Atom-Economical Palladium Carbon-Catalyzed de Novo Synthesis of Trisubstituted Nicotinonitriles

Article abstract of DOI:10.1021/acs.joc.7b01332

A de novo palladium carbon-catalyzed synthesis of trisubstituted nicotinonitriles from easily synthesized homopropagylic or homoallylic aromatic alcohols in the presence of nitriles has been explored. The mechanism proceeds with an interesting generation

Full text of DOI:10.1021/acs.joc.7b01332

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Article
Atom – Economic Palladium Carbon Catalysed de
novo synthesis of Tri- substituted Nicotinonitriles
Debayan Sarkar, Nilendri Rout, Manoj Kumar Ghosh, Santanab Giri, Kornelius Neue, and Hans Reuter
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01332 • Publication Date (Web): 11 Aug 2017
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The Journal of Organic Chemistry
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Atom – Economic Palladium Carbon Catalysed de novo synthesis of
Tri- substituted Nicotinonitriles
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Debayan Sarkara*, Nilendri Routa, Manoj Kumar Ghosha, Santanab Giria*, Kornelius Neueb and Hans Reuterb
aDepartment of Chemistry, NIT Rourkela, India-769008
bInstitute of Chemistry of New Materials, University of Osnabrück, Barbarastraβe-6, Germany
ABSTRACT: A de novo Palladium carbon catalyzed synthesis of tri-substituted nicotinonitriles from easily synthesized
homopropagylic or homoallylic aromatic alcohols in presence of nitriles has been explored. The mechanism proceeds with an inter-
esting generation of Pd(II) -C palladacycle followed by an oxidative aromatization to generate the pyridine core. The pyridine core
is generated with a noteworthy C-C bond cleavage incase with the substituted nitriles. The moderate yields and easy separation of
the products delivers a unique importance to this one pot methodology
INTRODUCTION
Aromatic aza-heterocycles play a crucial role in pharmaceuticals,
as natural products, functional materials and as well as important
reactive intermediates in crucial organic synthesis.1 Undoubtedly,
functionalized pyridines account for the highest range of applica-
tions amongst the group of aza-heterocycles. Pyridine analogues
play a significant understanding of the chemistry of biological
systems. It constitutes the central core of many enzymes like
NADP, which involves various oxidation–reduction processes.
Vitamins like pyridoxine (1.b) and niacin (1.d) (vitamin B6) con-
stitute another important set. Pyridine analogues comprise of the
largest fraction of pharmaceutical drugs (Fig-1). Thus, synthesis
of pyridine and its analogues has been a lucrative target through-
out years2; few of these available approaches are catalytic trans-
formations. The notable reports are Zn(OTf)2-promoted [1+5]
cycloaddition of isonitrile with substituted enamides3, Ag mediat-
ed addition of dithianes to unsaturated carbonyls4 , Rh catalyzed
C-H functionalisation of terminal alkynes with ketoximes5 , Mn
mediated reaction of cyclopropanols with vinyl azides6 and Cu-
catalysed oxidative sp3 C-H coupling.7 But none of these proto-
cols demonstrate a general atom economic synthetic view point
towards these biologically active substituted pyridines. Thus effi-
cient atom-economic catalytic approaches of these functionally
engineered pyridines, remains a challenge and enthusiastic task in
both academic and industrial scenario. Moreover, approaches
engulfing heterogeneous catalysis which do appear as a promising
option not only due to easy separation along with scaling up, but
also its utility in continuous flow reactors with advantages like
wide commercial availability, economic, less heavy metal con-
tamination, has yet to be explored in this direction.
Fig: 1 Biologically active pyridine molecules
In this connection, it is needless to mention that nicotine deriva-
tives have been one of the most important biologically active
members of this group due to their immense use not only as recre-
ational tobacco products but also as their pharmaceutical potency.
(S)- nicotine has been used as an active drug against many neuro-
degenerative drugs like Parkinson’s , Alzheimer’s, Schizophrenia
and many other CNS disorders.8 There have been conscious ef-
forts to synthesize these nicotine derivatives in last decade.9 The
“cyano”-functionality in the pyridyl core can be considered a
treasure-well for synthetic transformations. It delivers adequate
freedom to a chemist to execute the planned synthetic course.
Undoubtedly, substituted nicotinonitriles thus resemble an attrac-
tive aza-heterocycles, which can be functionalized to the desired
pyridine derivatives with ease. Although there has been some
interesting non-catalytic approaches, 10 catalytic efforts are scanty
on this direction.11 Interestingly, the mentioned aryl pyridines
have also evolved as trustworthy substrates for C-H activation.12
Thus it appeared to us that an atom-economic, catalytic synthesis
of polysubstiuted nicotinonitriles with easily available alkyl ni-
triles acting as both the nitrogen sources would be a commendable
target to achieve. It would be further accomplishing, if the catalyst
could be reused delivering a high commercial value. Propargyl
and allyl alcohols have emerged as highly effective candidates for
metal assisted transformations13 albeit, to the best of our
knowledge, they have not been explored to a satisfactory extent
towards synthesis of pyridine derivatives. Palladium catalysts
have been well known activator of alkynes.14 Herein, we report a
highly effective atom-economic palladium carbon catalyzed syn-
thesis of trisubstituted 3-cyano-pyridines or “Nicotinonitriles”
employing the easily available alkyl nitriles serving as both a
solvent and precursors. The heterogenous catalytic system delian-
ates an easy break through to this transformation. The key step
involves an unprecedented envisioned palladium assisted domino
nucleophilic additions to generate the six membered framework
followed by oxidative aromatization with a concomitant C-C bond
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cleavage in order to deliver the substituted pyridines in moderate
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yields and regioselectivity. It is believed that the present strategy
outweighs the available classical condensation methodologies like
Hantzch synthesis.15 Reppe’s acknowledged syntheses of pyri-
dines proceeding via metallacycle-mediated union of alkynes with
nitrile via [2+2+2] cycloadditions (Fig 2 (vii))16, three component
condensation (Fig 3) and the related metallacycle-mediated pro-
cesses remain substantially limited in scope, suffering from the
drawbacks with controlling regioselectivity.17 We were pleased to
discover that this one pot transformation to nicotinonitriles was
very generalized and worked well at room temperatures with both
homopropargylic and homoallylic alcohol precursors, whereas the
latter depicts slightly decreased reaction velocity and yields.
(ix) Ag (I) or Hg (II) –promoted cyclisation4
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(x) Rhenium catalyzed pyridine synthesis25
(i) Titanium catalysed metalated pyridines18
Fig: 2 Synthetic snapshots of substituted Pyridine analogues
(Homogenous catalysis)
(i) K5CoW12O40.3H2O catalysed 3-component condensation 26
(ii) Ru-catalyzed cycloisomerization19
(iii) Cu-catalysed coupling of vinylboronic acids to oxime o- car-
boxylates 20
Fig: 3 Synthesis of substituted pyridine analogues (Heterogenous
catalysis)
Our work:
(iv)Rh- catalyzed C-H activation/alkyne insertion.21
(v) Rh – carbenoid-catalysed ring expansion of isoxazoles22
RESULTS
We initiated our study by examining the reaction of 1-(p-
tolyl)but-3-yn-1-ol (1.1 ) in acetonitrile as a solvent (Table-1) in
presence of a wide variety of heterogenous and homogenous cata-
lytic conditions. In acetonitrile, at ambient temperature, homoge-
nous Pd-catalysts like Pd(dba), Pd(OAc)2 delivered sluggish reac-
tion. Use of other catalysts such as FeCl3, Co(OAc)2, NiCl2,
Cu(OAc)2, CuBr2, Cu(OAc)2,[Cu(CH3CN)4]PF6, Ru(CH3CN)3PF6
catalyzed delivered either no reaction or the oligomerization of
isonitrile .While virtually no reaction took place, albeit the cata-
lysts added were more than 20 mol%. Addition of molecular
sieves had no effect on the reaction outcome. In a calibrated
study in other solvents (Table-1(11-16)), it was concluded that an
excess of acetonitrile (20 equivalents) was found necessary for the
reaction completion. Use of other bases like KOBut, LiHMDS etc
(Table-1(17, 18, and 19)) delivered no traces of the product. Un-
der the optimized conditions, the reaction scope was investigated
with variety of substrates. (Table.2)
(vi) Electrophilic activation and coupling of vinyl/aryl-amides23
(vii) Metal mediated [2+2+2] cycloaddition16
(viii) Cy-
cloaddition24
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Table-1 Reaction Optimization
Gratifyingly 1-(p-tolyl)but-3-en-1-ol(1.3) on exposure to similar
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reaction conditions delivered the same nicotinonitrile at room
temperature with reduced yields but with longer duration. In-
creasing the temperature did not accelerate the reaction rate. All
of the tested homopropargyl and homoallyl alcohols acted as ex-
cellent substrates to react with the nitriles producing the corre-
sponding nicotinonitriles in good to moderate yields. Neverthe-
less, the reaction was not influenced by the nature of substituent
in the phenyl ring but any ortho-substitution with respect to the
alcoholic moiety significantly retarded the reaction rate presuma-
bly due to the steric effects. Running reaction batches in mixture
of solvents (Table -1, entries 11-16) with one being the nitrile,
exhibited a rapid decrease in the reaction yield highlighting the
kinetic molecular encountering playing a dominant role in this
transformation and thus rationalize a plausible concerted mecha-
nism involved in the reaction.
