominent methods for accomplishing complex organic scaffolds.4 In this context, palladium catalyzed
cross-coupling reactions of tosylhydrazone with aryl halides was first conceived by Barluenga and
Valdés.5 This intriguing discovery was extended to variety nucleophiles such as heteroaromatics, aryl
boronic acids, phenyl acetylenes, etc. to form C-C bonds to accomplish carbocyclic as well as
heterocyclic compounds.6 An extensive research has led to establish reaction of several hydrazones such
as tosylhydrazones, aliphatic chiral hydrazones, in situ generated hydrazones, with a variety of coupling
partners such as aromatic halides, aromatic boronic acids derivatives, and vinyl halides, alcohols and
thiols.7 For all these transformations, a catalytic amount of [Pd2(dba)3] or PdCl2(MeCN)2 has been used
in the presence of catalytic amount of ligands such as Xphos or dppp. It is Wang and coworkers,8 who
developed Pd chemistry in the presence of Cu additives for these cross-coupling reactions. The reaction
2
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
of hydrazones with aryl halides in the presence of [Pd2(dba)3] resulted in the formation of substituted
olefins,5 whereas the similar reaction of arylhydrazones with arylboronic acid resulted in the alkylation
or arylation of hydrazones to furnish corresponding biarylmethanes.6a Although [Pd2(dba)3] catalyzes the
cross coupling of aryl halides with unhindered hydrazones to form diarylethylenes, it is not effective
with sterically hindered hydrazones, which resulted in the formation of trisubstituted olefins as major
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
9
products, without any coupling of the aryl halide. However, it was revealed that PdCl2(MeCN)2 is
efficient in furnishing the tetrasubstituted olefins in good yields. 9 Aryl sulfonates, triflates, nonaflates
are also employed as coupling partners with hydrazones in the presence of Pd(OAc)2 and Pd2(dba)3.10
Further, C-C bond formation was accomplished using benzyl halides, hydrazones in the presence of
[Pd2(dba)3] employing P(2-furyl)3 as a ligand (Scheme 1).11
Scheme 1.
Generally, the coupling reactions require additional ligands like xphos12a or dppp12b etc,12c which are
expensive. Moreover, the reactions are not suitable in the presence of sensitive functional groups such as
hydroxyl, amino etc.7c, 14 Further, 1,3-azole-heteroaryl halides have not been explored as coupling
partners. In this context, herein we present our new findings on the reactions of aryl hydrazones with
aryl/heteroaryl
halides
in
the
presence
of
catalytic
amount
of
Pd(PPh3)2Cl2
(bis(triphenylphosphine)palladium dichloride) in the absence of any activating ligands to furnish the
corresponding substituted olefins.
Results and discussion
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
The preliminary studies were carried out with N-tosylhydrazone 1a and 4-methoxyhalobenzenes 2a
and 2b. Reaction of 1a with arylbromide (2a) in the presence of Pd2(dba)3 (2.5 mol%) and tert-BuOLi at
100 °C for 1 h resulted in the formation of 3a in 7% (entry 1, Table 1 ). In the absence of Pd catalyst, the
reaction of 1a did not proceed with arylbromide 2a (entry 2, Table 1). Further, it was found that Cs2CO3
was a better base for this reaction as the reaction provided the expected product in 70% with aryliodide
(2b), whereas similar reaction with arylbromide (2a) was not successful (entries 3 and 4, Table 1).
Increasing the amount of hydrazone resulted in the formation of the corresponding olefin in almost
quantitative yield with iodobenzene, whereas arylbromide 2a found to yield trace amount of product
(entries 5 and 6, Table 1). Similar reaction with tert-BuOLi resulted in the formation of 3a in almost
quantitative yield with aryliodide 2b and 7% with arylbromide 2a (entries 7 and 8, Table 1).
Interestingly, the reaction of hydrazone 1a with arylbromide 2a in the presence of Pd(PPh3)2Cl2 and
CuCl as an additive with tert-BuOLi resulted in the formation of 3a in 66% yield (entry 9, Table
1).However, the reaction in the absence of CuCl failed to produce the expected product (entry 10, Table
1).15 It was pleasing to find that the reaction of 1a in the presence of Pd(PPh3)2Cl2 (2.5 mol%), tert-
BuOLi afforded 3a in almost quantitative yields both with 2a as well as 2b (entries 11 and 12, Table 1).
It is remarkable to see that this cross-coupling reaction between hydrazone 1a and 2a or 2b catalyzed by
trans-Pd(PPh3)2Cl2 works very effectively in the absence of additives and noteworthy to mention that
most of the reactions with other catalysts require expensive additives such as xphos (entries 11 and 12,
Table 1). Further screening studies indicated that the reaction is compatible with MeOH as the reaction
of 1a and 2a in MeOH furnished the product 3a in almost quantitative yield (entry 13, Table 1). As this
result suggests that there is a possibility of the formation of MeOLi in the reaction, few more controls
were performed (entries 14 and 15). The reaction of 1a and 2a in the presence of NaOMe in 1,4-dioxane
resulted in the formation of 3a in quantitative yield (entry 14, Table 1). Next, control reaction of 1a and
2a in the presence of tert-BuONa in methanol did not afford the product (entry 15). These two control
reactions suggest that the reaction of tert-BuOLi in methanol is not generating MeOLi intermediate.
However, attempts to perform reaction in H2O were not encouraging, as this reaction of 1a and 2a in
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
4
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
water resulted in the formation of 3a in poor yield (entry 16, Table 1). Subsequent screening studies
indicated that the similar reaction using lesser amount of hydrazone (1.3 equiv) decreased the yield of 3a
(entry 17, Table 1). In an optimal reaction procedure, hydrazone (1.5 equiv) and halobenzene (1 equiv)
were heated at reflux in the presence of Pd(PPh3)2Cl2 (2.5 mol%) with tert-BuOLi (4 equiv) in 1,4-
dioxane for 1 h. However, using PPh3 as an external ligand failed to furnish expected product under
optimized reaction conditions (entry 18, Table 1). This control experiment clearly indicates that the
presence of external ligand does not promote the reaction under the optimal reaction conditions.
