Highly chemo- and regioselective allylic substitution with tautomerizable heteroarenes

Article abstract of DOI:10.1039/c5gc01028d

Tautomerizable heteroarenes, bearing multiple interconvertible nucleophilic centers exhibit high chemo- and regioselective allylation irrespective of allylating agents used under Pd-catalysis. The achieved selectivity may be attributed to the dominant lactam form of heteroarenes and Pd-catalyzed intramolecular allylic substitution. A generalized green protocol for chemo- and regioselective allylation of biologically relevant heteroarenes with allyl alcohols in dimethyl carbonate (DMC) as solvent was developed. Excellent selectivity was observed during intermolecular competition study demonstrating the differential nucleophilicity of tautomerizable heteroarenes and differential allyl palladium forming ability of a variety of allyl alcohols.

Full text of DOI:10.1039/c5gc01028d

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Highly chemo- and regioselective allylic substitution with
tautomerizable heteroarenes
Received 00th January 20xx,
Accepted 00th January 20xx
Dinesh Kumar, Sandeep R. Vemula, Gregory R. Cook*
Tautomerizable heteroarenes, bearing multiple interconvertible nucleophilic centers exhibit high chemo- and regio-
selective allylation irrespective of allylating agents used under Pd-catalysis. The achieved selectivity may be attributed to
the dominant lactam form of heteroarenes and Pd-catalyzed intramolecular allylic substitution. A generalized green
protocol for chemo- and regio-selective allylation of biologically relevant heteroarenes with allyl alcohols in dimethyl
carbonate (DMC) as solvent was developed. Excellent selectivity was observed during intermolecular competition study
demonstrating the differential nucleophilicity of tautomerizable heteroarenes and differential allyl palladium forming
ability of a variety of allyl alcohols.
DOI: 10.1039/x0xx00000x
www.rsc.org/
the quinazoline framework a highly sought scaffold for drug
development.4 In a model study, the reaction of 1a with
Introduction
different allylating reagents
2 was performed under base free
The selective functionalization of heteroarenes is a significant
problem in the early drug development process to generate
lead molecules.1 In this context, the Pd-catalyzed allylic
substitution reaction is a powerful tool for the construction of
C-C and C-X (N, O & S) bonds to obtain structural diversity.2
One of the general features of this transformation is that allyl
substrates with a wide range of activated leaving groups
(acetates, carbonates, halides, phosphates, carboxylates etc.)
can be utilized to form allylpalladium complexes, which
undergo nucleophilic attack to construct C-C/C-X bonds.2
Control of regio- and chemoselectivty is an important
consideration in the context of medicinal chemistry,3 and is
especially problematic during the direct allylation of
tautomerizable heteroarenes as it poses competitive reaction
pathways. Thus, the present work aims to delineate the factors
that control selectivity during Pd-catalyzed allylic substitution
of tautomerizable heteroarenes in the context of allylating
reagents, reaction conditions, and substrate. This work also
seeks to offer mechanistic insight to rationalize selectivity and
develop a generalized green allylation protocol.
conditions in the presence of a Pd(0) catalyst (Table 1). Among
the different allyl sources examined, chloride 2a, phenyl ether
2i, amine 2j, isothiocyanate 2l, cyanide 2p, and benzene 2q
proved ineffective. Other allylic substrates afforded allylated
products in modest to good yield. It is important to note that
the formation of 3a2 (amide-NH allylation) was observed as the
overwhelmingly major product in most of cases. However
trifluoroacetate 2f, isocyanate 2k, and urea 2m, the formation
of 3a1 was detected along with 3a2. Formation of 1-allyl