En Catalyst
Base
Solvent
Prod Starting
try
uct
(%)
(Mol%)
Recov-
ered (%)
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CH3CN
1
Pd/C
NaNH2
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10
(10%)
Pd/C (5%)
Pd/C
NaNH2
NaNH2
CH3CN
CH3CN
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20
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3
(3%)
Table-2 Substrate Scope
Lindlar’s
catalyst
NaNH2
CH3CN
CH3CN
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10% NaNH2
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(supported
on BaSO4)
Pd(OH)2 on NaNH2
Carbon
CH3CN
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6
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Pd(OAC)2
PdCl2
NaNH2
NaNH2
NaNH2
NaNH2
CH3CN
CH3CN
CH3CN
CH3CN
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28
15
10
30
60
54
72
84
60
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9
Pd(PPh3)2
10
11
Pd/C (10%) NaNH2
Ben-
zene+
CH3CN
(1:1)
Pd/C (10%) NaNH2
Pd/C (10%) NaNH2
Pd/C (10%) NaNH2
Pd/C (10%) NaNH2
Pd/C (10%) NaNH2
Toluene+ 40
CH3CN
(1:1)
50
80
90
85
75
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13
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16
THF+
CH3CN
(1:1)
15
6
Hexane+
CH3CN
(1:1)
DMSO+
CH3CN
(1:1)
13
16
DMF+
CH3CN
(1:1)
Pd/C (10%) n-BuLi
Pd/C (10%) tKOBu
CH3CN
CH3CN
NR
NR
NR
100
100
100
17
18
19
Pd/C (10%) LiHMDS CH3CN
Reaction Conditions: The reaction was conducted with 40mg
(0.25 mmol) of 1.1 as substrate, 2.5ml of acetonitrile 195 mg (5
mmol)of NaNH2 and the reaction was tabulated for 10hrs at room
temperature (250C).The yields specified are obtained after single
run.
Excess of the nitrile would be required to drive the reaction to
completion. The key oxidative aromatization would deliver the
projected trisubstituted nicotinonitrile.
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posed and the nitrile geometry is insignificant. This finding, that
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the first alkyl nitrile acts only as a supplier of the nitrile source ,
plays an important role in the pyridine –forming process and also
exhibits profound impact on the potential utility of methodology
and provides regiospecific access to a great variety of differential-
ly substituted nicotinonitriles. The charcoal component is ex-
pected to stimulate a facile removal of the alkoxy group prompt-
ing the desired ring annulations.
One selected compound (2.9) has been chosen to confirm its com-
position and to determine its solid state structure (Fig. 5) by single
crystal X-ray diffraction.28 A common feature of this kind of
compounds result from the two aromatic rings connected via a
slightly shortened C-C single bond [d (C6-C11) = 1.482(3) Å] as
steric hindrance will result in their non-coplanarity. Indeed, the
dihedral angle between both rings reveals a value of 21.2(1)°,
while they are almost planar with all endocyclic bond lengths and
angles in the normal ranges.
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PhCH2CN did not react to deliver the substituted pyridines where-
as other nitriles like n-propionitrile and n-butyronitrile delivered
better outcomes than acetonitrile. Homopropargyl alcohols acted
as marginally better substrates than the corresponding homoallylic
alcohols. Thus, it is assumed that the overall rate of the reaction
was mainly determined by the steric assignment in the phenyl
ring, the substitution pattern in the nitrile as well as the nature of
metallic activation of the precursors. The reaction was readily
expanded to napthyl homoallylic and homopropargyl alcohols
(Table 2(2.1, 2.2)). Halide substitution did not pose any negative
effect on the reaction (Table 2 -2.7). The nitriles served as the best
solvents to the reaction. The increased challenges associated with
such pursuits bear considerations regarding both reactivity and
stereo selectivity whereas the current transformation was found to
be a worthy demanding process, as running reaction batches in
mixture of nitriles delivered two distinct nicotinonitriles in 65 %
overall yield (Scheme 1). An assisted C-C bond cleavage is also a
part of the process. It is proposed that thermodynamic implausi-
bility related to this unprecedented bond cleavage is compensated
by the oxidative aromatization. It also implies, that mixture of two
homoallylic alcohols or homopropargyl alcohols or even mixture
of either of the homopropagyl alcohol and homoallylic alcohol
with the corresponding nitriles delivered only the desired nico-
tinonitriles in either cases. Thus the issues related to regioselectiv-
ity is triumphed over with the advantageous incorporation of the
nitriles into the pyridines core in the present study.
Fig- 5. Ball-and-stick model and atom numbering scheme of 2.9;
non-hydrogen atoms are drawn as thermal displacement ellipsoids
of 50% level. Selected bond lengths (Å) and angles (°): d(C13-
C18) = 1.445(3), d(C18-N2) = 1.148(3), <(C13-C18-N2) =
179.8(3), d(C3-O1) = 1.380(2), d(O1-C2) = 1.439(2), d(C1-C2) =
1.494(3), <(C3-O1-C2) = 115.5(1), <(C1-C2-O1) = 107.9(2),
d(C4-C10) = 1.505(3), d(C8-C9) = 1.507(3), d(C12-C17) =
1.499(3), d(C14-C16) = 1.495(3).
Scheme-1 Reaction with bisolvents
Scheme-2(a) Catalytic cycle with homopropargyl alcohols as
primary substrate
To shed light on the involved mechanistic pathway, the reaction
was set with a wide range of different homopropargylic substrates
enlisted in (Fig-4).
Fig-4 Different substrates tested
No reaction occurred either with substituted alkynes (3.2, 3.4,
3.6), or substituted homoallylic alcohols and alkyl homoallylic
alcohols (3.1, 3.5 &3.7).In the ongoing process, an oxidative aro-
matization27 induced unprecedented C-C bond cleavage is pro-
The theoretical investigations clearly support the mechanistic
outline. The initial step is the formation of the palladacycle (3)
(Scheme 2(b)) via oxidative insertion, along with the generation
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of charcoal supported Palladium(II). Subsequent base mediated
concerted ring annulation and final oxidative aromatization com-
1
pletes the cycle with the regeneration of Pd/C(0). The reaction
sequence requires an excess of sodium amide and generates am-
monia. There lies a probability of stabilization of solvated elec-
trons in the ammonia generated, which accelerates the oxidative
insertion and further accelerates the dearomatization reaction in
the catalytic cycle. The formation of the stabilized six membered
palladacycle is the driving force for the conversion of Pd(II) from
Pd (0). The reaction attains further thermodynamic stability
gained through oxidative aromatization. There has been such
precedence in heterogenous palladium carbon chemistry.29 Inter-
estingly, the reaction accelerates with substituted nitriles and en-
compasses a C-C bond cleavage to deliver the nicotinonitriles.
The dignified C-C bond cleavage may be attribute to the aromatic
energy gained in the transformation.
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Scheme-2(b) Catalytic cycle with homopropargyl alcohols as
primary substrate and substituted nitrile involving C-C bond
cleavage
We assumed that the most important phase of the reaction is the
formation of six membered ring from 3 to 4. To account that, we
have optimized the transition state and calculated the activation
energy barrier. The activation energy barrier from 3 to 4 for
Schemes 2(a) and Scheme 2(c) are ~13.0 and ~24.0 kcal/mol re-
spectively (Fig. 6). This clearly suggest that why reaction is going
faster in homopropargyl alcohol than homoallylic alcohol. We
have also checked the same transition state for other substituted
nitriles and found that the activation energy barrier is almost
comparable (~13.6 kcal/mol) with primary nitrile.
The retarded efficiency of the allylic alcohols in the transfor-
mation relates to the slothful tendency of the palladacycle genera-
tion in the catalytic cycle, which clearly suported by the theoreti-
cal calculation.