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
Table 1. Screening of Pd catalysts
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
NNHTs
1
2
[Pd]
X
base
1,4-dioxane
100 oC
3
4
5
6
7
8
+
O
O
1a
O
O
2a
3a
X = Br or I
1a
2a
[Pd]
base
conversiona
(%)
entry
additive
(2.5 mol%)
(4 equiv)
(mmol) (mmol)
9
Pd2(dba)3
1
2
3
1
1
1
1.5
1.5
1.5
none
CuCl
CuCl
tert-BuOLi
7
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
none
tert-BuOLi
ND
ND
Pd(OAc)2
Cs2CO3
4
5
6
1
1.5
1
CuCl
CuCl
CuCl
70b
trace
100b
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cs2CO3
Cs2CO3
Cs2CO3
1.5
1.5
1
Pd(OAc)2
Pd(OAc)2
7
8
1.5
1.5
1
1
CuCl
CuCl
tert-BuOLi
tert-BuOLi
7
100b
Pd(PPh3)2Cl2
Pd(OAc)2
9
1.5
1.5
1
1
CuCl
none
tert-BuOLi
tert-BuOLi
66
10
ND
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
11
12
1.5
1.5
1
1
none
none
tert-BuOLi
tert-BuOLi
100
100b
13
14
15
16
1.5
1.5
1.5
1.5
1
1
1
1
none
none
none
none
tert-BuOLi
100c
100
NDc
27d
NaOMe
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
tert-BuONa
tert-BuOLi
Pd(PPh3)2Cl2
17
1.3
1
none
tert-BuOLi
93
18
1.5
1
tert-BuOLi
NDe
PdCl2
PPh3
a By 1H NMR analysis with respect to starting material. b4-iodoanisole.
c Reaction was performed in MeOH as solvent at 60 oC. d Reaction was
performed in H2O as solvent at 100 oC. e Reaction was carried out with
PdCl2 (5 mol%), PPh3 (10 mol%). ND=Not detected
After successfully achieving the optimal conditions for cross-coupling reaction, we focused our
attention to study the scope of the reaction (Table 2). Tosylhydrazone 1a reacted well with 4-
methoxybromobenzene 2a or and 4- methoxyiodobenzene 2b in 1h to furnish the product 3a in excellent
yields (95% and 93%, entries 1 and 2, Table 2). Similarly, 4-methyliodobenzene and 4-
methylbromobenzene (2c and 2d) underwent smooth coupling with hydrazone 1a and furnished the
product 3b (90% and 88%, entries 3 and 4, Table 2). 3-Methoxybromobenzene 2e underwent a smooth
6
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
coupling with tosylhydrazone 1b in 1h to afford 3c in good yield (87%, entry 5, Table 2). Hydrazone 1c
reacted with a variety of substituted aromatic bromides and aromatic iodides. As can be seen in Table 2,
coupling reaction of hydrazone 1c proceeded smoothly with 4-bromoacetophenone, 4-bromoanisole, 4-
iodoanisole, 4-bromotoluene and 4-iodotoluene to furnish the products 3d, 3e, and 3f in good to
excellent yields (entries 6-10).13 It is interesting to see that carbonyl group does not interfere in the
reaction (entry 6). It is known that substrates that contain hydroxyl and amine groups are not good
substrates for coupling as they have tendency of forming the corresponding ethers and substituted
amines. 7c, 14 To test this hypothesis, 4-bromophenol (2g) was reacted with hydrazone 1b using Pd2(dba)3
(1 mol%) in the presence of xphos (4 mol%) under the standard reaction conditions that have been
employed earlier.5 But this reaction resulted in the formation of a complex mixture with trace amount of
starting material. Interestingly, the similar reaction of 4-bromophenol (2g) and hydrazone 1b under the
present reaction conditions produced a remarkable result as it furnished the corresponding olefin 3g in
good yield (72%, entry 11, Table 2). This observation was substantiated by the reaction of hydrazone 1d
derived from 1-(3-hydroxyphenyl)ethanone, which contains OH group, with 1-bromo-3,5-
bis(trifluoromethyl)benzene (2h) and 1-bromo-4-chlorobenzene (2i) to furnish the coupled products 3h
and 3i in 92% and 90% respectively (entries 12 and 13, Table 2). Similarly, the reaction of hydrazone 1a
with 2-bromoaniline (2j) and 2-iodoaniline (2k) furnished the coupled product 3j in 88% and 92%
(entries 13, 14, Table 2). As observed in the reaction of 4-bromophenol (entry 11), 2-bromoaniline in a
reaction with hydrazone 1b in the presence of Pd2(dba)3 (1 mol%) and xphos (4 mol%) resulted in the
formation of dimer of haloaniline 5,10-dihydrophenazine in almost quantitative yield.16 Whereas the
similar reaction of 2-bromoaniline (2j) and hydrazones 1a or 1b under the present reaction conditions
furnished the olefins 3j and 3k in good to excellent yields (entries 15 and 16, Table 2). In these
examples (entries 11-16), phenolic OH group as well as NH2 groups were intact during the reaction
conditions, and hydrazone 1a underwent a facile coupling with halides containing amine and phenolic
OH groups. More importantly, formation of corresponding ethers or substituted amines was not
observed. It was found that the coupling reaction tolerates nitrile and chloro functionalities as 4-
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
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
bromobenzonitrile (2l) and 4-chlorobromobenzene (2i) underwent a smooth coupling reaction with
hydrazone 1e to form the products 3l and 3m respectively in excellent yields (entries 17-18, Table 2).
Importantly, these examples demonstrate that heterocyclic compound such as 1e is a good precursor for
the coupling reaction. Aliphatic hydrazones such as 1f and 1g were found to be good precursors as they
underwent coupling reaction with aromatic bromides and iodides. Accordingly, 1f in a reaction with 2a
and 2b furnished the coupled product 3n in good to excellent yields (entries 19-20, Table 2). However,
reaction of 1g with 2a furnished a mixture of 3o (as E:Z mixtures in 94:6 ratio) and 3p in 91% (88:12
ratio)( entry 21, Table 2). It was further found that the reaction of 1f with 2a did not proceed in water.
This result is on agreement with our observation that the reaction of 1a with 2a under the present
reaction conditions forms the product 3a in poor yield (entry 13, Table 1).
