A direct facile and effective synthesis of various 1,1-heterodiaryl alkenes through Pd catalyzed cross coupling reaction using N-tosylhydrazones via C-OH bond activation

Article abstract of DOI:10.1016/j.tetlet.2015.10.022

At this event for the first time, the direct arylation with the generation of a facile and effective process for the synthesis of alkenes has been established through in situ C-OH activation afterward Pd catalyzed C-C bond formation of heteroarenols with

Full text of DOI:10.1016/j.tetlet.2015.10.022

Tetrahedron Letters 56 (2015) 6585–6589
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A direct facile and effective synthesis of various 1,1-heterodiaryl
alkenes through Pd catalyzed cross coupling reaction using
N-tosylhydrazones via C–OH bond activation
⇑
Poojan K. Patel, Jignesh P. Dalvadi, Kishor H. Chikhalia
Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380009, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
At this event for the first time, the direct arylation with the generation of a facile and effective process for
the synthesis of alkenes has been established through in situ C–OH activation afterward Pd catalyzed C–C
bond formation of heteroarenols with N-tosylhydrazones. The noticeable features of these reactions are
(1) No stoichiometric organometallic reagents desired, (2) No necessity of halides or pseudohalides (3)
Environmentally benign, low toxic, and step economical reaction, (4) Easy to handle, mild conditions
required, and give moderate to excellent yield.
Received 30 July 2015
Revised 4 October 2015
Accepted 6 October 2015
Available online 9 October 2015
Keywords:
C–OH bond activation
Diaryl alkenes
Ó 2015 Elsevier Ltd. All rights reserved.
N-Tosylhydrazones
Heteroarenols
Pd catalyzed cross coupling
The heterodiaryl compounds are found in numerous naturally
occurring compounds and major pharmacologically active sub-
stances exhibiting an extensive range of biological activity.1,2
Moreover, they also possess numerous applications in materials
sciences. They have directed extensive efforts devoted to a varia-
tion of synthetic methodologies and are studied widely over dec-
is a challenging reaction on industrial scale. Further, mostly all
methods involve pre-activation of the both coupling partners
which is inherently wasteful. Since, the insertion of the activating
group (pseudo) of halides itself is not trivial, it often requires sev-
eral steps and hazardous chemicals such as POCl3, SOCl2, PCl5, PBr3,
POBr3 etc. from various heteroarenols,14,15 and therefore generates
waste from reagents, solvents, and purifications. Hence, it is not a
desirable approach.
For the advancement of feasible, environmentally compatible,
and cheap chemical processes our attention has been moved to
the novel type of coupling partners C–H activation16–18 and C–
OH activation.19 The direct arylation of C–H bond activation is
known to suffer from regioselective and over functionalization
problems, while the direct arylation of heteroarenols C–OH bond
activation is chemoselective, readily accessible, stable, low in tox-
icicity and an inexpensive alternative of heteroaryl halides14,20–23
(Fig. 1).
On the other hand, N-tosylhydrazones have emerged as a new
type of versatile coupling partners because of their various valu-
able applications in synthesis.24–30 They are swiftly synthesized
from the corresponding ketones and can be used readily as precur-
sors for the generation of the metal–carbene complex through the
preparation of diazo compounds without employing any
organometallic reagents. Further, to the best of our knowledge no
single example of C–OH bond activation has hitherto been
unreported with N-tosylhydrazones. In this context, inspired from
ades. In recent decades,
a-substituted heterodiaryl olefins have
also revealed numerous biological activities such as anti-tubulin3
and cytotoxicity activity4 and precursors of some important bio-
logically active compounds.5,6 Though, their various application
in medicinal chemistry, very limited scopes are accessible for syn-
thesis.6–10 To enhance the scope of this class of derivatives; a novel,
robust, effective, low toxic, inexpensive starting material, and envi-
ronmentally companionable procedure is required.