The optimized intermediates involved in Scheme 2(a) and (c) are
given along with the schemes.The optimization has been per-
formed by using B3LYP form for the generalized gradient ap-
proximation (GGA) to the exchange-correlation potential and
LANL2DZ form for the basis set embedded in Gaussian09 soft-
ware.30 The vibrational frequency calculation has also been per-
formed to make sure that the intermediates are the local minima
on the potential energy surface.
Fig 6: Energy profile diagram from 3 to 4 in Schemes 2(a) and 2
(c). (
trile;
stands for homopropargyl alcohol with primary ni-
stands for homoallylic alcohol with primary nitrile;
RC = reaction complex; TS = transition state and PC = product
complex)
The generated nicotinonitriles can act as facile template for a
variety of important transformations towards important molecules
like fluorescent indolizine, curindolizine, rosabulin.
Scheme -2(c) Catalytic cycle with homoallylic alcohols as prima-
ry substrate
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mixture , after completion the reaction mixture was quenched
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with ammonium chloride solution. The organic layer was extract-
ed with ethyl acetate. The combined organic layers were washed
with brine, dried over Na2SO4, filtered and concentrated under
vaccume. The mass was subjected to column chromatography
over silica gel to afford corresponding homoallylic alcohol.
General Experimental procedure for the synthesis of substi-
tuted pyridines(c) .Palladium Charcoal (10%) (6mol%) was add-
ed to a well stirred solution of homopropargylic/ homoallyic alco-
hols in corresponding nitrile (acetonitrile/propionitrile
/butonitrile) and stirred for 5mins. Sodium amide (20 eq.) was
added to the mixture then the reaction was left for stirring about
10-12h at room temperature. The completion of the reaction was
monitored by TLC. After completion of reaction the reaction was
quenched with distilled water. The organic layer was extracted
with ethyl acetate. The combined organic layers were washed
with brine, dried over Na2SO4, filtered and concentrated under
vaccume. The mass was subjected to column chromatography
over neutral alumina, elution with appropriate solvents afforded
corresponding nicotinonitrile.
2, 4-dimethyl-6-(naphthalen-1-yl) nicotinonitrile (2.1) Palladi-
um charcoal (10%)(6 mol%) was added to the well stirred solu-
tion of 1-(naphthalen-1-yl)but-3-yn-1-ol(47mg, 0.24mmol) in
acetonitrile(5ml). After 5min NaNH2 (195mg, 5mmol) was added
to the solution then the reaction mixture allowed to stirred for 9hr.
The reaction progress was monitored by TLC. Then the mixture
was quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with petroleum ether afforded 2, 4-dimethyl-6-(naphthalen-1-yl)
nicotinonitrile (2.1) as a white solid (44mg, 70 %) Rf = 0.7 (in 10
% ethyl acetate in petroleum ether). mp 120-125°C; 1H NMR(400
MHz, CDCl3); δ = 8.03 (dd, J = 7.2Hz, 3.2Hz, 1H), 8.00-7.92 (m,
2H), 7.61-7.511 (m, 4H), 7.39 (s, 1H), 2.89 (s, 3H), 2.63 (s, 3H)
13C NMR (100 MHz,CDCl3) δ = 161.5, 161.2, 151.4, 136.9,
133.8, 130.6, ,129.7, 128.4, 127.5, 126.7, 126.0, 125.1, 125.0,
123.2, 116.4, 108.1, 23.9, 20.5 , IR (Neat Film, NaCl) 2922,
2220, 1587, 1258, 1029, 842 cm-1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C18H15N2 259.1235; Found 259.1223.
CONCLUSION
In conclusion, we have realized an atom-economic synthesis of
tri-substituted nicotinoniriles employing cheap nitriles acting both
the “N”-sources as well as the solvent of the reaction. The synthe-
sis employs easily available substrates like homo propargyl/allylic
alcohol and economic Pd/C catalyst at room temperature. To the
best of our information, this is the first synthesis of such trisubsti-
tuted nicotinonitriles employing heterogenous catalysis. The
sequence leading to the pyridine core encompasses an unprece-
dented concerted addition of the nitriles to the activated homopro-
pargyl and homoallylic alcohols. The formation of heterogeneous
Pd(II)-C followed by the unprecedented oxidative aromatization
induced C-C bond cleavage in case of substituted nitriles seems
noteworthy and thus rules out any issues with regiospecificity
which has been a prime concern in earlier endeavors. The theoret-
ical study distinctly supports the mechanistic outlook. The elite
reaction efficiency, good yields ,wide reaction scope, easy availa-
bility of starting materials along with products delivers a fast and
straight forward route to biologically active tri-substituted nico-
tionitriles which supersede the available once.
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EXPERIMENTAL SECTION
All reactions were carried out under oven dried glassware. Ace-
tonitrile, propionitrile, and butonitrile was dried over potassium
carbonate and phoshphorous pentoxide for use. All other reagents
were purchased from, Avra chemicals, Sigma-Aldrich, and
HIMEDIA and used without further purification. Palladium Char-
coal(10%) was purchased from SRL. Na2SO4 was dried in oven &
used for drying the crude reaction mixture before chromatrogra-
phy.Chromatography was performed using (100-200mesh) silica
gel& neutral aluminium oxide. Analytical TLC was performed
with 0.25 mm coated commercial silica gel plates (E.Merck, DC-
kiesel gel 60 F254) and visualized with UV light, iodine and vanil-
lin stain. 1H and 13C NMR spectra were recorded on a Bruker (400
MHz, 100 MHz respectively). Chemical shifts are reported in
delta (δ), chemical shift relative to deuterochloroform (7.28 ppm)
1
1
for H NMR & 77.0 for 13C NMR). Data for H reported as fol-
lows- Chemical shift (δ ppm) (multiplicity, coupling constant
(Hz), integration). Multiplicity recorded as follows s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplate, dd = doublet of a
doublet. IR spectra were examined by using of a perkin Elmer
spectrum-2 spectrometer using Thin film deposit on NaCl plated
and frequency reported in absorption (cm-1). High Resolution
Mass Spectra (HRMS) were measured in a QTOF I (quadrupole-
hexapole-TOF) mass spectrometer with an orthogonal Z-spray-
electrospray interface on Micro (YA-263) mass spectrometer
2, 4-dimethyl-6-(naphthalen-1-yl) nicotinonitrile (2.2) Palladi-
um charcoal (10%)(6mol%) was added to the well stirred solu-
tion of 1-(naphthalen-1-yl)but-3-en-1-ol (40mg, 0.20mmol) in
acetonitrile(4ml). After 5min NaNH2 (156mg, 4mmol) was added
to the solution then the reaction mixture allowed to stirred for
12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with petroleum ether afforded 2 , 4-dimethyl-6-
(naphthalen-1-yl) nicotinonitrile (2.2) as a white solid (31mg, 60
%). Spectra same as 2.1
General Procedure for synthesis of Homopropargylic alco-
hol(A).Aldehyde (1 eq), zinc (1.5 eq) was dissolved in dry THF.
The mixture was allowed to stir for 10min then propagyl bromide
(1.5 eq) was added. The reaction mixture was stirred for 5hrs. The
reaction was then quenched with aqueous solution of ammonium
chloride. The organic layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated under vaccume. The mass was
subjected to column chromatography to afford corresponding
homopropargylic alcohol.
General Procedure for synthesis of Homoallylic alco-
hol(B).Activated magnesium (2eq) (under Iodine) was taken in
dry THF. Allyl bromide (1.5eq) was added to the solution and
stirred for 15min (until the formation of Grignard reagent),If the
Grignard does not form then the mixture was heated with hot
water. The aldehyde (1 eq) was added dropwise to the reaction
6-(2-methoxynaphthalen-1-yl)dimethylnicotinonitrile
Palladium charcoal (10%)(6mol%) was added to the well stirred
solution of 1-(2-methoxynaphthalen-1-yl)but-3-yn-1-ol
(2.3)
(70mg,.31mmol) in acetonitrile(7ml).After 5min NaNH2
(241mg,6.2mmol) was added to the solution then the reaction
mixture allowed to stirred for 12hr. The reaction progress was
monitored by TLC. Then the mixture was quenched with distilled
water and extracted with ethyl acetate (2X3 ml) and dried over
sodium sulphate. Solvent was evaporated and the mass was sub-
jected to neutral alumina column, elution with petroleum ether
afforded as 6-(2-methoxynaphthalen-1-yl)nicotinonitrile (2.3) a
white solid (55mg, 61 %) Rf = 0.6 in 10 % ethyl acetate in petro-
1
leum ether. mp 140-145°C; H NMR(400 MHz, CDCl3); 7.95 (d,
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The Journal of Organic Chemistry
J = 9.2Hz, 1H), 7.85-7.82 (m, 1H), 7.39-7.33 (m, 4H), 7.27 (s,
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
1H), 3.88 (s, 3H), 2.87 (s, 3H), 2.63 (s, 3H) 13C NMR (100 MHz,
CDCl3) δ =161.5, 158.6, 153.9, 151.0, 132.5, 130.7, 128.8, 127.9,
126.9, 125.0, 124.1, 123.7, 122.3, 116.5, 113.1, 108.2, 56.4, 23.9,
20.4 ; IR (Neat Film, NaCl) 2932, 2240, 1580, 1248, 1039, 890
cm-1 ; HRMS(ESI-TOF) m/z: [M + H]+ calcd for C19H17N2O
289.1341 ; Found 289.1332.