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
Table 2. Palladium catalyzed coupling reactionsa
8
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
Arene
R2
Pd(PPh3)2Cl2
NNHTs
R1
1
2
3
4
5
6
7
8
+
Arene-X
R2
tert-BuOLi, 1,4-dioxane, 100 0C
R1
time yield
(%)b
(h)
entry hydrazone
halo-arenes
X
product
NNHTs
9
R1
R2
R1
1
R2
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
1a: R1 = -OMe
1a: R1 = -OMe
1a: R1 = -OMe
1a: R1 = -OMe
3a: R1 = R2 = -OMe
3a: R1 = R2 = -OMe
3b: R1 = -OMe, R2 = -Me1 90
3b:R1 = -OMe, R2 = -Me 1 88
2a : X=Br, R2 = -OMe
2b: X=I, R2 = -OMe
2c:X=I, R2 = -Me
1
1
95
93
2
3
4
2d:X=Br, R2 = -Me
O
NNHTs
Br
X
O
5
1b
3c
1
87
2e
NNHTs
R
R
1c
1c
1c
1c
1c
3d: R = -C(O)Me
3e: R = -OMe
3e
3f: R = -Me
3f
6
7
8
9
2f: X = Br, R = -C(O)Me
2a: X = Br, R = -OMe
2b: X = I, R = -OMe
2d: X = Br, R = -Me
2c: X = I, R = -Me
2
2
2
2
2
91
93
85
90
90
10
Br
OH
OH
11 1b
3g
6
72c
2g
NNHTs
Br
CF3
HO
HO
CF3
HO
CF3
CF3
12 1d
3h
2
2
92c
2h
Br
Cl
Cl
13 1d
3i
90c
2i
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
Table 2 continued….
1
2
3
4
time yield
(%)b
(h)
entry hydrazone
halo-arenes
product
5
6
NH2
NNHTs
7
8
X
9
O
O
NH2
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
14 1a
2j: X = Br
2k: X = I
3j
3j
2
2
88d
92d
15
1a
NH2
Br
NH2
16 1b
2j
3k
6
92
Br
NNHTs
N
N
R
R
17 1e
18 1e
2l: X = Br, R = -CN
2i: X = Br, R = -Cl
3l: R = -CN
3m: R = -Cl
2
3
93
91
NNHTs
X
R
OMe
19
20
1f
1f
2a: X=Br, R = -OMe
2b: X=I, R = -OMe
3n
3n
6
5
91
93
X
NNHTs
O
O
O
4
1g
E:Z (94:6)
91e
3p
21
3o
2a: X=Br
a
Reactions conditions: 1a (1.5 equiv.), 2a (1.0 equiv.), Pd(PPh3)2Cl2
(2.5 mol%), tert-BuOLi (4.0 equiv.) in 1,4-dioxane . b isolatd yields. c Cs2CO3
(4 equiv.), d 90 0C. e 3o:3p are formed in 88:12 ratio.
Synthesis of heteroaromatics is an important area of research which provides an access for
biologically and pharmaceutically activity compounds. Surprisingly, the cross-coupling reactions are not
used to accomplish heterocyclic derivatives that are compiled in Table 3. As the present strategy
presents an opportunity to accomplish corresponding heterocyclic derivatives, 2-halo-benzo[d]thiazoles
2m and 2n were subjected for coupling reaction with hydrazones 1f and 1g to obtain corresponding
coupled products 3q and 3r in excellent yields (entries 1-3, Table 3). It is noteworthy that it is not easy
10
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
to synthesize these classes of benzothiazoles using traditional methods, which require multistep
sequences using ketones precursors.17 Similarly, hydrazones 1f and 1a coupled smoothly with 3-
bromopyridine (2o) and 2-bromopyridine (2p) to furnish products 3s and 3t (entries 4 and 5, Table 3).
1
2
3
4
5
6
7
8
9
Table 3. Palladium catalyzed coupling reactions with heterocyclic compoundsa
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
hydrazone
halo-arene
S
product
S
yield (%)b
time (h)
X
NNHTs
N
N
3q
3q
1f
1f
2m: X = Cl
1
2
94
86
6
7
2n: X = Br
S
S
Br
NNHTs
N
N
3r
3
1g
2n
80
86
6
6
N
Br
NNHTs
N
3s
4
5
1f
2o
NNHTs
Br
N
N
6
68c
O
O
3t
1a
2p
a reaction conditions: hydrazone (1.5 equiv), heteroarylhalides (1 equiv),
Pd catalyst (2.5 mol%), tert-BuOLi (4 equiv), dioxane, 100 oC. b isolatd yields.
c Yield based on 1H NMR
The application and usefulness of this methodology is further demonstrated by employing ketones as
the precursors (Table 3). In this one-pot tandem reaction, the hydrazone was generated in situ by treating
corresponding ketones with tosylhydrazine, and hydrazones thus generated were subjected for coupling
reaction with aryl halides in the presence of Pd(PPh3)2Cl2 (2.5 mol%) with tert-BuOLi (4 equiv)
(Scheme 2). As can be seen in Scheme 2, ketones 4a, 5a, and 6a underwent a smooth tandem reaction
with 2a, 2e, and 2f respectively in dioxane to furnish the expected couple products 3a, 3c, and 3d in
good yields (entries 1-3, Scheme 2).18
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
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 2. Tandem reaction of in situ generated ketones with aryl halidesa
A tentative mechanism of this transformation is presented in Scheme 3, based on the literature
precedence.7,8,11,19 Pd0 (I), undergoes an oxidative insertion with aromatic halide (2a) to form Pd
complex II. Azo-compound IIIB generated by hydrazone (1a) via IIIA in the presence of base inserts
into Pd complex (II) to form the palladium complex IV.19c Migration of aryl group from intermediate IV
leads to product 3a, and regenerates Pd catalyst.
12
ACS Paragon Plus Environment

Page 13 of 25
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
Scheme 3. Tentative mechanism
Br
PPh3
Pd
O
2a
PPh3
O
3a
I
PPh3
Br Pd
PPh3
O
Ph3P
Ph3P Pd
O
II
N
N
IV
ESI MS: 841.25 (M+)
IIIB
NNHTs
B
NNTs
IIIA
1a
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have demonstrated a Pd catalyzed, ligand-free cross coupling reaction of aryl
halides with hydrazones to furnish corresponding substituted olefins. The salient feature of this
methodology is, the coupling reaction is performed in the absence of ligand. The coupling reaction
exhibits an excellent selectivity in the presence of hydroxyl and amine functionalities. Additionally, the
method provides excellent avenue to accomplish a variety of heterocyclic derivatives, which are difficult
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
to access from other traditional methods and hitherto are not synthesized by employing similar coupling
reactions. Application of the present methodology is demonstrated in tandem reaction of ketones to the
corresponding substituted olefins in a single pot experiment.
