Synthesis of Diverse Nitrogen Heterocycles via Palladium-Catalyzed Tandem Azide–Isocyanide Cross-Coupling/Cyclization: Mechanistic Insight using Experimental and Theoretical Studies

Article abstract of DOI:10.1002/adsc.201700928

A rapid and elegant tandem azide–isocyanide cross-coupling/cyclization protocol has been developed based on a nitrene transfer reaction. The palladium-catalyzed ligand-free methodology led to the synthesis of three different heterocyclic scaffolds with excellent atom/step/redox economy. Studies based on first-principles-based quantum calculations and control experiments unraveled a concerted process of nitrene transfer reaction on isocyanides, ruling out the metallaaziridine intermediate reported earlier. This finding could pave the way for novel applications of nitrene transfer reactions to generate bioactive heterocycles. (Figure presented.).

Full text of DOI:10.1002/adsc.201700928

Title: Synthesis of diverse N-heterocycles via Pd-catalyzed tandem
azide-isocyanide cross-coupling/cyclization: Mechanistic insight
using experimental and theoretical studies
Authors: Arshad Ansari, Ramdas Pathare, Antim Maurya, Vijai
Agnihotri, Shannawaz Khan, Tapta Roy, Devesh Sawant, and
Ram Pardasani
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700928
Link to VoR: http://dx.doi.org/10.1002/adsc.201700928

10.1002/adsc.201700928
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of diverse N-heterocycles via Pd-catalyzed tandem
azide-isocyanide cross-coupling/cyclization: Mechanistic insight
using experimental and theoretical studies
Arshad J. Ansari,a Ramdas S. Pathare,b Antim K. Maurya,c Vijai K. Agnihotri,c
Shahnawaz Khan,d Tapta Kanchan Roy,e* Devesh M. Sawant,a* and Ram T.
Pardasanib*
a
Department of Pharmacy, Central University of Rajasthan NH8 (Jaipur-Ajmer Highway), Bandarsindri, Ajmer-305817
E-mail: dms@curaj.ac.in
Department of Chemistry, Central University of Rajasthan E-mail: rtpardasani@curaj.ac.in
Natural Product Chemistry and Process Development division, CSIR-Institute of Himalayan Bioresource Technology
b
c
Palmpur, Himachal Pradesh -176061 E-mail: vijai@ihbt.res.in
Department of Chemistry, Bhupal Nobles’ University, Udaipur-313001, India
d
E-mail: khancdri@gmail.com
e
Department of Chemistry and Chemical Sciences Central University of Jammu, Jammu, 180011
E-mail: taptakanchan@gmail.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A rapid and elegant tandem azide-isocyanide reaction on isocyanides, ruling out metalla-aziridine
cross-coupling/cyclization protocol is developed based on intermediate reported earlier. This finding would pave way
nitrene-transfer reaction. The Pd-catalyzed ligand-free for novel applications of nitrene-transfer reactions to
methodology led to the synthesis of three different generate bioactive heterocycles.
heterocyclic scaffolds with excellent atom/step/redox Keywords: Nitrene-transfer, DFT Calculation,
economy. Studies based on first-principles based quantum Carbodiimide, Azide-isocyanide cross-coupling, Pd-imido,
calculation and control experiments unraveled a concerted palladaaziridines
process of nitrene-transfer
Introduction
Azide-isocyanide cross-coupling reactions have
emerged as a powerful strategy for generating
functionalized
unsymmetric
carbodiimides.[1]
Compared to the traditional methods for the synthesis
of unsymmetric carbodiimides, such as dehydration of
ureas,[2] desulfurization of thioureas (using toxic
mercury[3] or iodine[4]), condensation of isocyanates
with iminophosphorane,[5] thermal/photochemical
degradation of tetrazoles[6] and rearrangements of
amidoximes,[7] reactions involving azide-isocyanide
cross-coupling are faster, efficient and atom/step/redox
economic. The synthetic utility of azide-isocyanide
cross-coupling reaction is, however, limited because it
requires stoichiometric amount of expensive transition-
metals.[1a,8,9] Recent milestones of employing transition
metals such as Fe1a, Ni[9e], Pd[10] Rh[8c] and Cu[8a,b] at
catalytic amount has the potential to revolutionize
azide-isocyanide cross-coupling reactions by allowing
sustainable generation of unsymmetric carbodiimides.