and the mass was subjected to neutral alumina column, elution
with petroleum ether afforded 6-(4-chlorophenyl)-2, 4-
dimethylnicotinonitrile (2.7) as a white solid (29mg, 43 %) Rf =
1
2
3
4
5
6
7
8
1
0.7 in 10 % ethyl acetate in petroleum ether. mp 115-120°C; H
NMR(400 MHz, CDCl3); 7.99 (dd , J = 6.8Hz, 2Hz, 2H), 7.50-
7.46 (m, 3H), 2.82(s, 3H), 2.60 (s, 3H); 13C NMR (100
MHz,CDCl3) δ = 161.7, 157.5, 151.8, 136.2, 136.0, 129.1, 128.9,
118.2, 116.4, 108.1, 23.9, 20.6; IR (Neat Film, NaCl) 2933, 2216,
1521, 1240, 815 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C14H12ClN2 243.0689; Found 243.0673.
6-(4-(allyloxy)-3-methylphenyl)-2,4-dimethylnicotinonitrile
(2.8) Palladium Charcoal (10%) (6mol%) was added to the well
stirred solution of 1-(4-(allyloxy)-3-methylphenyl)but-3-en-1-ol
(30mg, .14mmol) in acetonitrile (3ml).After 5min NaNH2
(109mg, 2.8mmol) was added to the solution then the reaction
mixture allowed to stirred for 9hr. The reaction progress was
monitored by TLC. Then the mixture was quenched with distilled
water and extracted with ethyl acetate (2X3 ml) and dried over
sodium sulphate. Solvent was evaporated and the mass was sub-
jected to neutral alumina column, elution with petroleum ether
6-(4-methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.4) Palladi-
um charcoal (10%)(6mol%) was added to the well stirred solu-
tion of 1-(4-methoxyphenyl)but-3-yn-1-ol (49mg,.28mmol) in
acetonitrile(5ml).After 5min NaNH2 (218mg,5.6mmol) was added
to the solution then the reaction mixture allowed to stirred for 8hr.
The reaction progress was monitored by TLC. Then the mixture
was quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with petroleum ether afforded 6-(4-methoxyphenyl)-2, 4-
dimethylnicotinonitrile (2.4) as a white solid (45mg, 68 %) Rf =
0.7 in 10 % ethyl acetate in petroleum ether.1H NMR(400 MHz,
CDCl3); 8.01 (dd, J = 6.8Hz, 2Hz, 2H), 7.45 (s, 1H), 7.01 (dd, J =
7Hz, 2.4Hz, 2H), 3.89 (s, 3H), 2.81 (s, 3H), 2.57 (s, 3H) 13C
NMR (100 MHz,CDCl3) δ = 161.6, 161.3, 158.5, 151.4, 130.3,
128.8, 117.6, 116.9, 114.2, 107.0, 55.4, 24.0, 20.6; IR (Neat Film,
NaCl) 2921, 2218, 1583, 1459, 823 cm-1 ; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for for C15H15N2O 239.1184; Found
239.1179.
6-(4-methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.5) Palladi-
um Charcoal (10%)(6mol%) was added to the well stirred solu-
tion of 1-(4-methoxyphenyl)but-3-en-1-ol (45mg,.25mmol) in
acetonitrile(4ml).After 5min NaNH2 (195mg,5mmol) was added
to the solution then the reaction mixture allowed to stirred for
12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with petroleum ether afforded 6-(4-
methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.5) as a white solid
(36mg, 60 %) Rf = 0.7 in 10 % ethyl acetate in petroleum ether.
Spectra same as 2.4
2, 4-dimethyl-6-(p-tolyl)nicotinonitrile (2.6) Palladium charcoal
(10%)(6mol%) was added to the well stirred solution of 1-(p-
tolyl)but-3-yn-1-ol (80mg,.5mmol) in acetonitrile (8ml).After
5min NaNH2 (390mg, 10mmol) was added to the solution then the
reaction mixture allowed to stirred for 7hr. The reaction progress
was monitored by TLC. Then the mixture was quenched with
distilled water and extracted with ethyl acetate (2X3 ml) and dried
over sodium sulphate. Solvent was evaporated and the mass was
subjected to neutral alumina column, elution with petroleum ether
afforded 2, 4-dimethyl-6-(p-tolyl)nicotinonitrile (2.6) as a white
solid (79mg, 70 %) Rf = 0.7 in 10 % ethyl acetate in petroleum
ether. 1H NMR(400 MHz, CDCl3); 7.94 (d, J = 8Hz, 2H), 7.49 (s,
1H), 7.30 (d, J = 8Hz, 2H), 2.82 (s, 3H), 2.58 (s, 3H), 2.43 (s, 3H)
13C NMR (100 MHz, CDCl3) δ = 161.5, 158.8, 151.4, 140.3,
134.9, 129.5, 127.1, 118.0, 116.6, 107.4, 23.9, 21.2, 20.5; IR
(Neat Film, NaCl) 2935, 2210, 1510, 1250, 825 cm-1 ; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C15H15N2 223.1235; Found
223.1226.
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
afforded
6-(4-(allyloxy)-3-methylphenyl)-2,
4-
dimethylnicotinonitrile (2.8) as a white solid (28mg, 71 %) Rf =
1
0.6 in 10 % ethyl acetate in petroleum ether H NMR(400 MHz,
CDCl3); 7.86-7.82 (m, 2H), 7.44 (s, 1H), 6.9 (d, J = 8.4Hz, 1H),
6.14-6.05 (m, 1H), 5.49-5.43 (m, 1H), 5.33-5.30 (m, 1H), 4.63-
4.622 (m, 2H), 2.80 (s, 3H), 2.56 (s, 3H), 2.34(s, 3H) 13C NMR
(100 MHz,CDCl3) δ =161.4, 158.7, 158.5, 151.2, 133.0, 129.8,
129.6, 127.3, 126.1, 117.5, 117.1, 116.7, 111.1, 106.8, 68.6, 23.9,
20.5, 16.3; IR (Neat Film, NaCl) 2905, 2242, 1515, 1220, 827 cm-
1
; HRMS(ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O
279.1497; Found 279.1482.
6-(4-ethoxy-3, 5-dimethylphenyl)-2, 4-dimethylnicotinonitrile
(2.9) Palladium Charcoal (10%) (6mol%) was added to the well
stirred solution of 1-(4-ethoxy-3,5-dimethylphenyl)but-3-en-1-ol
(50mg, .23mmol) in acetonitrile (5ml). After 5min NaNH2
(179mg, 4.6mmol) was added to the solution then the reaction
mixture allowed to stirred for 12hr. The reaction progress was
monitored by TLC. Then the mixture was quenched with distilled
water and extracted with ethyl acetate (2X3 ml) and dried over
sodium sulphate. Solvent was evaporated and the mass was sub-
jected to neutral alumina column, elution with petroleum ether
afforded
6-(4-ethoxy-3,
5-dimethylphenyl)-2,
4-
dimethylnicotinonitrile (2.9) as a white solid (44mg, 65 %) Rf =
1
0.5 in 10 % ethyl acetate in petroleum ether. mp 125-130°C; H
NMR(400 MHz, CDCl3); 7.68 (s, 2H), 7.45 (s, 1H), 3.92-3.87 (q,
J = 7.2Hz, 2H), 2.81 (s, 3H), 2.57 (s, 3H), 2.36 (s, 6H), 1.45 (t, J
= 6.8Hz, 3H) 13C NMR (100 MHz,CDCl3) δ = 161.4, 158.8,
157.9, 151.3, 133.0, 131.5, 127.8, 118.1, 116.7, 107.2, 67.9, 23.9,
20.5, 16.4, 15.6; IR (Neat Film, NaCl) 2915, 2219, 1535, 1032,
790 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H21N2O 281.1654; Found 281.1648.