1
2
3
4
5
6
7
8
9
Experimental Section
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
General procedures for the preparation of tosylhydrazones: A mixture of ketone (20 mmol) and
methanolic solution (30 mL) of p-toluenesulfonylhydrazide (20 mmol) was refluxed for 0.5-2 h. Then
the mixture was allowed to cool to room temperature, the precipitated product was filtered, which was
washed thoroughly with hexane to get corresponding tosylhydrazone as a crystalline product.
Typical experimental procedure for coupling reaction of hydrazone with arylbromide: A well
stirred mixture of tosylhydrazone (1a, 130 mg, 0.4 mmol), 4-bromoanisole (2a, 50 mg, 0.267 mmol),
Pd(PPh3)2Cl2 (5 mg, 0.0067 mmol) in 1,4-dioxane (3 mL) under nitrogen atmosphere was heated at 100
°C. To this hot clear solution was added tert-BuOLi (84 mg, 1 mmol), and the reaction was stirred at
100 °C for 1h (monitored by TLC). Then the reaction mixture was cooled to room temperature and
diluted with EtOAc (10 mL) and passed through a short Celite pad, the solvent was evaporated under
reduced pressure, and purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product 3a as a
white solid, yield: 61 mg (94%).
Typical experimental procedure for one-pot tandem reaction of ketone, tosylhydarzine with
arylbromide: A well stirred mixture of 4-methoxyacetophenone (60 mg, 0.4 mmol), tosylhydrazide (74
mg, 0.4 mmol), in dioxane (3 mL) was heated at 90 °C for 2h. To this reaction mixture was added 4-
bromoanisole (2a, 50 mg, 0.267 mmol), Pd(PPh3)2Cl2 (5 mg, 0.0067 mmol), tert-BuOLi (84 mg, 1
mmol) under nitrogen atmosphere at 100 °C and reaction was further stirred at 100 °C for 2h (monitored
by TLC). Then the reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL)
and passed through a short Celite pad, the solvent was evaporated under reduced pressure, and purified
on a silica gel column (hexane/EtOAc, 99:1) to obtain the product 3a as a white solid, yield: 48 mg
(74%).
14
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
N'-(1-(3-hydroxyphenyl)ethylidene)-4-methylbenzenesulfonohydrazide (1d); Prepared according to
the above procedure, the precipitated product was filtered as White solid: Yield: 1.88 g (84%), mp 126-
127 ºC. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.21-7.13 (m,
1
2
3
4
5
6
7
8
9
3H), 6.85-6.83 (m, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 155.7, 152.1, 144.3, 138.7, 135.2,
129.7, 129.5, 128.1, 118.8, 116.9, 112.96; IR (neat, cm-1): 3325, HRMS (ESI): Calculated for
C15H16N2O3S (M+Na): 327.0779, found (M+H): 327.0777.
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
General procedure for coupling reaction of tosylhydrazones with aryl halides:
A well stirred mixture of tosylhydrazone (0.4 mmol), aryl halide (0.267 mmol), Pd(PPh3)2Cl2 (0.0067
mmol) in 1,4-dioxane (3 mL) under nitrogen atmosphere was heated at 100 °C. To this hot clear solution
was added tert-BuOLi (1 mmol) at 100 °C till the completion of the reaction (monitored by TLC). Then
the reaction mixture was cooled to room temperature and diluted with EtOAc and passed through a short
Celite pad, the solvent was evaporated under reduced pressure, and purified on a silica gel column.
Typical experimental procedure for one-pot tandem reaction of ketone, tosylhydarzine with
arylbromide: A well stirred mixture of ketone (60 mg, 0.4 mmol), tosylhydrazide (0.4 mmol), in
dioxane (3 mL) was heated at 90 °C for 2h. To this reaction mixture was added arylbromide (0.267
mmol), Pd(PPh3)2Cl2 (5 mg, 0.0067 mmol), tert-BuOLi (84 mg, 1 mmol) under nitrogen atmosphere at
100 °C and reaction was further stirred at 100 °C for 2h (monitored by TLC). Then the reaction mixture
was cooled to room temperature and diluted with EtOAc (10 mL) and passed through a short Celite pad,
the solvent was evaporated under reduced pressure, and purified on a silica gel column.
4,4'-(ethene-1,1-diyl)bis(methoxybenzene) (3a);8 Prepared as shown in general procedure. Crude
reaction mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as
White solid: Yield: 0.048g (94%) from 4-iodoanisole and 0.061g (95%) from 4-bromoanisole ; mp 135-
1
137 ºC (lit. 8 m.p. 136-138 ºC). Rf = 0.9 (hexane/EtOAc, 20 : 1). H NMR (400 MHz, CDCl3): δ 7.27
(d, J = 8.4 Hz, 4H), 6.86 (d, J = 8.4 Hz, 4H), 5.29 (s, 2H), 3.82 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
159.3, 148.9, 134.3, 129.1, 113.5, 111.6, 55.3; IR (neat, cm-1): 2935, 2837, 1607, 1508, 1252, 841, 738;
HRMS (ESI): Calculated for C16H16O (M+H): 225.1279, found (M+H): 225.1278.
1
2
3
4
5
6
7
8
1-methoxy-4-(1-(p-tolyl)vinyl)benzene (3b);8 Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as White solid:
Yield: 0.058g (88%) from 4-bromotoluene and 0.046g (90%) from 4-iodotoluene. mp 72-74 ºC (lit.8 mp
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
73-74 ºC ). Rf = 0.95 (hexane/EtOAc, 20 : 1); H NMR (400 MHz, CDCl3): δ 7.28-7.23 (m, 4H), 7.01
(d, J = 7.7 Hz, 2H), 6.86 (d, J = 8.24 Hz, 2H), 5.33 (d, J = 5.56 Hz, 2H), 3.82 (s, 3H), 2.36 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 159.3, 149.3, 138.91, 137.4, 134.2, 129.4, 128.8, 128.2, 113.5, 112.3, 55.3,
21.3; IR (neat, cm-1): 2918, 2850, 1607, 1508, 1250, 832; HRMS (ESI): Calculated for C16H16O
(M+H): 225.1279, found (M+H): 225.1278.