generally follows three important steps: (a)
coordination of metal with azide and isocyanide,[11] (b)
extrusion of dinitrogen to generate nitrenes,[12] and (c)
transfer of nitrenes on isocyanides [Eq(1)].[13] First two
steps have been repeatedly explored and well
]
understood by experimental[14 and computational
studies,[15] and involved formation of metal-imido
complex A (a nitrene-intermediate).[11] In contrast,
mechanistic details for the third step are vague and
three fundamental questions remained to be answered
for the third step: (1) What is the nature of nitrene-
transfer reaction? (2) Is it concerted or stepwise? (3)
Has any intermediate, such as metallaaziridine
[10]
As carbodiimides are crucial building blocks in
synthesis, these transformations could be effectively
applied for generating bioactive heterocycles.
Clearly, exiting opportunities in the field azide-
isocyanide cross- coupling reactions are still untapped
and better understanding of its mechanism could
expand its synthetic utility. The reaction course
intermediate
B,[10,16]
involved
during
this
transformation? Solving this puzzle would open up
1
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.a
new vistas for transition-metal catalyzed nitrene-
transfer reactions[17] and expand its horizons for new
applications in synthetic organic chemistry.
In continuation of our efforts to synthesize bioactive
heterocycles,[18] we applied azide-isocyanide cross-
coupling on ortho-functionalized aryl azides and
isocyanides, leading to a tandem sequence of coupling
and cyclization in the presence of palladium as catalyst
[Eq(2)]. The tandem reaction reported herein has many
distinct advantages over the oxidative coupling of
amine and isocyanide reported earlier,[19] such as
redox-neutral condition and no dependence over dry
condition (without Molecular sieves); thus it exhibited
broader substrate scope and applications. The first-
principles based Density Functional Theory (DFT)
calculation on the tandem reaction revealed that the
intermolecular nitrene-transfer reaction is progressing
through a three-membered transition-state followed by
formation of high thermodynamically stable
carbodiimide. The latter is a concerted reaction devoid
of the metalla-aziridine intermediate B. This finding
helped us to unravel the mystery of nitrene-transfer
reaction on isocyanides.
entry
Pd(mol%)
Y
2
2
2
2
solvent
THF
THF
THF
THF
time yield %
1
2
3
4
Pd(PPh3)4 (10)
Pd2dba3 (10)
Pd(PPh3)2Cl2 (10)
Pd(CH3CN)2Cl2
(10)
24
24
24
24
45
58
Traces
Traces
5
6
7
8
PdCl2 (10)
2
2
2
2
2
2
2
2
THF
THF
THF
THF
Dioxane
Toluene
1,2-DCE
Toluene
24
2
30
15
Pd(TFA)2(10)
Pd(OAc)2 (10)
-
2
24
8
78
NRb
69
9
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (7.5)
Pd(OAc)2 (7.5)
Pd(OAc)2 (7.5)
Pd(OAc)2 (5)
Pd(OAc)2 (7.5)
Pd(OAc)2 (7.5)
10
11
12
13
14
15
16
17
2
90
6
50
2
90
1.5 Toluene
Toluene
2
88
1
2
75
1.5 Toluene
1.5 Toluene
1.5 Toluene
2
2
2
69
87c
86d
Results and Discussion
aAll reaction were carried out at 60 C. 1 recovered as
o
b
such.cIn Presence of TEMPO. dIn presence of Galvinoxyl.
In order to explore the conditions to promote a tandem
cross coupling of azide and isocyanide, followed by
intramolecular cyclization, 2-azidobenzoic acid 1 and
isocyanides 2 were reacted in the presence of 10 mol%
were compatible with standard reaction conditions.
Iodine- and nitro-substitutions could offer a handle for
further synthetic transformation. Various aliphatic
isocyanide were successfully incorporated with good
to excellent yield, but aromatic isocyanide failed to
give corresponding cross-coupling product 19. Owing
to enhanced nucleophilicity, benzamides 21-24
exhibited rapid and good conversion compared to
corresponding acids affording the desired product, 25-
32 in good to excellent yields (75-94%). Both aliphatic
and aromatic substituents on nitrogen of amide were
well tolerated in the standard reaction conditions,
adding third diversity on the molecule. Interestingly,
Photophysical investigation of 3 was carried out in
various solvents (refer SI, Section S8). The salient
photophysical properties of 2-(tert-butylamino)-4H-
benzo[d][1,3]oxazin-4-one in DCM with λmax 401.5
nm and Quantum yield 0.58.