2,4-dimethyl-6-(o-tolyl)nicotinonitrile(2.10) Palladium Charcoal
(10%) (6mol%) was added to the well stirred solution of 1-(o-
tolyl)but-3-yn-1-ol (90mg, .56mmol) in acetonitrile (6ml).After
5min NaNH2 (437mg, 11.2mmol) was added to the solution then
the reaction mixture allowed to stirred for4hr. If the reaction does
not proceed then reaction mixture was refluxed. The reaction
progress was monitored by TLC. Then the mixture was quenched
with distilled water and extracted with ethyl acetate (2X3 ml) and
dried over sodium sulphate. Solvent was evaporated and the mass
was subjected to neutral alumina column, elution with petroleum
ether afforded 2, 4-dimethyl-6-(o-tolyl) nicotinonitrile (2.10) as a
white solid (85mg, 68 %) Rf = 0.8 in 10 % ethyl acetate in petro-
6-(4-chlorophenyl)-2, 4-dimethylnicotinonitrile (2.7) Palladium
Charcoal (10%)(6mol%) was added to the well stirred solution of
1-(4-chlorophenyl)but-3-yn-1-ol (51mg,.28mmol) in acetonitrile
(5ml).After 5min NaNH2 (218mg, 5.6mmol) was added to the
solution then the reaction mixture allowed to stirred for 12hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
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leum ether . mp 97-105°C;1H NMR(400 MHz, CDCl3); 7.38-7.27
water and extracted with ethyl acetate (2X3 ml) and dried over
(m, 5H), 2.83 (s, 3H), 2.60 (s, 3H), 2.37 (s, 3H), 13C NMR (100
MHz,CDCl3) δ = 162.0, 161.1, 151.2, 138.9, 135.7, 130.9, 129.3,
128.9, 125.9, 122.2, 116.4, 107.7, 23.8, 20.4, 20.2; IR (Neat Film,
NaCl) 2930, 2214, 1580, 1220, 821 cm-1 ;HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C15H15N2: 223.1235; Found 223.1229.
sodium sulphate. Solvent was evaporated and the mass was sub-
jected to neutral alumina column, elution with 5% ethyl acetate
petroleum ether afforded 6-(4-((4-fluorobenzyl)oxy)phenyl)-2,4-
dimethylnicotinonitrile (2.14) as a white solid (55mg, 65%) Rf =
1
2
3
4
5
6
7
8
1
0.7 in 10 % ethyl acetate in petroleum ether H NMR(400 MHz,
CDCl3); 8.01(d, J = 8.8Hz, 2H), 7.46-7.42 (m, 3H), 7.12-7.06 (m,
4H), 5.11 (s, 2H), 2.81 (s, 3H), 2.58 (s, 3H) 13C NMR (100
MHz,CDCl3) δ = 161.5, 160.2, 151.4, 130.6, 129.2, 129.2, 128.7,
117.5, 116.7, 115.5, 115.3, 115.0, 107.0, 69.3, 23.9, 20.5; IR
(Neat Film, NaCl) 2966, 2218, 1585, 1245, 820 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H18FN2O 333.1403;
Found 333.1401.
2-methyl-6-(naphthalen-1-yl)-4-propylnicotinonitrile (2.15)
Palladium Charcoal (10%) (6mol%) was added to the well stirred
solution of 1-(naphthalen-1-yl)but-3-yn-1-ol (60mg, 0.31 mmol)
in butonitrile (6ml).After 5min NaNH2 (234mg, 6mmol) was add-
ed to the solution then the reaction mixture allowed to stirred for
6hr. The reaction progress was monitored by TLC. Then the mix-
ture was quenched with distilled water and extracted with ethyl
acetate (2X3 ml) and dried over sodium sulphate. Solvent was
evaporated and the mass was subjected to neutral alumina col-
umn, elution with 5% ethyl acetate petroleum ethe afforded 2-
6-(3-methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.11)
Palladium Charcoal (10%) (6mol%) was added to the well stirred
solution of 1-(3-methoxyphenyl)but-3-yn-1-ol (60mg,.34mmol) in
acetonitrile(4ml).After 5min NaNH2 (265mg, 6.8mmol) was add-
ed to the solution then the reaction mixture allowed to stirred for
8hr. The reaction progress was monitored by TLC. Then the mix-
ture was quenched with distilled water and extracted with ethyl
acetate (2X3 ml) and dried over sodium sulphate. Solvent was
evaporated and the mass was subjected to neutral alumina col-
umn, elution with petroleum ether afforded 6-(3-methoxyphenyl)-
2, 4-dimethylnicotinonitrile (2.11) as a colourless liquid (47mg,
58%) Rf = 0.7 in 10 % ethyl acetate in petroleum ether 1H
NMR(400 MHz, CDCl3); 7.62-7.56 (m, 2H), 7.51 (s, 1H), 7.41 (t,
J = 8Hz, 1H), 7.04-7.01 (m, 1H), 3.91 (s, 3H), 2.84 (s, 3H), 2.60
(s, 3H) 13C NMR (100 MHz,CDCl3) δ = 163.1, 161.5, 160.2,
153.1, 140.7, 131.3, 121.1, 120.1, 118.0, 117.3, 114.1, 109.5,
56.8, 25.4, 22.1; IR (Neat Film, NaCl) 2924, 2215, 1527, 1029,
822 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H15N2O 239.1184; Found 239.1177.
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
methyl-6-(naphthalen-1-yl)-4-propylnicotinonitrile (2.15) as
a
yellow liquid (53mg, 61 %) Rf = 0.7 in 10 % ethyl acetate in pe-
troleum ether 1HNMR(400 MHz, CDCl3); 8.153-8.12 (m, 1H),
7.96-7.91 (m, 2H), 7.64-7.51 (m, 2H), 3.05-3.01 (m, 2H), 2.6 (s,
3H), 1.98-1.93 (m, 2H), 1.07 (t, J = 7.6 Hz,3H) 13C NMR (100
MHz,CDCl3) δ = 170.9 , 166.9, 166.2, 136.3, 133.8, 130.5, 129.7,
128.3, 127.4, 126.6, 125.9, 125.1, 118.4, 41.6, 24.2, 22.4, 13.9;
IR (Neat Film, NaCl) 2922, 2216, 1588, 1230, 950 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H19N2 287.1548; Found
287.1541.
6-(2-methoxy-3-methylphenyl)-2, 4- dimethylnicotinonitrile
(2.16) Palladium Charcoal (10%) (6mol%) was added to the well
stirred solution of 1-(2-methoxy-3-methylphenyl)but-3-yn-1-ol
(50mg, 0.26mmol) in acetonitrile(5ml).After 5min NaNH2
(203mg, 5.2mmol) was added to the solution then the reaction
mixture allowed to stirred for 9hr. The reaction progress was
monitored by TLC. Then the mixture was quenched with distilled
water and extracted with ethyl acetate (2X3 ml) and dried over
sodium sulphate. Solvent was evaporated and the mass was sub-
jected to neutral alumina column, elution with petroleum ether
6-(3-methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.12)
Palladium Charcoal (10%) (6mol%) was added to the well stirred
solution of 1-(3-methoxyphenyl)but-3-en-1-ol (54mg,.3mmol) in
acetonitrile (5ml).After 5min NaNH2 (234mg, 6mmol) was added
to the solution then the reaction mixture allowed to stirred for
12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with petroleum ether afforded 6-(3-
methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.12) as a colour-
less liquid (36mg, 50%) Rf = 0.7 in 10 % ethyl acetate in petrole-
um ether. Spectra same as 2.11
2-ethyl-4-methyl-6-(o-tolyl) nicotinonitrile (2.13) Palladium
Charcoal (10%) (6mol%) was added to the well stirred solution
of 1-(o-tolyl)but-3-yn-1-ol (40mg,.25mmol) in acetoni-
trile(4ml).After 5min NaNH2 (195mg, 5mmol) was added to the
solution then the reaction mixture allowed to stirred for 6hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with 5% ethyl acetate petroleum ether afforded 2-ethyl-4-methyl-
6-(o-tolyl)nicotinonitrile (2.13) as a yellow liquid (38mg, 64 %)
afforded
6-(2-methoxy-3-methylphenyl)-2,
4-
dimethylnicotinonitrile (2.16) as a colourless liquid (33mg, 50 %)
1
Rf = 0.7 in 10 % ethyl acetate in petroleum ether H NMR(400
MHz, CDCl3); 7.71 (s, 1H), 7.57 (dd, J = 7.6Hz, 1.6Hz, 1H), 7.29
(d, J = 6.4Hz,1H), 7.15 (t, J = 7.6Hz, 1H), 3.52 (s, 3H), 2.84 (s,
3H), 2.59 (s, 3H), 2.37 (s, 3H) 13C NMR (100 MHz,CDCl3) δ
=162.8, 159.9, 157.9, 152.5, 134.1, 133.5, 133.3, 130.4, 125.9,
124.1, 118.1, 109.2, 62.3, 25.4, 22.0, 17.5; IR (Neat Film, NaCl)
2981, 2230, 1567, 1210, 956 cm-1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C16H17N2O 253.1341; Found 253.1337.