Generally, traditional methods to prepare 1,1-diarylalkenes are
typically synthesized by heck reaction,11 Grignard reaction,4 or by
metal-catalyzed reactions using expensive, toxic, air/moisture sen-
sitive organometallic reagents such as organotin,10 organozinc,8
organoboron,7 oraganolithium, organomagnesium salts,12 vinyl
phosphates,7 etc. Organometallic reagents are classically synthe-
sized from heteroaryl halides using harsh reaction conditions such
as halogen–lithium exchange reactions which necessitate low tem-
peratures, inert atmosphere, and they are highly flammable.2,13 It
⇑
Corresponding author. Tel.: +91 079 26300969.
E-mail address: chikhalia_kh@yahoo.com (K.H. Chikhalia).
http://dx.doi.org/10.1016/j.tetlet.2015.10.022
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6586
P. K. Patel et al. / Tetrahedron Letters 56 (2015) 6585–6589
(a) Reaction of tautomerizable heterocycles with various urea derivatives via C-OH
using mild reaction conditions, first 4,6-dimethoxy-1,3,5-triazin-
2-ol (1b) was activated in situ with the phosphonium reagent,
followed by C@C bond generation using acetophenone N-tosylhy-
drazones (2a) (Table 1, entry 1). These were the essential variety
of C–OH bond activation by phosphonium coupling and subse-
quent Pd-catalyzed C@C coupling with N-tosylhydrazones in a
one pot synthesis (Table 1).
activation
O
OH
Ar
O
HN
N
H
Pd
Ar
X
N
+
H2N
N
H
X
N
(b) Reaction of various alkenyl tosylates and mesylates with N-tosylhydrazones via
carbene insertion
To scrutinize the efficacy of the reaction firstly we activate 4,6-
dimethoxy-1,3,5-triazin-2-ol (1b) using PyBroP. Kang et al. firstly
R
N
proposed in situ generations of C–OH bond activation of
a
TsHN
OTs/OMs
tautomerizable heterocycle, and demonstrated a wider range of
functional group tolerance. For the most appropriate phosphonium
coupling condition we get: PyBroP (1.2 equiv) and triethylamine
(2 equiv) in 1,4-dioxane at rt for 2 h. However we have also sum-
marized the results with the other phosphonium coupling reagents
such as (BOP, PyBOP, BrOP, and PyAOP) but they were not found to
be very productive. (Table 1).
Pd
+
X
O
X
O
R
X= O, NR
X= O, NR
(c) Recent work
R
N
After the activation of the C–OH bond, we inspected the numer-
ous cross-coupling reaction conditions for C@C bond formation
using N-tosylhydrazones as a coupling partner employing our
previously optimized catalyst system: Pd2(dba)3 (1.5 mol %),
t-BuBrettphos (3 mol %), in 1,4-dioxane at 90 °C for 1–2 h. To our
delight, the desired coupling product was isolated in 87% yield
(see Table 1) achieved the highest yield among all the other
ligands. Form our observations we found that Xphos is also very
good catalyst and gives better yield upto 83% and one can be used
as an option of t-BuBrettphos at higher concentration. Inspired by
preliminary results we continued to enhance the yield by screening
the ligands, bases, and solvents for viability of the coupling tactics.
The results of the reaction optimization are summarized in (Table 1,
ESI).
NNHTs
R
X
OH
1. Tautomerization activation
2. Pd Cross Coupling
X
N
+
N
N
Figure 1. Recent and previous work of our group.
our previous work;19,27 we have reported Pd catalyzed cross
coupling of heteroarenols with N-tosylhydrazones (Fig. 1).
Herein, we represent a novel, effective, and alternate approach
for the synthesis of 1,1-heterodiaryl alkenes by using Pd catalyzed
cross coupling reaction of tautomerizable heterocycles with
various N-tosylhydrazones via in situ C–OH activation.