To further expand the general applicability of our
protocol, next we explored the tandem azide-
isocyanide cross coupling/5-exo-dig cyclization
reaction for the synthesis of five-membered
heterocyclic rings such as benzoxazoles, benzothiazole
and benzimidazole (scheme 2). 2-Azidophenols 33, 34
were reacted with a range of isocyanides under
standard reaction conditions to furnish diversified 2-
aminobenzoxazoles 35-40 in good to excellent yields.
Both aliphatic and aromatic isocyanides were
successfully incorporated in title compounds. Similarly,
o
of Pd(PPh3)4 in THF at 60 C to produce 3 in 45%
yield (entry 1, table 1). Pd(OAc)2 was found to be
efficient among various Pd-catalysts source scrutinized
and afforded 3 in a 78 % yield (entry 7). Reaction
failed to initiate in the absence of catalyst (entry 8).
Screening of different solvents revealed that the
reaction was performed best in toluene to deliver 3 in
88% yield (Table 1, entries 7, 9-11). Decreasing the
amount of catalytic loading of Pd(OAc)2 and
equivalence of isocyanide to 7.5% and 1.5 equiv
respectively had no detrimental effect on the reaction
(entries 9, 11-12). The reaction failed to initiate at
room temperature and worked optimally at 60 oC (refer
SI for details). Addition of free radical quencher, such
as TEMPO and Galvinoxyl, did not alter the course of
reactions (entry 16 and17). In nutshell, the standard
reaction conditions includes Pd(OAc)2 of 7.5 mol%,
o
isocyanide of 1.5 equivalence in toluene at 60 C.
Delightfully, the protocol furnished best yields (88%)
(entry
13)
of
2-(tert-butylamino)-4H-
benzo[d][1,3]oxazin-4-one 3.
With the optimized condition in hand, a variety of
functionalized 2-azidobenzoic acids 1, 4-6 and
benzamides 21-24 were subjected to the standard
condition with isocyanides 2, 7-11 for the synthesis of
benzooxazinones 3, 12-18 & 20 and quinazolinones
25-32 respectively (Scheme 1). The substrate bearing
electron withdrawing group such as F, I, Cl and NO2
2
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
Scheme1. Substrate scope of Benzooxazinones and
Quinazolinones.
Figure 1. Control Experiment.
2-azidothiophenol 41 and 2-azidoaniline 43 were -
condensed with tert-butyl isocyanide to produce 2-
aminobenzothiazoles 42 and biologically relevant 2-
aminobenzimidazoles 44 in 72% and 78% isolated
yields respectively. It is worth noting that ortho
substitution in arylazides, such as carboxylic acid (1,
4-6), amides (21-24), hydroxy (33-34), thiol (41) and
amino (43), had remarkable effect on the cross-
coupling step of the tandem reaction as substrates 45
devoid of such groups furnished poor yield 56% of the
corresponding carbodiimides 46 in the optimized
reaction conditions (Fig1A and refer S6.1 of, SI for
details). Next, the possibility of urea as reaction
intermediate 47 was ruled out based on control
Scheme 2. Substrate scope of Benzazoles
3
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
Figure 2. (A) Computed Gibbs free-energy profile of the overall reaction. All the relative energies are given in kcal/mol at
the B3LYP/6-31G**(LANL2DZ with ECP for Pd) level of theory. (B) Proposed catalytic cycle of the tandem reaction
experiment, where, 47 failed to produce title
compound 19, under standard reaction conditions
(Fig 1B, refer section S6.4 in SI).
TS (Fig 4A). Intermediate 50 underwent extrusion of
dinitrogen to form 52 (Fig 2). The step is associated
with an energy barrier of 18.22 kcal/mol. Further,
chemical kinetic studies of the tandem cross-
coupling/cyclization reaction revealed that both
Pd(OAc)2 and tert-butyl isocyanide followed first
order kinetics with 6 [Fig 1D and section S6.3 SI],
thus both Pd-catalyst and isocyanide participated in
the turn-over limiting step. The presence of
coordination complex 50 and Pd-imido complex 52
(Fig 3) are unequivocally implicated based on high-
resolution mass spectra (m/z 444.7902 for 50b and
To explore the reaction mechanism, a series of
control experiments (Fig 1and refer section S6 SI)
and DFT computations (Fig 2A) were carried out.