6-(3-isobutoxy-4-methoxyphenyl)-2, 4-dimethylnicotinonitrile
(2.17) Palladium Charcoal (10%) (6mol%) was added to the well
stirred solution of 1-(3-isobutoxy-4-methoxyphenyl)but-3-en-1-ol
(80mg,.32mmol) in acetonitrile (8ml).After 5min NaNH2 (250mg,
6.4mmol) was added to the solution then the reaction mixture
allowed to stirred for 12hr. The reaction progress was monitored
by TLC. Then the mixture was quenched with distilled water and
extracted with ethyl acetate (2X3 ml) and dried over sodium sul-
phate. Solvent was evaporated and the mass was subjected to
neutral alumina column, elution with petroleum ether afforded 6-
1
Rf = 0.5 in 10 % ethyl acetate in petroleum ether H NMR(400
MHz, CDCl3); 7.41 (d, J = 6.8Hz, 1H), 7.34-7.28 (m, 3H includ-
ing CDCl3), 7.10 (s, 1H) ,3.02 (q, J = 7.6Hz, 2H), 2.57 (s, 3H),
2.43 (s, 3H), 1.41 (t, J = 7.8Hz, 3H) 13C NMR (100 MHz,CDCl3)
δ =171.4, 167.0, 166.7, 138.2, 135.9, 130.9, 129.2, 129.0, 125.9,
117.3, 32.7, 24.2, 20.2, 12.9; IR (Neat Film, NaCl) 2986, 2215,
1577, 894 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H17N2 237.1392; Found 237.1386.
6-(4-((4-fluorobenzyl)oxy)phenyl)-2,4-dimethylnicotinonitrile
(2.14)Palladium Charcoal (10%) (6mol%) was added to the well
stirred solution of 1-(4-((4-fluorobenzyl)oxy)phenyl)but-3-en-1-
ol (70mg, .26mmol) in acetonitrile (4ml).After 5min NaNH2
(195mg, 5.2mmol) was added to the solution then the reaction
mixture allowed to stirred for 12hr. The reaction progress was
monitored by TLC. Then the mixture was quenched with distilled
(3-isobutoxy-4-methoxyphenyl)-2,
4-dimethylnicotinonitrile
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The Journal of Organic Chemistry
(2.17) as a white solid (46mg, 47 %) Rf = 0.7 in 10 % ethyl ace-
tate in petroleum ether H NMR(400 MHz, CDCl3); 7.65 (d, J =
J = 4.8, 3H), 3.07(q, J = 7.6Hz, 2H), 2.62(s, 3H), 1.48(t, J =
7.6Hz, 3H) 13C NMR (100 MHz,CDCl3) δ = 172.0, 167.2, 163.6,
134.5, 134.3, 133.2, 130.1, 128.8, 128.5, 127.6, 127.1, 127.0,
126.4, 124.0, 113.6, 32.81, 24.3, 12.9; IR (Neat Film, NaCl)
3005, 2218, 1567, 1200, 934 cm-1 ; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C19H17N2 273.1392; Found 273.1381.
1
1
2
3
4
5
6
7
8
2.4Hz, 1H), 7.57 (dd , J = 8.4Hz, 2Hz, 1H), 7.45 (s, 1H), 6.96 (d,
J = 8.8Hz, 1H), 3.94 (s, 3H), 3.90 (d, J = 6.8Hz, 2H), 2.82 (s,
3H), 2.58 (s, 3H), 2.27-2.16 (m, 1H), 1.09 (d, J = 6.8Hz, 6H) 13C
NMR (100 MHz,CDCl3) δ = 161.5, 158.5, 151.4, 151.2, 149.0,
143.2, 130.5, 120.2, 117.6, 116.7, 112.1, 111.6, 107.0, 75.5, 56.0,
28.1, 23.9, 20.5, 19.2 ; IR (Neat Film, NaCl) 2983, 2220, 1583,
1240, 954 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
C19H23N2O2 311.1760 ; Found 311.1752.
6-(4-(benzyloxy)-3-methylphenyl)-2, 4-dimethylnicotinonitrile
(2.18)Palladium Charcoal (10%) (6mol%) was added to the well
stirred solution of 1-(4-(benzyloxy)-3-methylphenyl)but-3-en-1-ol
(70mg, .26mmol) in acetonitrile (7ml). After 5min NaNH2
(203mg, 5.2mmol) was added to the solution then the reaction
mixture allowed to stirred for 12hr. The reaction progress was
monitored by TLC. Then the mixture was quenched with distilled
water and extracted with ethyl acetate (2X3 ml) and dried over
sodium sulphate. Solvent was evaporated and the mass was sub-
jected to neutral alumina column, elution with petroleum ether
6-(4-(allyloxy)-3-methylphenyl)-2-ethyl-4-
methylnicotinonitrile (2.21) Palladium Charcoal (10%)(6mol%)
was added to the well stirred solution of 1-(4-(allyloxy)-3-
methylphenyl)but-3-yn-1ol (90mg, .42mmol) in propionitrile
(9ml).After 5min NaNH2 (320mg, 8.2mmol) was added to the
solution then the reaction mixture allowed to stirred for 12hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with5% ethyl acetate petroleum ether afforded 6-(4-(allyloxy)-3-
methylphenyl)-2-ethyl-4-methylnicotinonitrile (2.21) as a yellow
liquid (78mg, 64 %) Rf = 0.7 in 10 % ethyl acetate in petroleum
ether 1H NMR(400 MHz, CDCl3); 7.91 (d, J = 8Hz, 2H), 7.32 (s,
1H), 6.91 (d, J = 8Hz, 1H), 6.15-6.05 (m, 1H), 5.49-5.30 (m, 2H),
4.64-4.62 (m, 2H), 2.99(q, J = 7.9Hz, 2H),2.55 (s, 3H), 2.34 (s,
3H), 1.43 (t, J = 7.2Hz, 3H) 13C NMR (100 MHz,CDCl3) δ
=171.7, 166.7, 158.7, 133.0, 129.4, 129.2, 127.2, 125.9, 117.1,
112.5, 111.0, 68.6, 32.7, 24.2, 16.3, 12.9; IR (Neat Film, NaCl)
2225, 1612, 1245, 956 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C19H21N2O 293.1654; Found 293.1652.
6-(2-((4-chlorobenzyl)oxy)-5-methylphenyl)-4-methyl-2-
propylnicotinonitrile (2.22) Palladium Charcoal (10%)(6mol%)
was added to the well stirred solution of 1-(2-((4-
chlorobenzyl)oxy)-5-methylphenyl)but-3-yn-1-ol(69mg,.23mmol)
in butonitrile (7ml).After 5min NaNH2 (179.4mg,4.6mmol) was
added to the solution then the reaction mixture allowed to stirred
for 12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with 5% ethyl acetate petroleum ether afforded 6-
(2-((4-chlorobenzyl)oxy)-5-methylphenyl)-4-methyl-2-
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
afforded
6-(4-(benzyloxy)-3-methylphenyl)-2,
4-
dimethylnicotinonitrile (2.18) as a white solid (52mg, 62 %) Rf =
1
0.5 in 10 % ethyl acetate in petroleum ether H NMR(400 MHz,
CDCl3); 7.89-7.83 (m, 2H), 7.48-7.35 (m, 6H), 6.98 (d, J = 8.4Hz,
1H), 5.18 (s, 2H), 2.81 (s, 3H), 2.57 (s, 3H), 2.38 (s, 3H) 13C
NMR (100 MHz,CDCl3) δ = 161.5, 158.7, 158.6, 151.2, 136.8,
129.6, 128.4, 127.8, 127.5, 126.9, 126.1, 117.6, 116.8, 111.3,
106.8, 69.7, 23.9, 20.5, 16.4; IR (Neat Film, NaCl) 2930, 2226,
1582, 932 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H21N2O 329.1654; Found 329.1648.