Afterward, successful completion of the optimistic reaction
outcomes, the substrate scope with respect to both coupling
In our initial exploration to examine the optimum conditions for
the direct synthesis of various 1,1-heterodiaryl alkene derivatives
partners was discovered. First, we investigated
a variety of
Table 1
Reaction optimizationa
OH
O
N
O
NNHTs
N
N
N
N
+
N
O
O
3a
2a
1a
Phosphonium coupling
Phos-phonium salt
Pd catalyzed C@C coupling
Entry
Solvent
Catalyst
Ligand
Base
Solvent
Yieldb
%
1
2
3
4
5
6
7
8
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
BOP
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAC)2
Pd(Ph3P)2Cl2
Pd(Ph3P)4
Xphos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
LiOtBu
KOtBu
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THF
Toluene
Acetonitrile
DMF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
83
37
49
67
53
87
81
63
61
57
74
65
53
59
43
48
0
Xantphos
Josiphos
Dppf
BINAP
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
t-BuBrettphos
9
10
11
12
13
14
15
16
17
BrOP
PyBOP
PyAOP
HATU
PyBroP
PyBroP
PyBroP
PyBroP
a
Phosphonium coupling: Ar-OH (1 mmol), Phosphonium salt (1.30 mmol), Et3N (2.0 mmol), solvent (5.0 mL), rt, 2 h; Pd catalyzed C@C coupling: Catalyst: 5 mol %, Ligand:
3 mol %, N-tosylhydrazone 1.0 mmol, Base: 3.0 mmol, Solvent: 5 mL, at 100 °C for 2 h.
b
Isolated yields.

P. K. Patel et al. / Tetrahedron Letters 56 (2015) 6585–6589
6587
Table 2
Scope of the reaction of a variety of N-tosylhydrazones with tautomerizable heterocyclesa
O
N
O
OH
NNHTs
N
N
N
N
+
N
O
O
R
R
2a
Entry
1
N-Tosylhydrazones
Product
Yieldb
NNHTs
O
N
O
N
N
3a
3b
87
93
1a
3a
NNHTs
O
N
O
N
N
2
3
NO2
NO2
2a
3b
O
O
N
O
N
N
N
F
NNHTs
3a
3c
86
62
F
3c
N
O
F
F
N
NNHTs
4
3d
4a
F
3d
O
O
O
N
N
N
O
N
N
N
N
NNHTs
5a
5
6
3e
3f
74
63
F
3e
NNHTs
O
N
6a
3f
NNHTs
O
N
7
3g
46
71
7a
3g
NNHTs
O
O
N
N
O
N
N
N
8
9
3h
3i
8a
3h
NNHTs
O
N
O
80
9a
O
3i
(continued on next page)

6588
P. K. Patel et al. / Tetrahedron Letters 56 (2015) 6585–6589
Table 2 (continued)
Entry
N-Tosylhydrazones
Product
Yieldb
87
NNHTs
O
O
N
N
O
N
N
NC
10
3j
CN
3k
NNHTs
O
N
N
F3C
11
3k
83
11a
CF3
3k
a
Reaction condition: Ar-OH: 1.0 mmol, PyBroP: (1.3 mmol) and Et3N: (2.0 mmol) in 1,4-dioxane: 5 mL at room temp for 2 h; then, Pd2(dba)3: 5.0 mol %, t-BuBrettphos:
3 mol %, N-tosylhydrazone: 1.0 mmol, CS2CO3: 3.0 mmol, and 1,4-dioxane: 5 mL, at 100 °C for 2 h.
b
Isolated yields.
Table 3
Scope of the reaction of a variety of N-tosylhydrazones with various tautomerizable heterocyclesa
N
R1
NHNHTs
R1
X
OH
+
N
X
R
R
Entry
N-Tosylhydrazones
Heteroarenols
Product
Yieldb
NNHTs
N
N
OH
N
N
1
3l
87
O
O
NNHTs
O
2
3
3m
3n
73
69
N
OH
OH
N
O
O
NNHTs
N
N
N
N
O
NNHTs
O
N
N
OH
S
N
S
N
4
3o
77
HN
HN
O
NNHTs
N
N
N
N
OH
5
6
3p
3q
79
80
O2N
O2N
NNHTs
S
N
OH
S
N
a
Reaction condition: Ar-OH: 1.0 mmol, PyBroP: (1.3 mmol) and Et3N: (2.0 mmol) in 1,4-dioxane: 5 mL at room temp for 2 h; then, Pd2(dba)3: 5.0 mol %, t-BuBrettphos:
3 mol %, N-tosylhydrazone: 1.0 mmol, CS2CO3: 3.0 mmol, and 1,4-dioxane: 5 mL, at 100 °C for 2 h.
b
Isolated yields.