Unless otherwise stated, all calculations and energies
in the main text and SI are the Gibbs free energies
computed at the B3LYP/6-31G(d,p)/Lanl2DZ (with
ECP for Pd) level of theory. Based on these studies
the proposed catalytic cycle of the tandem reaction is
depicted in Fig 2B. The tandem reaction begins with
the coordination of Pd(OAc)2 with 2-azidobenzoic
acid 1 (or 6) to furnish 48a (or 48b respectively),
which on deacetylation generates 49 (Fig 2).
Stoichiometric studies supported the formation of
coordination complex 48b, which was converted to
o
14 on reacting with isocyanide in toluene at 60 C
(Fig 1C, and section S6.2, SI). In the next step,
coordination of isocyanide with Pd to generate
intermediate 50 was found to be barrierless (Fig 2).
This observation was further substantiated by
scanning the corresponding potential energy surface
(PES) along reaction coordinates of Pd-isocyanide
bond formation process, which revealed a smooth
downhill path from 49 to 50 without any intervening
Figure 3. ESI-MS of Stoichiometric reaction of 6 with
isocyanide.
4
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
isocyanide that generates carbodiimide 55 (Fig 2). A
careful literature search reveals the possibility of
metallaaziridine 54 as reaction intermediate.[10,16]
Theoretical calculations predicted that the
intermolecular nitrene transfer reaction is progressing
through a three- membered transition-state 53‡ with
an energy barrier of 37.61 kcal/mol. Despite of its
structural resemblance with 53‡, the intermediate 54
was not observed at all; instead reaction proceeded to
the formation of carbodiimide 55. To attain the
insight into the details of this step Intrinsic Reaction
Coordinate (IRC) calculations were carried out. IRC
are often used to determine the topology of the PES,
by which one can authenticate the reaction path by
connecting
the
stationary
points
under
consideration.[21] For this reaction, IRC calculations
showed that the transition-state 53‡ was well
connected to the two minima 52 and 55 (Fig 4B), not
with 54. A careful investigation of reaction path
embedded in the reaction valley along the IRC
inferred that the nitrene-transfer process on
isocyanides followed a concerted path and is highly
asynchronous. The geometrical parameters, such as
bond distances, at each IRC points reveal interesting
insights associated with the path (Fig 4B). As
reaction progress from 52, nitrene attacks
electrophilically on isocyanide carbon to form C-N
bond. The formation of C-N bond initiated in pro-TS
with the gradual reduction in the bond distance and it
led to a three membered transition-state 53‡. During
this event, C-Pd bond remains unperturbed. The
electrophilic attack of nitrene over isocyanide carbon
remained unabated even in post-TS, increasing
multiplicity of C-N bond to C=N. The rapidly
increasing C-N bond strength put considerable strain
on three-membered ring and drove breaking of the
lethargic C-Pd bond around the reaction coordinate
+7 (Fig 4B). Beyond this point, C-Pd bond
dissociated abruptly with the simultaneous and
spontaneous formation of O-Pd bond that led to
bidentate acetate ligand in 55. This observation
inferred that imido-ligand of Pd in 52 was transferred
over isocyanide in a concerted fashion and no
metallaaziridine intermediate 54 was observed. In
order to rule out the limitations of present level of
theory, conversion of 52 to 55 was tested in several
other level of theories (see S7, SI for more details)
and all relevant calculations produced similar results.
These observations were further validated by PES
scan along the nitrene-transfer (C-N) reaction
coordinate of 52 (Fig 4C). Following the PES along
the reaction path, the structure around the reaction
coordinate +7 of Fig 4 is in close proximity to
metallaaziridine intermediates 54, where no minima
is found and the steep descending potential at this
point reconfirms that intermediate 54 is not a stable
species. As a result carbodiimide 55 observed
exclusively instead of the predicted palladaaziridine
54.[10] Both the IRC and PES scan unequivocally
established that the metalla-aziridine intermediate 54
is not a stable species and a concerted path is
followed to form 55 and ruled out the intermediacy of
Figure 4. (A) PES scan for the coordinatyion of isocyanide
to metal for C-Pd bond is barrierless; (B) Calculation of
IRC which follows the minimum energy reaction pathway
in mass-weighted cartesian coordinates between the 53‡
and its reactant 52 and products 55; (C) PES scan along
the nitrene-transfer (C-N) reaction coordinate.
m/z 416.8582 for 52b)of the tandem reaction carried
out at stoichiometric scale (Fig 3).