6-(2-methoxyphenyl)-2, 4-dimethylnicotinonitrile(2.19)
Palladium Charcoal (10%) (6mol%) was added to the well stirred
solution of 1-(2-methoxyphenyl)but-3-yn-1-ol (60mg, .34mmol)
in acetonitrile (4ml).After 5min NaNH2 (265mg, 6.8mmol) was
added to the solution then the reaction mixture allowed to stirred
for 12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with petroleum ether afforded 6-(2-
methoxyphenyl)-2, 4-dimethylnicotinonitrile (2.19) as a white
solid (49mg, 60 %) Rf = 0.7 in 10 % ethyl acetate in petroleum
propylnicotinonitrile (2.22) as a yellow liquid (55mg, 60%) Rf =
0.7 in 10 % ethyl acetate in petroleum ether1H NMR (400 MHz,
CDCl3); 7.72 (d, J = 2Hz, 1H), 7.55 (s, 1H), 7.37-7.19 (m, 5H),
6.93(d, J = 8Hz, 1H),5.09 (s, 2H), 2.98-2.94 (m, 2H), 2.49 (s, 3H),
2.37 (s, 3H), 1.93-1.88 (m, 2H), 1.05 (t, J = 7.2Hz, 3H) 13C NMR
(100 MHz,CDCl3) δ = 170.6, 165.9, 162.5, 154.3, 135.2, 133.6,
131.5, 131.4, 131.0, 128.5, 128.3, 127.1, 118.3, 113.2, 70.0, 41.7,
24.1, 22.4, 20.4, 13.9; IR (Neat Film, NaCl) 2950, 2218, 1570,
1234, 970 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H24ClN2O : 391.1577; Found 391.1571.
1
ether H NMR(400 MHz, CDCl3); 7.81 ( dd , J = 7.6Hz, 1.6Hz,
1H), 7.66 (s, 1H), 7.44-7.40 (m, 1H), 7.12-7.08 (m, 1H), 7.02 (d, J
= 8.4Hz, 1H), 3.89 (s, 3H), 2.82 (s, 3H), 2.58 (s, 3H) 13C NMR
(100 MHz,CDCl3) δ = 162.6, 159.3, 158.5, 151.9, 132.7, 132.4,
129.0, 124.7, 122.6, 118.2, 112.8, 108.9, 57.0, 25.4, 22.1 ; IR
(Neat Film, NaCl) 2950, 2213, 1578, 1230, 950 cm-1 ; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C15H15N2O 239.1184 ;
Found 239.1180.
4-ethyl-2-methyl-6-(naphthalen-2-yl)nicotinonitrile(2.20)
Palladium Charcoal (10%)(6mol%) was added to the well stirred
solution of 1-(naphthalen-2-yl)but-3-yn-1-ol (20mg,.1mmol) in
propionitrile (3ml).After 5min NaNH2 (78mg,2mmol) was added
to the solution then the reaction mixture allowed to stirred for
12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with 5% ethyl acetate petroleum ether afforded 4-
ethyl-2-methyl-6-(naphthalen-2-yl)nicotinonitrile(2.20) as a yel-
low liquid (18mg,60 %) Rf = 0.7 in 10 % ethyl acetate in petrole-
um ether 1H NMR(400 MHz, CDCl3); 8.62(s, 1H), 8.21(dd, J =
8.8Hz, 1.6Hz, 1H), 8.01-7.96(m, 2H), 7.91(t, J = 4Hz, 1H), 7.56(t,
2-ethyl-4-methyl-6-(p-tolyl)nicotinonitrile(2.23)
Charcoal (10%)(6mol%) was added to the well stirred solution of
1-(p-tolyl)but-3-yn-1-ol (50mg,.31mmol) in propionitrile
Palladium
(5ml).After 5min NaNH2 (241mg, 6.2mmol) was added to the
solution then the reaction mixture allowed to stirred for 9hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with 3% ethyl acetate petroleum ether afforded 2-ethyl-4-methyl-
6-(p-tolyl)nicotinonitrile (2.23) as a yellow liquid(40mg,55 %) Rf
= 0.7 in 10 % ethyl acetate in petroleum ether 1H NMR(400
MHz, CDCl3); 7.99 (d, J = 8Hz, 2H), 7.36 (s, 1H), 7.30 (d, J =
8Hz, 2H), 3.01(q, J = 8Hz,2H), 2.56 (s, 3H), 2.43 (s, 3H), 1.43 (t,
J = 7.6Hz, 3H) 13C NMR (100 MHz,CDCl3) δ= 171.8, 166.9,
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163.6, 140.6, 134.4, 129.4, 126.9, 112.9, 32.7, 24.2, 21.2, 12.8;
4-methyl-2-propyl-6-(p-tolyl)nicotinonitrile(2.27)
Palladium
IR (Neat Film, NaCl)2986, 2221, 1617, 1243, 976 cm-1 ; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H17N2 237.1392; Found
237.1386.
Charcoal (10%) (6mol%) was added to the well stirred solution
of 1-(p-tolyl)but-3-yn-1-ol (80mg, .5mmol) in butoni-
trile(8ml).After 5min NaNH2 (390mg, 10mmol) was added to the
solution then the reaction mixture allowed to stirred for 12hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with with 5% ethyl acetate petroleum ether afforded 4-methyl-2-
propyl-6-(p-tolyl)nicotinonitrile (2.27) as a yellow liquid (75mg,
60%) Rf = 0.7 in 10 % ethyl acetate in petroleum ether 1H
NMR(400 MHz, CDCl3); 7.99 (d, J = 8Hz, 1H), 7.36(s, 1H),7.30
(d, J = 8Hz, 1H), 2.97 (m, 1H), 2.55(s, 3H), 2.43(s, 3H),1.95-
1.89(m, 2H), 1.04 (t, J = 2Hz, 3H) ; ) 13C NMR (100
MHz,CDCl3) δ= 170.9, 166.8, 163.6, 140.6, 134.4, 129.4, 126.9,
113.0, 41.5, 24.2, 22.1, 21.3, 13.9; IR (Neat Film, NaCl) 2996,
2210, 1645, 1260, 954 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C17H19N2 251.1548; Found 251.1542.
1
2
3
4
5
6
7
8
4-methyl-2-propyl-6-(o-tolyl)nicotinonitrile(2.24)
Palladium
Charcoal (10%)(6mol%) was added to the well stirred solution of
1-(o-tolyl)but-3-yn-1-ol (70mg, .43mmol) in butonitrile
(7ml).After 5min NaNH2 (343.2mg, 8.8mmol) was added to the
solution then the reaction mixture allowed to stirred for 7hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with with 5% ethyl acetate petroleum ether petroleum ether af-
forded 4-methyl-2-propyl-6-(o-tolyl)nicotinonitrile (2.24) as a
yellow liquid (65mg, 60 %) Rf = 0.7 in 10 % ethyl acetate in pe-
troleum ether 1H NMR(400 MHz, CDCl3);7.41-7.29 (m, 4H),
7.10(s, 1H), 2.98-2.94 (m, 2H), 2.57 (s, 3H), 2.41 (s, 3H), 1.95-
1.85 (m, 2H), 1.0 3 (t, J = 7.6Hz, 3H); 13C NMR (100
MHz,CDCl3) δ = 170.5, 167.0, 166.6, 138.2, 135.9, 130.9, 129.2,
129.0, 125.9, 117.4, 41.5, 24.2, 27.3, 20.2, 13.9; IR (Neat Film,
NaCl) 2950, 2216, 1583, 1459, 890 cm-1 ; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C17H19N2 251.1548 ; Found 251.1540.