P. K. Patel et al. / Tetrahedron Letters 56 (2015) 6585–6589
6589
in situ generation of diazo compounds (VII) from N-tosylhydra-
zones (VI) in the presence of base; (4) it inserts into heteroaryl-
PdII-phosphonium complex (VIII) to give a palladium–carbene
species; (5) obtaining of unstable Pd carbene complex that under-
goes migratory insertion of the heteroaryl group to synthesize the
alkyl palladium complex (IX); (6) in the end, b-hydrogen elimina-
tion would provide the 1,1-heterodiaryl alkenes (X) and regenerate
Pd0 complex.
In summary, we have demonstrated a viable, economical, very
effectual method for the synthesis of Pd catalyzed C–C coupling
of a wide-ranging heteroarenols with various substituted N-tosyl-
hydrazones, via in situ C–OH bond activation using phosphonium
coupling reagent under mild and effective reaction conditions to
synthesize various 1,1-heterodiaryl alkenes in moderate to
excellent yields.
O
O
N
PF6
N
P
N
N
N
N
P
N
N
N
N
Br
PF6
+
N
O
O
N
O
OH
I
II
III
N
P
N
H
PF6
N
O
O
N
PF6
N
N
N
P
N
N
O
N
Pd(0)
O
O
Ar
IV
N
N
III
O
X
O
N
PF6
V
N
N
(0)
N
P
N
PF6
O
Pd O
N
N
P
N
Acknowledgements
(II)
Pd
O
N
Ar
N
The authors are thankful to Department of Chemistry, Gujarat
University, Ahmedabad for all support and facilities. Both authors
are thankful to the UGC BSR and GUJCOST for providing financial
assistance.
N
N2
O
N
O
Ar
VII
IX
O
N
P
N
N
N
NHTs
N
(I I)
Pd
Supplementary data
N
O
O
N
N2
Ar
PF6
Ar
VI
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
022.
VIII
Figure 2. Proposed reaction mechanism.
References and notes
N-tosylhydrazones with 4,6-dimethoxy-1,3,5-triazin-2-ol through
Pd catalyzed direct arylation via C–OH bond activation (Table 2)
for the generation of various 1,1-heterodiaryl olefin derivatives.
The acquired results summarized in Table 2 explain that the
enhanced conditions evidenced are to be simplified for the cou-
pling of N-tosylhydrazones with 4,6-dimethoxy-1,3,5-triazin-2-ol.
The tosylhydrazones bearing electron donating groups were effi-
caciously engaged and afforded good yields at their C2, C3 and C4
positions (entries 6–9, Table 2), formed their analogous adducts in
good to excellent yields. The reaction was also well-organized with
N-tosylhydrazones containing electron-withdrawing groups, pro-
ducing excellent yields of the corresponding coupling products
(entries 2–5, 10–11; Table 2). In general, diverse N-tosylhydrazones
were found to couple smoothly with tautomerizable heterocycles to
give the corresponding adducts in decent yields.
1. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359.
2. Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058.
3. Tréguier, B.; Lawson, M.; Bernadat, G.; Bignon, J.; Dubois, J.; Brion, J.-D.; Alami,
M.; Hamze, A. ACS Comb. Sci. 2014, 16, 702.
4. Froimowitz, M.; Gu, Y.; Dakin, L. A.; Nagafuji, P. M.; Kelley, C. J.; Parrish, D.;
Deschamps, J. R.; Janowsky, A. J. Med. Chem. 2007, 50, 219.