As mentioned earlier one of the important goals of
our study is to understand the nature of nitrene-
transfer reaction of Pd-imido intermediate 52 on
5
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
light or I2/ KMnO4 staining. Melting points were
palladaaziridine 54 in the nitrene-transfer reaction on
isocyanides. Despite of a high energy barrier of 37.61
kcal/mol, the very high thermodynamic stability of 55
(exergonic to 52 by 43.76 kcal/mol) drives the
nitrene-transfer reaction, a rate determining step
(RDS). Hence, the tandem reaction reported herein is
a thermodynamically-controlled reaction.
1
uncorrected. H, 13C NMR, Recorded on Bruker’s Ascend
500MHz spectrophotometer operating at 500.3 MHz for 1H
and 125.8 MHz for 13C experiments; spectra were recorded
at 295 K in CDCl3; chemical shifts were calibrated to the
residual proton and carbon resonance of the solvent:
CDCl3 (1H δ 7.269; 13C δ 77.0). Mass spectra were
recorded on electrospray ionization quadrupole time of
flight (ESI-QTOF-MS).The abbreviations used: s=singlet,
d=doublet, t=triplet, q=quartet, dd=double doublet,
m=multiplet, br s = broad singlet & br = broad signal.
In the next step, acetic acid coordinates with Pd to
form 56, ejects carbodiimide out of coordination with
metal to generate 58 (via 57‡) and brings
carbodiimide closer to the carboxylate of benzoate.
Subsequently, formation of a hydrogen bond between
acetate and nitrogen of carbodiimide in 59 activates
azomethine group by increasing its electrophilicity.
These couple of events set a stage for an imminent 6-
exo-dig cyclization of carboxylate on carbodiimide in
59 to furnish thermodynamically stable product 61
(by 23.27 kcal/mol). The intramolecular cyclization
requires a meagre free energy of activation of 6.14
kcal/mol, which is very much feasible in the standard
reaction condition. During reaction monitoring, no
intermediate was observed on TLC, which further
supports that 6-exo-dig cyclization would have
occurred with coordination of Pd-catalyst. Finally,
the regeneration of catalyst is realized via 62‡ and 63
to furnish the title compound 3 with a reaction barrier
of only 8.16 kcal/mol.
General
Procedure
2-(tert-butylamino)-4H-
benzo[d][1,3]oxazin-4-one (3): A Schlenk tube equipped
with a stir-bar was charged with 2-azido-4-chloro-benzoic
acid (100mg, 1 equiv) and toluene 2ml as a solvent, the
reaction tube was purged with argon. After 5 min
Pd(OAc)2 (7.5 mol% 10mg)was added to the reaction
mixture under by argon purging and was followed by
addition of isocyanide (76 mg, 1.5 equiv). The mixture was
stirred at 60 oC for 2-6 hrs unless noted by TLC monitoring.
After cooling to room temperature, the reaction mixture
was quenched with EtOAc, which was washed with water
and brine successively, dried over anhydrous sodium
sulphate, filtered and concentrated in vacuum. Purification
by silica gel (100-200 mesh) chromatography (EtOAc:
Hexane) to yield the desired product. White solid,
1
m.p.:129-131oC, H NMR (δ ppm) (500 MHz, CDCl3),: δ
8.02 (dd, J = 1.2, 7.9, Hz, 1H), 7.62 (t, J = 7.67 Hz, 1H),
7.27 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.52 Hz, 1H), 4.85 (br
s, 1H), 1.49 (s, 9H) ppm. 13C NMR (CDCl3, 125 MHz): δ
160.1, 152.1, 150.3, 136.5, 128.6, 124.5, 123.5, 113.3, 52.0,
+
28.8 ppm. HRMS (ESI) m/z calcd for C12H15N2O2
[M+H+]: 219.1128, found 219.1120.
Acknowledgements
Conclusion
We are grateful to CSIR [Grant No. 02(0201)/14/EMR-II], DST
[Grant No. SB/FT/CS-012/2014 and FIST grant SR/FST/CSI-
257/2014(c)] and CURaj. for funds. TKR thanks CMSD,
University of Hyderabad for computational support and Central
University of Jammu for infrastructural support.