6-(2-methoxyphenyl)-4-methyl-2-propylnicotinonitrile (2.25)
Palladium Charcoal (10%)(6mol%) was added to the well stirred
solution of 1-(2-methoxyphenyl)but-3-yn-1-ol (60mg,.34mmol) in
butonitrile (4ml).After 5min NaNH2 (266mg,6.8mmol) was added
to the solution then the reaction mixture allowed to stirred for
12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with 5% ethyl acetate petroleum ether petroleum
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
6-(4-ethoxy-3,5-dimethylphenyl)-4-methyl-2-
propylnicotinonitrile(2.28) Palladium Charcoal (10%) (6mol%)
was added to the well stirred solution of 1-(4-ethoxy-3,5-
dimethylphenyl)but-3-en-1-ol (30mg,.14mmol) in butonitrile
(3ml). After 5min NaNH2 (109mg, 2.8mmol) was added to the
solution then the reaction mixture allowed to stirred for 12hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with with 5% ethyl acetate petroleum ether afforded 6-(4-ethoxy-
3, 5-dimethylphenyl)-4-methyl-2-propylnicotinonitrile (2.28) as a
yellow liquid (28mg, 64%) Rf = 0.7 in 10 % ethyl acetate in petro-
leum ether 1H NMR(400 MHz, CDCl3); 7.73 (s, 2H), 7.32 (s,
1H), 3.89 (q, J = 6.8Hz, 2H), 2.94 (t, J = 7.6Hz, 2H), 2.55 (s,
2H), 2.37 (s, 6H), 1.94-1.87 (m, 2H), 1.45 (t, J = 7.2Hz, 3H), 1.04
(t, J = 7.2Hz, 3H) 13C NMR (100 MHz,CDCl3) δ = 170.8, 166.7,
163.6, 158.2, 132.4, 131.4, 131.1, 129.2, 127.6, 113.1, 67.9, 41.6,
24.2, 22.2, 16.4, 15.6, 13.9; IR (Neat Film, NaCl) 3010, 2249,
1650, 1256, 939 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C20H25N2O 309.1967; Found 309.1958.
ether
afforded
6-(2-methoxyphenyl)-4-methyl-2-
propylnicotinonitrile (2.25) as a yellow liquid (50mg, 55 %) Rf =
1
0.7 in 10 % ethyl acetate in petroleum ether H NMR(400 MHz,
CDCl3); 7.93 (dd, J = 7.6Hz, 1.6Hz, 1H), 7.57 (s, 1H), 7.45-7.41
(m, 1H), 7.10 (t, J = 7.2Hz, 1H), 7.02 (d, J = 8Hz, 1H), 3.90 (s,
3H), 2.95 (t, J = 7.6Hz, 2H), 2.55 (s, 3H), 1.93-1.88 (m, 2H), 1.04
(t, J = 2Hz, 3H) 13C NMR (100 MHz,CDCl3) δ = 165.9, 162.4,
157.5, 144.2, 139.7, 131.05, 121.0, 118.1, 111.2, 55.4, 41.6, 24.3,
22.3, 13.9 ; IR (Neat Film, NaCl) 2912, 2214, 1588, 1234, 946
cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19N2O
267.1497; Found 267.1492.
6-(4-(allyloxy)-3-methylphenyl)-4-methyl-2-
propylnicotinonitrile (2.29) Palladium Charcoal (10%) (6mol%)
was added to the well stirred solution of 1-(4-(allyloxy)-3-
methylphenyl)but-3-en-1-ol (79mg, .36mmol) in butonitrile
(8ml).After 5min NaNH2 (289mg, 7.2mmol) was added to the
solution then the reaction mixture allowed to stirred for 12hr. The
reaction progress was monitored by TLC. Then the mixture was
quenched with distilled water and extracted with ethyl acetate
(2X3 ml) and dried over sodium sulphate. Solvent was evaporated
and the mass was subjected to neutral alumina column, elution
with with 5% ethyl acetate petroleum ether afforded 6-(4-
(allyloxy)-3-methylphenyl)-4-methyl-2-propylnicotinonitrile
(2.29) as a yellow liquid (68mg, 61%) 1H NMR(400 MHz,
CDCl3); 7.91-7.88 (m, 2H), 7.88 (s, 1H), 6.90 (d, J = 9.2Hz, 1H),
6.15-6.05 (m, 1H), 5.49-5.44 (m, 1H), 5.32 (dd, J = 10.4Hz,
1.2Hz, 1H), 4.63-4.62 (m, 2H), 2.94 (t, J = 7.6Hz, 2H), 2.54 (s,
3H), 2.34 (s, 3H), 1.94-1.89 (m, 2H), 1.04 (t, J = 7.6Hz, 3H) 13C
NMR (100 MHz,CDCl3) δ = 170.8, 166.6, 163.4, 158.7, 133.0,
129.4, 129.2, 127.2, 125.9, 117.1, 112.5, 111.0, 68.6, 41.6, 24.2,
22.2, 16.3, 13.9; IR (Neat Film, NaCl) 2995, 2232, 1620, 1230,
946 cm-1 ;HRMS (ESI-TOF) m/z: [M + H]+ for C20H23N2O
307.1810; Found 307.1803.
6-(4-methoxyphenyl)-4-methyl-2-propylnicotinonitrile (2.26)
Palladium Charcoal (10%)(6mol%) was added to the well stirred
solution of 1-(4-methoxyphenyl)but-3-yn-1-ol (49mg,.28mmol) in
butonitrile(4ml).After 5min NaNH2 (219mg, 5.6mmol) was added
to the solution then the reaction mixture allowed to stirred for
12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with 5% ethyl acetate petroleum ether afforded 6-
(4-methoxyphenyl)-4-methyl-2-propylnicotinonitrile (2.26) as a
yellow liquid (45mg, 60%) Rf = 0.7 in 10 % ethyl acetate in petro-
1
leum ether H NMR(400 MHz, CDCl3) 8.06(dd, J = 7Hz, 2Hz,
2H), 7.31(s, 2H), 7.00(dd, J = 6.8Hz, 2Hz, 2H), 3.87(s, 3H), 2.95-
2.91(m, 2H), 2.54(s, 3H), 1.91(q, J = 7.6Hz, 2H), 1.04(t, J =
7.2Hz, 3H) 13C NMR (100 MHz,CDCl3) δ = 170.8, 166.7, 163.1,
130.4, 129.6, 128.5, 114.0, 113.5, 112.4, 55.2, 41.5, 24.2, 22.1,
13.9; IR (Neat Film, NaCl) 2943, 2214, 1600, 1235, 945 cm-1
;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19N2O
267.1497; Found 267.1491.
2-ethyl-6-(4-methoxyphenyl)-4-methylnicotinonitrile (2.30)
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The Journal of Organic Chemistry
Palladium Charcoal (10%) (6mol%) was added to the well stirred
10. (a)Zhang, Y. B.; Zhang, W. X.; Feng, F. Y.; Zhang, J. P.;
Chen, X. M. Angew. Chem. Int. Ed. 2009, 121, 5391-5394.(b)
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1
2
3
4
5
6
7
8
solution of 1-(4-methoxyphenyl)but-3-yn-1-ol (49mg,.28mmol) in
propionitrile (5ml).After 5min NaNH2 (219mg, 5.6mmol) was
added to the solution then the reaction mixture allowed to stirred
for 12hr. The reaction progress was monitored by TLC. Then the
mixture was quenched with distilled water and extracted with
ethyl acetate (2X3 ml) and dried over sodium sulphate. Solvent
was evaporated and the mass was subjected to neutral alumina
column, elution with 5% ethyl acetate petroleum ether afforded
2-ethyl-6-(4-methoxyphenyl)-4-methylnicotinonitrile (2.30) as a
yellow liquid(38mg, 53 %) Rf = 0.3 in 10 % ethyl acetate in petro-
11. Wang, R.; Falck, J. R. Org. Chem. Front. 2014, 1, 1029-1034.
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4592-4593.
9
1
leum ether H NMR(400 MHz, CDCl3);8.09 (t, J = 6.8Hz, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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43
44
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49
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55
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60
7.33 (s, 1H), 7.01 (dd, J = 7.2Hz, 1.6Hz, 2H), 3.89 (s, 3H), 2.99(q,
J = 7.6Hz, 2H), 2.55 (s, 3H), 1.42 (t, J = 7.6Hz, 3H) ; 13C NMR
(100 MHz,CDCl3) δ = 171.7, 166.8, 163.2, 161.5, 129.6, 128.5,
114.0, 112.4, 55.2, 32.7, 24.2, 12.8; IR (Neat Film, NaCl) 2912,
2244, 1588, 1212, 932 cm-1 ; HRMS (ESI-TOF) m/z: [M + H]+
for C16H17N2O 253.1341; Found 253.1337.
ACKNOWLEDGMENT
We sincerely acknowledge Department of Science and Technolo-
gy (DST), Govt. of India (Grant no. SB/FT/CS-076/2012), Board
of
Research
in
Nuclear
Sciences
(BRNS)
(2013/20/37C/2/BRNS/2651) and INSPIRE-DST, Govt. of India
(Grant No.04/2013/000751). NR thanks DST for research fellow-
ship .MKG thanks NIT Rourkela for research fellowship. . S.Giri
thanks DST-Inspire Award (IFA14-CH-151), Govt. of India for
financial support and NIT Rourkela for central computing facili-
ties
ASSOCIATE CONTENT
Supporting information
20. Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918-
6919.
1
Copies of H and 13C spectra of all new compounds , Computa-
21. Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: sarkard@nitrkl.ac.in , giris@nitrkl.ac.in
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GRAPHICAL ABSTRACT
Heterogeneous
Solvent incorporation
NaNH2
Upto 70% Yield
30 Examples
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