5. Rennison, D.; Bova, S.; Cavalli, M.; Ricchelli, F.; Zulian, A.; Hopkins, B.; Brimble,
M. A. Bioorg. Med. Chem. 2007, 15, 2963.
6. Liu, J.; Yi, H.; Zhang, X.; Liu, C.; Liu, R.; Zhang, G.; Lei, A. Chem. Commun. 2014,
7636.
7. Hansen, A. L.; Ebran, J.-P.; Gogsig, T. M.; Skrydstrup, T. Chem. Commun. 2006,
4137.
8. Hansen, A. L.; Ebran, J.-P.; Gøgsig, T. M.; Skrydstrup, T. J. Org. Chem. 2007, 72,
6464.
9. Ojha, D. P.; Prabhu, K. R. J. Org. Chem. 2012, 77, 11027.
10. Chen, S.-H. Tetrahedron Lett. 1997, 38, 4741.
11. Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew.
Chem., Int. Ed. 2006, 45, 3349.
Next, the prospect of variation in tautomerizable heteroarenols
involving quinazoline, quinoline, quinoxaline, thieno pyrazine,
pyridazine was also explored (Table 3). The list of the compounds
summarized in Table 3, suggest that the Pd catalyzed PyBroP
enabled phosphonium coupling condition was very useful for the
direct arylation of various tautomerizable heteroarenols with
N-tosylhydrazones. Both electron-releasing and electron-with-
drawing groups, including methoxy, alkyl, benzyl, nitro, fluoro,
cyano, –CF3, etc. groups are well-suited with the reaction, giving
the analogous in moderate to high yields. Further, in most cases,
the reaction advanced effortlessly and the anticipated products
were formed in satisfactory yields (Table 3).
12. Gauthier, D.; Beckendorf, S.; Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. J. Org.
Chem. 2009, 74, 3536.
13. Marshall, J. A. Chem. Rev. 2000, 100, 3163.
14. Kumar, Y. S.; Dasaradhan, C.; Prabakaran, K.; Nawaz Khan, F.-R.; Jeong, E. D.;
Chung, E. H.; Hyun Gyu, K. RSC Adv. 2014, 4, 40259.
15. Peng, Y.; Huang, P.; Wang, Y.; Zhou, Y.; Yuan, J.; Yang, Q.; Jiang, X.; Deng, Z.; Xu,
J. Org. Biomol. Chem. 2014, 12, 5922.
16. Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
17. McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
18. Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
19. Dalvadi, J. P.; Patel, P. K.; Chikhalia, K. H. Tetrahedron 2014, 70, 9394.
20. Kang, F.-A.; Lanter, J. C.; Cai, C.; Sui, Z.; Murray, W. V. Chem. Commun. 2010,
1347.
21. Li, S.-M.; Huang, J.; Chen, G.-J.; Han, F.-S. Chem. Commun. 2011, 12840.
22. Sharma, A.; Vachhani, D.; Van der Eycken, E. Org. Lett. 2012, 14, 1854.
23. Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130, 11300.
24. Barroso, R.; Valencia, R. A.; Cabal, M.-P.; Valdés, C. Org. Lett. 2014, 16, 2264.
25. Barluenga, J.; Valdés, C. Angew. Chem., Int. Ed. 2011, 50, 7486.
26. Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560.
27. Patel, P. K.; Dalvadi, J. P.; Chikhalia, K. H. RSC Adv. 2014, 4, 55354.
28. Barluenga, J.; Moriel, P.; Valdés, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46,
5587.
Based on the literature survey,23,26,28 the proposed plausible
mechanism for the generation of 1,1-heterodiarylalkenes is out-
lined in Figure 2. It most likely proceeds through the following
steps: (1) Tautomerization and activation in the presence of
Et3N and PyBroP (II) to form the heterocycle–phosphonium inter-
mediate (III); (2) Oxidative addition of Pd0 (IV) catalyst to the
heterocycle–phosphonium intermediate to generate heteroaryl-
PdII-phosphonium species (V) via C–OH bond activation; (3)
29. Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
30. Ye, F.; Wang, C.; Ma, X.; Hossain, M. L.; Xia, Y.; Zhang, Y.; Wang, J. J. Org. Chem.
2015, 80, 647.