1-methoxy-3-(1-phenylvinyl)benzene (3c);20 Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as Colorless
1
oil: Yield: 0.049g (87%). Rf = 0.95 (hexane/EtOAc, 20:1). H NMR (400 MHz, CDCl3): δ 7.31-7.33
13
(m, 5H), 7.22-7.24 (m, 1H), 6.93 (m, 3H), 5.46 (s, 2H), 3.78 (s, 3H); C NMR (100 MHz, CDCl3): δ
159.4, 149.9, 142.9, 141.3, 129.1, 128.1, 127.7, 120.8, 114.4, 113.9, 113.1, 55.2; IR (neat, cm-1): 2920,
2850, 1597, 1578, 143, 1239, 777, 698. HRMS (ESI): Calculated for C15H15O (M+H): 211.1123, found
(M+H): 211.1123.
1-(4-(1-phenylprop-1-en-1-yl)phenyl)ethanone (3d); Prepared as shown in general procedure. Crude
reaction mixture was purified on a silica gel column (hexane/EtOAc, 98:2) to obtain the product as
Light yellow oil: Yield: 0.054g (91%), Rf = 0.85 (hexane/EtOAc, 20:1). 1H NMR (400 MHz, CDCl3): δ
7.98 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.15-7.71 (m, 7H), 6.31 (q, J = 7.0 Hz, 0.4H), 6.23 (q,
J = 7.0 Hz, 0.6H), 2.63 (s, 1.7H), 2.57 (s, 1.2H), 1.78 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 197.8, 197.7, 147.5, 145.3, 142.2, 141.7, 139.1, 135.6, 130.3, 129.9, 128.2, 128.2, 127.1, 127.0, 126.6,
16
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
125.2, 26.6, 26.5, 15.8, 15.7; IR (neat, cm-1): 2914, 1682, 1603, 1356, 1267, 760, 701; HRMS (ESI):
1
2
3
Calculated for C17H16O (M+Na): 259.1099, found (M+Na): 259.1099.
4
5
6
7
1-methoxy-4-(1-phenylprop-1-en-1-yl)benzene 3e);21 Prepared as shown in general procedure. Crude
8
9
reaction mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as
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
Colourless oil: Yield: 0.056g (93%), Rf = 0.95 (hexane/EtOAc, 20:1). H NMR (400 MHz, CDCl3): δ
7.36 (t, J = 7.2 Hz, 1H), 7.09-7.3 (m, 7H), 6.79 (d, J = 8.3 Hz, 1H), 6.05-6.014 (m, 1H), 3.83 (s, 1.6H),
13
3.83 (s, 1.4H), 1.77 (d, J = 6.9 Hz, 1.5H), 1.73 (d, J = 7.0 Hz, 1.6H); C NMR (100 MHz, CDCl3): δ
158.6, 158.4, 143.4, 141.97, 141.8, 140.3, 135.7, 132.3, 131.2, 128.2, 128.1, 128.0, 127.3, 126.7, 126.6,
123.8, 122.4, 113.4, 55.2, 55.2, 15.8, 15.6; IR (neat, cm-1): 3361, 2925, 1645, 1508, 1245, 702; HRMS
(ESI): Calculated for C16H16O (M+H): 225.1279, found (M+H): 225.1279.
1-methyl-4-(1-phenylprop-1-en-1-yl)benzene (3f); Prepared as shown in general procedure. Crude
reaction mixture was purified on a silica gel column (hexane) to obtain the product as Colorless oil:
Yield: 0.058g (90%) from 4-bromotoluene and 0.043g (90%) from 4-Iodotoluene. Rf = 0.9
1
(hexane/EtOAc, 20:1). H NMR (400 MHz, CDCl3): δ 7.36 (t, J = 7.0, 1H), 7.17-7.30 (m, 5H), 7.05-
7.11 (m, 3H), 6.13 (q, J = 7.0 Hz, 1H), 2.38 (s, 1.5H), 2.23 (s, 1.6H), 1.75 (t, J = 8.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 143.2, 142.22, 142.2, 140.2, 136.9, 136.4, 130.0, 129.9, 128.8, 128.7, 128.0,
127.9, 127.2, 127.0, 126.7, 126.6, 123.9, 123.2, 21.2, 21.0, 15.7, 15.6; IR (neat, cm-1): 3023, 2922,
2855, 1510, 1441, 810, 759, 701.
4-(1-phenylvinyl)phenol (3g); Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (PE:EA, 20:1) to obtain the product as Colourless oil: Yield: 0.041g
1
(72%) from 4-bromophenol. Rf = 0.6 (hexane/EtOAc, 20:1). H NMR (400 MHz, CDCl3): δ 7.306-
7.332 (m, 5H), 7.203-7.245 (m, 4H), 6.7865 (d, J = 8.76 Hz, 2H), 5.38 (d, J = 1.28 Hz, 1H), 5.34 (d, J =
13
1.28 Hz, 1H); C NMR (100 MHz, CDCl3): δ 155.4, 149.4, 132.4, 129.6, 128.3, 128.1, 127.6, 117.2,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
114.99, 112.9; IR (neat, cm-1): 3399, 2926, 1984, 1509, 1223, 851, 699; HRMS (ESI): Calculated for
1
2
3
C14H12O (M+H): 197.0966, found (M+H): 197.0961
4
5
6
7
8
9
3-(1-(3,5-bis(trifluoromethyl)phenyl)vinyl)phenol (3h); Prepared as shown in general procedure.