In summary, a tandem reaction involving Pd-
catalyzed azide-isocyanide cross-coupling followed
by 6-exo-dig cyclization for the synthesis of three
different types of heterocycles, benzooxazinones,
quinazolinones and benzazoles, has been developed.
Our methodology exhibited excellent atom/step/redox
economy and is faster, ligand-free and devoid of any
dry condition. Pd-imido intermediate 52 is the main
hero of the sensational mechanistic drama. The
nitrene-transfer on isocyanide is a concerted and
thermodynamically-controlled turnover limiting step
of the tandem reaction. The possibility of
metallaziridines 54 as a reaction intermediate during
the nitrene-transfer step is successfully ruled out. The
study unearthed crucial mechanistic findings, which
will assist in the development of new methodologies
based on catalytic nitrene-transfer reactions, and
could open new vistas for transition-metal catalyzed
synthesis of novel heterocycles.
References
[1] a) R. E. Cowley, M. R. Golder, N. A. Eckert, M. H. Al-
afyouni, P. L. Holland, Organometallics 2013, 32,
5289-5298; b) P. L. Holland, R. E. Cowley, N. A.
Eckert, Chem. Commun. 2009, 1760–1762.
[2] a) C. Palomo, R. Mestres, Synthesis 1981, 373-374; b)
R. T. Yu, T. Rovis, J. Am. Chem. Soc. 2008, 130,
3262–3263.
[3] a) V. Strukil, I. Dilovic, D. Matković-Čalogović, J.
Saame, I. Leito, P. Šket, J. Plavec, M. Eckert-Maksić,
New J. Chem. 2012, 36, 86-96.
[4] a) T. Peddarao, A. Baishya, M. K. Barman, A. Kumar,
S. Nembenna, New J. Chem. 2016, 40, 7627–7636; b)
A. R. Ali, H. Ghosh, B. K. Patel, Tetrahedron Lett.
2010, 51, 1019–1021.
Experimental
General Cosideration: All the reactions were carried out
in schlenk tube under Ar atmosphere using standard
techniques. All solvents used in synthesis were purchased
from Spectrochem. Aliphatic isocyanides were purchased
from Sigma-Aldrich and phenyl isocyanides were
synthesized in our lab. All starting reagents were also
synthesised in lab, other reagents being purchased from
Aldrich or Spectrochem were used as such without
purification. Analytical TLC was performed using 2 x 4
cm plate coated with 0.25mm thickness of silica gel (60F-
254 Merck) and visualization was accomplished with UV
[5] a) T. Saito, N. Furukawa, T. Otani, Org. Biomol. Chem.
2010, 8, 1126-1132; b) W. Zeng, P. Dang, X. Zhang, Y.
Liang, C. Peng, RSC Adv. 2014, 4, 31003–31006.
[6] D. Begue, A. Dargelos, H. M. Berstermann, K. P.
Netsch, P. Bednarek, C. Wentrup, J. Org. Chem. 2014,
79, 1247–1253.
6
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
[7] A. Dondoni, J. Org. Chem 1977, 42, 3372–3377.
J. Am. Chem. Soc. 2009, 131, 2116–2118. d) Z. Zhang,
Z. Li, B. Fu, Z. Zhang, Chem. Commun. 2015, 51,
16312–16315.
[8]a) L. Maestre, M. R. Fructos, M. M. Díaz-Requejo, P. J.
Pérez, Organometallics 2012, 31, 7839–7843; b) E.
Haldón, M. Besora, I. Cano, X. C. Cambeiro, M. A.
Pericàs, F. Maseras, M. C. Nicasio, P. J. Pérez, Chem-
Eur. J. 2014, 20, 3463–3474; c) Z. Zhang, F. Xiao, B.
Huang, J. Hu, B. Fu, Z. Zhang, Org. Lett. 2016, 18,
908–911.
[17] a) B. J. Stokes, H. Dong, B. E. Leslie, A. L.
Pumphrey, T. G. Driver, J. Am. Chem. Soc. 2007, 129,
7500–7501; b) Y. Liu, C. M. Che, Chem-Eur. J. 2010,
16, 10494–10501; c) E. T. Hennessy, T. A. Betley, D.
N. Zalatan, J. Du Bois, A. D. Ryabov, A. R. Dick, M. S.
Sanford, J. A. Labinger, J. E. Bercaw, J. T. Groves, et
al., Science 2013, 340, 591–595.