Crude reaction mixture was purified on a silica gel column (hexane/EtOAc, 90:10) to obtain the product
as Colourless oil: Yield: 0.052g (92%), Rf = 0.39 (hexane/EtOAc, 10:1) 1H NMR (400 MHz, CDCl3): δ
7.83 (s, 1H), 7.77 (s, 2H), 7.25 (t, J = 8 Hz, 1H), 6.86-6.76 (dd, J1 = 9.2 Hz, J2 = 2.5 Hz, 2H), 5.64 (s,
1H), 5.54 (s, 1H), 4.9 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 155.7, 147.4, 143.5, 141.4, 131.67 (q, J
= 33 Hz ), 129.9, 128.24 (d, J = 3.6 Hz), 123.3 (q, J = 271.1), 121.5 (m), 117.3, 115.5, 114.9 ; IR (neat,
cm-1): 2926, 2854, 1713, 1279, 1181, 1138, 900. HRMS (ESI): Calculated for C16H10F6O (M-H):
331.0558, found (M-H): 331.0559.
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-(1-(4-chlorophenyl)vinyl)phenol (3i): Prepared as shown in general procedure A. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 99:1 ) to obtain the product as colourless
1
oil: Yield: 0.054g (90%), Rf = 0.55 (hexane/EtOAc, 80:20) , H NMR (400 MHz, CDCl3): δ 7.25-7.31
(m, 4H), 7.21(t, J = 8 Hz, 1H), 6.88 (m, 1H), 6.79 (m, 2H), 5.458 (d, J = 1 Hz, 1H), 5.4257 (d, J = 1 Hz,
1 Hz), 4.83 (br s, 1H) ; 13C NMR (100 MHz, CDCl3): δ 155.4, 148.5, 142.7, 139.7, 133.6, 129.56,
129.5, 128.3, 120.8, 115.1, 114.9, 114.8; IR (neat, cm-1): 3320, 2943, 1450, 624 ; HRMS (ESI):
Calculated for C14H11ClO (M-H): 229.0420, found (M+H): 226.0394.
2-(1-(4-methoxyphenyl)vinyl)aniline (3j) : Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 80:20) to obtain the product as waxy solid :
Yield: 0.057g (88%) from 2-bromoaniline and 0.047 (92%) from 2-iodoaniline, Rf = 0.5
1
(hexane/EtOAc, 5:1); H NMR (400 MHz, CDCl3): δ 7.303 (dt, J1 = 9 Hz, J2 = 2 Hz, 2H), 7.13 (m,
2H), 6.84 (dt, J1 = 8.8 Hz, J2 = 2.5 Hz, 2H), 6.78 (td, J1 = 7.5 Hz, J2 = 1 Hz, 1H), 6.69 (dd, J1 = 8 Hz, J2
= 0.9 Hz, 1H), 5.69 (d, J = 1.5 Hz, 1H), 5.24 (d, J = 1.5 Hz, 1H) 3.79 (s, 3H), 3.57 (br s, 2H); 13C NMR
18
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
(100 MHz, CDCl3): δ 159.6, 146.5, 143.9, 132.1, 130.7, 128.6, 127.8, 127.6, 118.3, 115.5, 114.2, 113.9;
IR (neat, cm-1): 3320, 2943, 1450, 624 ; HRMS (ESI): Calculated for C15H15NO (M+H): 226.1232,
found (M+H): 226.1237.
1
2
3
4
5
6
7
8
9
2-(1-phenylvinyl)aniline (3k); Prepared as shown in general procedure. Crude reaction mixture was
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
purified on a silica gel column (hexane/EtOAc, 20:1) to obtain the product as colourless crystalline solid
1
: Yield: 0.052g (92%) from 2-bromoaniline, mp 61-64 ºC; Rf = 0.6 (hexane/EtOAc, 5:1); H NMR
(400 MHz, CDCl3): δ 7.38-7.37 (m, 2H), 7.34-7.28 (m, 3H), 7.18-7.1 (m, 2H), 6.78 (td, J1 = 7.5 Hz, J2
= 1 Hz, 1H), 6.69 (dd, J1 = 8 Hz, J2 = 0.9 Hz, 1H), 5.79 (d, J = 1.5 Hz, 1H), 5.35 (d, J = 1.5 Hz, 1H)
3.55 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 147.2, 143.9, 139.6, 130.8, 128.7, 128.5, 128.1, 127.3,
126.6, 118.3, 116.1, 115.5; IR (neat, cm-1): 3376, 3052, 1613, 752 ; HRMS (ESI): Calculated for
C14H13N (M+H): 196.1126, found (M+H): 196.1121.
4-(1-(pyridin-3-yl)vinyl)benzonitrile (3l); Prepared as shown in general procedure A. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 70:30) to obtain the product as Brown oil:
1
Yield: 0.051g (93%), Rf = 0.4 (hexane/EtOAc, 80:20) , H NMR (400 MHz, CDCl3): δ 8.59-8.42 (m,
2H), 7.64-7.67 (m, 2H), 7.56-7.59 (m, 1H), 7.41-7.44(m, 2H), 7.291-7.32 (m, 1H), 5.66 (d, J = 7.64 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ 149.4, 149.1, 145.5, 144.8, 135.9, 135.4, 132.3, 128.6, 123.3,
118.6, 118.4, 111.9; IR (neat, cm-1): 2923, 2852, 2228, 1606, 1406, 850, 716 ; HRMS (ESI):
Calculated for C14H10N2 (M+H): 207.0922, found (M+H): 207.0921.
3-(1-(4-chlorophenyl)vinyl)pyridine (3m); Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 70:30) to obtain the product as brown oil;
1
Yield: 0.051g (93%), Rf = 0.4 (hexane/EtOAc, 80:20). H NMR (400 MHz, CDCl3): δ 8.61-8.57 (m,
2H), 7.59-7.58 (m, 1H), 7.34-7.24 (m, 5H), 5.54 (d, J = 18.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
149.1, 149.1, 145.8, 138.8, 136.6, 135.4, 134.1, 129.3, 128.6, 123.1, 116.2; IR (neat, cm-1): 2956, 2924,
2852, 1490, 1402, 1013, 906, 835, 714 ; HRMS (ESI): Calculated for C13H10ClN (M+H): 216.058,
found (M+H): 216.058.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
4'-methoxy-2,3,4,5-tetrahydro-1,1'-biphenyl (3n);10b Prepared as shown in general procedure. Crude
reaction mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as
Colourless oil: Yield: 0.046g (91%) from 4-bromoanisole and 0.047 (93%) from 4-Iodoanisole. Rf = 0.9
1
2
3
4
5
6
7
8
1
(hexane/EtOAc, 20:1) H NMR (400 MHz, CDCl3): δ 7.32-7.29 (m, 2H), 6.86-6.83 (m, 2H), 6.04-6.01
9
(m, 1H), 3.8 (s, 3H), 2.4-2.35 (m, 2H), 2.21-2.16 (m, 2H), 1.8-1.74 (m, 2H), 1.68-1.61 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 158.4, 135.9, 135.3, 125.9, 123.1, 113.5, 55.3, 27.5, 25.8, 23.1, 22.2; IR
(neat, cm-1): 2933, 2858, 1602, 1512, 1249, 1178, 829 HRMS (ESI): Calculated for C13H16O (M+H):
189.1279, found (M+H): 189.1279.
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-(but-2-en-2-yl)-4-methoxybenzene (3o);22 Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as colourless
1
oil; Yield: 0.039g. (91%), Rf = 0.95 (hexane/EtOAc, 20:1) H NMR (400 MHz, CDCl3): δ 7.32-7.28
(m, 2H), 6.09-6.08 (m, 2H), 5.81-5.75 (qq, J1 = 6.8 Hz, J2 = 1.2 Hz, 1H), 3.8 (s, 3H), 2.00-1.99 (t, J =
1.2 Hz, 3H), 1.79-1.71 (dd, J1 = 6.8 Hz, J2 = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 158.3, 136.7,
134.8, 126.8, 120.8, 113.5.
2-(cyclohex-1-en-1-yl)benzo[d]thiazole (3q);23 Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 99:1) to obtain the product as colorless oil;
Yield: .048g (96%) from 2-bromobenzothiazole and 0.053g (86%) from 2-chlorobenzothiazole. Rf = 0.4
(hexane/EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): δ 7.97 (dq, J1= 8.2 Hz, J2 = 0.56 Hz, 1H), 7.81 (dq,
J1 = 7.92 Hz, J2 = 0.44 Hz, 1H), 7.42 (m, 1H), 7.32 (m, 1H), 6.81 (m, 1H), 2.68 (m, 2H), 2.31 (m, 2H),
13
1.82 (m, 2H), 1.72(m, 2H); C NMR (100 MHz, CDCl3): δ 170.3, 153.7, 134.1, 134.1, 133.4, 125.9,
124.8, 122.8, 121.3, 26.4, 26.1, 22.3, 21.9; (neat, cm-1): 2943, 2832, 1777, 1716, 1526, 1496, 983, 757 ;
HRMS (ESI): Calculated for C13H13NS (M+H): 216.0847, found (M+H): 216.0845.
(Z)-2-(but-2-en-2-yl)benzo[d]thiazole (3r);24 Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (hexane/EtOAc, 99:1). Yield: 0.035g (80 %), Rf = 0.4
20
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
(hexane/EtOAc, 5:1) 1H NMR (400 MHz, CDCl3) δ 8.0-7.96 (m, 1H), 7.98-7.96 (m, 1H), 7.57-7.32 (m,
1
2
3
4
13
2H), 6.65-6.63 (m, 1H), 2.28 (s, 3H), 2.23 (dd, J1 = 6.8 Hz, J2 = 1.2 Hz, 3H); C NMR (100 MHz,
CDCl3): 171.5, 153.8, 131.5, 129.5, 124.8, 122.8, 121.2, 36.2, 24.01, 14.5; IR (neat, cm-1); 2923, 1433,
906, 726; HRMS (ESI): Calculated for C11H12NS (M+H): 190.069, found (M+H): 190.0694.
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
3-(cyclohex-1-en-1-yl)pyridine (3s); Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (hexane/EtOAc, 70:30) to obtain the product as colourless liquid;
Yield: 0.043g (86%), Rf = 0.5 (hexane/EtOAc, 80:20). 1H NMR (400 MHz, CDCl3): δ 8.64-8.63 (d, J =
1.96 Hz, 1H), 8.48-8.43 (dd, J1 = 4.7 Hz, J2 =1.28 Hz, 1H), 7.66-7.62 (dt, J1 = 7.96 Hz, J2 = 2 Hz, 1H),
7.234-7.21 (dd, J1 = 7.9 Hz, J2 = 4.1 Hz, 1H), 6.18-6.16 (m, 1H), 2.42-2.38 (m, 2H), 2.248-2.08 (m, 2H),
1.83-1.77 (m, 2H), 1.71-1.65 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 147.6, 146.7, 137.9, 133.9,
132.1, 126.6, 123.0, 27.1, 25.8, 22.8, 21.9 ; IR (neat, cm-1): 2925, 2854, 1465, 1112, 964, 752 ; HRMS
(ESI): Calculated for C11H13N (M+H): 160.1126, found (M+H): 160.1122.
2-(1-(4-methoxyphenyl)vinyl)pyridine (3t); Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (90: 1); Yield: 0.040g (60%), followed by preparatory TLC
1
to obtain the product as a colourless liquid; Rf = 0.4 (hexane/EtOAc, 85:15). H NMR (400 MHz,
CDCl3): δ 8.64 (d, J = 5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.31-7.28 (m, 3H), 7.23-7.19 (m, 1H), 6.89
(d, J = 8.6 Hz, 2H), 5.86 (s, 1H), 5.55 (s, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3): 159.3, 158.9,
149.3, 148.6, 136.2, 132.8, 129.5, 122.8, 122.3, 116.4, 113.6, 55.3, IR (neat, cm-1): 2929, 1599, 1248,
1167, 1019, 835; HRMS (ESI): Calculated for C14H14NO (M+H): 212.1075, found (M+H): 212.1074.