[9] a) A. I. Nguyen, R. A. Zarkesh, D. C. Lacy, M. K.
Thorson, A. F. Heyduk, Chem. Sci. 2011, 2, 166-169;
b) M. Yousif, D. J. Tjapkes, R. L. Lord, S. Groysman,
Organometallics 2015, 34, 5119–5128; c) Q. X. Dai, H.
Seino, Y. Mizobe, Organometallics 2012, 31, 4933–
4936; d) G. Proulx, R. G. Bergman, Organometallics
1996, 15, 684–692; e) S. Wiese, M. J. B. Aguila, E.
Kogut, T. H. Warren, Organometallics 2013, 32, 2300–
2308.
[18] a) S. Sharma, R. S. Pathare, A. K. Maurya, K. Gopal,
T. K. Roy, D. M. Sawant, R. T. Pardasani, Org. Lett.
2016, 18, 356–359; b) S. Sharma, S. Singh, A. Kumari,
D. M. Sawant, R. T. Pardasani, Asian J. Org. Chem.
2017, DOI 10.1002/ajoc.201700098; c) R. S. Pathare, S.
Sharma, S. Elagandhula, V. Saini, D. M. Sawant, M.
Yadav, A. Sharon, S. Khan, R. T. Pardasani, Eur. J.
Org. Chem. 2016, 5579–5587; d) P. Maloo, T. K. Roy,
D. M. Sawant, R. T. Pardasani, M. M. Salunkhe, RSC
Adv. 2016, 6, 41897–41906.
[10] Z. Zhang, Z. Li, B. Fu, Z. Zhang, Chem. Commun.
2015, 51, 16312–16315.
[11] S. Cenini, E. Gallo, A. Caselli, F. Ragaini, S.
Fantauzzi, C. Piangiolino, Coord. Chem. Rev. 2006,
250, 1234–1253 and references theirin.
[19] a) B. Liu, M. Yin, H. Gao, W. Wu, H. Jiang, J. Org.
Chem. 2013, 78, 3009–3020; b) T. Vlaar, R. V. A. Orru,
B. U. W. Maes, E. Ruijter, J. Org. Chem. 2013, 78,
10469–10475.
[12] S. Chiba, Synlett 2012, 21–44 and references theirin.
[20] a) D. H. Ess, S. E. Wheeler, R. G. Iafe, L. Xu, N.
Celebi-Olcum, K. N. Houk, Angew. Chem. Int. Ed.
2008, 47, 7592–7601; b) W. Quapp, M. Hirsch, D.
Heidrich, Theor. Chem. Acc. 1998, 100, 285–299; c) Z.
C. Kramer, B. K. Carpenter, G. S. Ezra, S. Wiggins, J.
Phys. Chem. A 2015, 119, 6611–6630; d) L. Zhang, Y.
Wang, Z. J. Yao, S. Wang, Z. X. Yu, J. Am. Chem. Soc.
2015, 137, 13290–13300. e) S. Shaik, D. Danovich, G.
N. Sastry, P. Y. Ayala,H. B. Schlegel, J. Am. Chem.
Soc. 1997, 199, 9237–9247;. f) J. Li, S. Shaik, H. B.
Schlegel, J. Phys. Chem. A, 2006, 110, 2801–2806.
[13] D. J. Mindiola, G. L. Hillhouse, Chem. Commun.
2002, 1530, 1840–1.
[14] T. J. Mooibroek, E. Bouwman, E. Drent,
Organometallics 2012, 31, 4142–4156.
[15] Y. Liu, X. Guan, E. L. M. Wong, P. Liu, J. S. Huang,
C. M. Che, J. Am. Chem. Soc. 2013, 135, 7194–7204.
[16] a) L. Li, K. E. Kristian, A. Han, J. R. Norton, W.
Sattler, Organometallics 2012, 31, 8218–8224; b) P.
Bazinet, G. P. A. Yap, D. S. Richeson,
Organometallics 2001, 20, 4129–4131; c) J. A. Bexrud,
P. Eisenberger, D. C. Leitch, P. R. Payne, L. L. Schafer,
[21] W. Quapp, J. Mol. Struct. 2004, 695–696, 95–10
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10.1002/adsc.201700928
Advanced Synthesis & Catalysis
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Synthesis of diverse N-heterocycles via Pd-
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