Reaction of hydrazone (1a) and 2-bromoaniline (2j) with Pd2(dba)3 in the presence of xphos: A
well stirred mixture of tosylhydrazone (1b, 220 mg, 0.75 mmol), 4-bromoanilene (2m, 100 mg, 0.58
mmol), Pd2(dba)3 (9 mg, 0.01 mmol) and xphos (28 mg, 0.06 mmol) in 1,4-dioxane (4 mL) under
nitrogen atmosphere was heated at 90 °C. To this hot clear solution was added tert-BuOLi (186 mg, 2.3
mmol), and the reaction was stirred at 90 °C for 6h (monitored by TLC). Then the reaction mixture was
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
cooled to room temperature and diluted with EtOAc (10 mL) and passed through a short Celite pad, the
solvent was evaporated under reduced pressure, and purified on a silica gel column (hexane/EtOAc,
20:1) to obtain the product 5,10-dihydrophenazine 7 as a white solid, yield: 74 mg (70%); mp 278 °C
1
2
3
4
5
6
7
8
1
(lit.25 mp 280 °C). Rf = 0.4 (hexane/EtOAc, 10 : 1); H NMR (400 MHz, CDCl3): δ 8.29-8.24 (4, 4H),
9
13
7.88-7.84 (m, 4H),; C NMR (100 MHz, CDCl3): δ 143.5, 130.5, 129.7,; IR (neat, cm-1); 2925, 2854,
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
1465, 1112, 964, 752 ; IR (neat, cm-1); 3328, 2948, 2832, 1118, 1023, 639; HRMS (ESI): Calculated
for C12H10N2 (M+): 182.0844, found (M+): 182.0840.
Acknowledgment
Financial support by IISc and RL Fine Chem is acknowledged with thanks. Thanks are due to Dr. A.
R. Ramesha, Prof. P. S. Mukherjee and Prof. K. R. Prasad for useful discussion. DPO thanks CSIR-
UGC for a fellowship.
Supporting Information Available
13
1H and C spectra, spectral data of all compounds and ESI-MS of IV. This material is available free
of charge via the Internet at http://pubs.acs.org
References and Notes
(1)
(a) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500. (b) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Wendlandt, A. E.; Suess,
A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062.
(2)
(3)
(a) Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457. (b) Jana, R.; Pathak, T. P.; Sigman,
M. S. Chem. Rev. 2011, 111, 1417.
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. Acc. Chem Res. 2008, 41, 1013. (c) Daugulis, O.; Do, H.-Q.;
22
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792.
1
2
3
4
5
6
7
8
(4)
(a) Greenman, K. L.; Carter, D. S. ; Vranken, D. L. V. Tetrahedron ; 2001, 57, 5219; (b)
Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873. (d) Kudirka, R. Vranken, D. L. V. J. Org. Chem. 2008, 73, 3585. (e) Peng,
C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008, 130, 1566. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-
J. Chem. Commun. 2010, 46, 677. (g) Satoh, T.; Miura, M. Chem. -Eur. J. 2010, 16, 11212.
Barluenga, J.; Moriel, P.; Valdés, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587.
(a) Barluenga, J. Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Nature Chemistry 2009, 1, 494.
(b) Zhao, X.; Wu, G.; Zhang Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 3296. (c) Zhou, L.;
Ye, F.; Ma, J.; Zhang, Y.; Wang J. Angew. Chem., Int. Ed. 2011, 50, 3510. (d) Xiao, Q.; Xia,
Y.; Li, H. Zhang, Y.; Wang J. Angew. Chem., Int. Ed. 2011, 50, 1114.
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
(5)
(6)
(7)
(a) Barluenga, J. Escribano, M. Aznar, F. Valdés, C. Angew. Chem., Int. Ed. 2010, 49, 6856.
(b) Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Adv. Synth. Catal. 2010, 352,
3235. (c) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdés, C. Angew. Chem., Int. Ed.
2010, 49, 4993.
(8)
Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun. 2010, 46, 1724.
Brachet, E.; Hamze, A.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Org. Lett. 2010, 12, 4042.
(a)Tréguier, B.; Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2009, 50,
6549. (b) Barluenga, J.; Florentino, L.; Aznar, F.; Valdés, C. Org. Lett. 2011, 13, 510.
Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009, 11, 4732.
Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560.
(9)
(10)
(11)
(12)
(13)
The products were obtained as mixture of E and Z isomers in almost 50: 50 ratios (47:53,
see 1H spectrum in supporting information).
(14)
Hamze, A.; Treguier, B.; Brion, J.-D.; Alami, M. Org. Biomol. Chem. 2011, 9, 6200.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
(15)
(16)
Formation of the product 3a in the reaction of 1a and 2a with Pd(OAc)2 (2.5 mol%), in the
presence of CuCl (20 mol%), is due to the insertion of Cu into arylhalides, and further
transmetalation with Pd is similar to the one that has been observed by Wang and co-
workers; Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.2010, 132, 13590.
The reaction of hydrazone 1a and 2-bromoaniline 2j with Pd2(dba)3 in the presence of xphos
resulted in the formation of 5,10-dihydrophenazine.
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
(17)
(18)
Corey E. J.; Boger, D. L. Tetrahedron Lett. 1978, 1, 5.
Yields obtained in these reactions are around 70-75%, whereas similar reaction with
hydrazone resulted in the formation of products in 87-95%.
(19)
We thank anonymous referees’ for suggesting to correct the mechanism. (a) Albéniz, A. C.;
Espinet, P.; Manrique, R.; Pérez-Mateo, A. Angew. Chem., Int. Ed. 2002, 41, 2363. (b)
Albeniz, A. C.; Espinet, P.; Manrique, R. A.; Perez-Mateo, R. Chem. -Eur. J. 2005, 11,
1565.(c) Khanna, A.; Maung, C.; Johnson, K. R.; Luong, T. T.; Van Vranken, D. L.; Org.
Lett. 2012, 14, 3233.
(20)
(21)
Arnold, D. R.; Du, X.; Henseleit, K. M., Can. J. Chem. 1991, 69, 839.
Zhao, X.; Wu, G.; Yan, C. Lu, K.; Li, H.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 5580-
5583.
(22)
(a) Uijttewaal, A. P.; Jonkers, F. L.; Gen, A. V. D. J. Org. Chem. 1978, 43, 3306.
(b) McIntyre, S.; Hçrmann, E.; Menges, F.; Smidt, S. P.; Pfaltz, A. Adv. Synth. Catal. 2005,
347, 282 – 288.
(23)
(24)
Gerelle, M.; Dalencon, A. J.; Willis, M. C. Tetrahedron Lett. 2012, 53, 1954–1957.
Florio, S. Ingrosso, G.; Ronzinia, L.; Epifania, E. Tetrahedron 1991, 41, 3365-3314.
24
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
Russell, G. A.; Konaka, R.; Strom, E. T.; Danen, W. C.; Chang, K.-Y.; Kaupp, G. J. Am.
Chem. Soc.1968, 90, 4646.
(25)
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
25
ACS Paragon Plus Environment