quinazolin-4(3H)-one 3a3 was not observed in any cases. In the
absence of the Pd-catalyst, no reaction was observed.
Table 1: Reaction of 1a with allylating reagents in presence of Pd(0) catalysis
under neutral condition.a
Entry
Allylating agent
% Conversionb
3a1 3a2 3a3
Yield (%)c, d
3a2
Results and discussion
1
2a; X = Cl
0
0
0
0
0
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
To begin, 4-hydroxy quinazoline 1a was chosen as a model
substrate as it represents a reactant with three distinct
tautomerizable nucleophilic centers (-OH and –NH). Apart
from that its broad spectrum of biological activities renders
2
2b; X = Br
76
81
82
85
85
95
100
0
62
68
70
71
72
88
86
0
3
2c; X = I
4
2d; X = OH
5
2e; X = OAc
2f; X = OCOCF3
2g; X = OCO2Me
2h; X = OP(O)(OEt)2
2i; X = OPh
2j; X = NH2
6
7
8
9
10
0
0
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a1a (0.5 mmol) was treated with 2d (2 equiv, 1 mmol) in various solvents (1 mL)
at 100 °C in presence of Pd(PPh3)4 (10 mol%) for 12 h. bBased on GC-MS.
cIsolated yield of 3a2.
11
12
2k; X = NCO
2l; X = NCS
4
0
65
0
0
0
52
0
13
14
15
2m; X = NHCONH2
2n; X = SMe
2o; X = SO2Me
6
0
0
60
26
38
0
0
0
49
15
25
A variety of transition metal-catalyzed allylic substitution
are known and the choice of metal and ligand can significantly
affect the regioselectivity.6 Thus, the reaction of 1a with 2d
was investigated in the presence of different Pd catalysts (see
Table 3 & SI-Table 4) and other transition metal catalysts (Rh,
Ru, Ir, Ni, Fe, Au, and Cu; see Table 3 & SI-Table 6-8). The
formation of 3a2 was observed with all Pd catalysts with
varying yield, however Pd(PPh3)4 was found distinctly superior.
Rh, Ir, and Ni catalysts also resulted in the formation of 3a2
whereas other metals were ineffective. Of particular note, no
significant effect of catalysts and ligands was observed on the
selectivity (see Table 3, 4 & SI-Table 5 & 8).
16
17
2p; X = CN
2q; X = Ph
0
0
0
0
0
0
0
0
a1a (0.5 mmol) was treated with 2 (2 equiv, 1 mmol) in toluene (1 mL) at 100 °C
(oil bath temp) in presence of Pd(PPh3)4 (10 mol %) for 12 h. bBased on GC-MS. c
Isolated yield of 3a2. dNo product formation was observed (1a was found intact)
in absence of catalyst.
To examine the effect of base on chemoselectivity, the
entire set of reactions shown in Table 1 were reinvestigated in
the presence of K2CO3 (see SI-Table 2). No significant
difference in the outcomes was observed with the exception
that 2a, 2i, 2j, and 2l, which were ineffective without base,
exhibited allylation to form 3a2 (and 3a1 in case of 2m). It is
interesting to note the formation of 3a2 with 2j under basic
conditions. This was likely formed through a nucleophilic ring-
opening cascade by allylamine rather than ionization of the
allyl group as the reaction also formed 3a2 in the absence of
Table 3: Investigation of different transition metal catalysts on the selectivity
control during the reaction of 1a with 2d in DMC.a
Entry
Catalyst
% Conversionb
Yield (%)c
3a1 3a2 3a3
3a2
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
(PPh3)4Pd
(PPh3)2PdCl2
(TFA)2Pd
[PdCl(C3H5)]2
(C6H5CN)2PdCl2
Pd2(dba)3
Pd(dppf)Cl2
[Ir(1,5-cod)Cl]2
RhCl(PPh3)3
Ni(PPh3)4
[Ru(p-cymene)Cl2]2
Fe(acac)3
(Ph3P)AuCl
CuI(I)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
21
18
100
8
41
40
13
12
5
32
14
15
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
12
10
91
traces
28
Pd(PPh3)4. Further, the inability of 2j, 2p, and 2q to perform
allylation with Pd(0) under neutral/basic conditions could be
explained on the basis of lack of ionization of the allylic leaving
to form a π-allylpalladium complex.
28
Tautomeric equilibrium is susceptible to various reaction
conditions such as solvents, catalysts (metal salts),
temperature, pH etc. which significantly affect the subsequent
reaction outcomes.5,6 To test whether the selectivity in the
reaction of 1a was vulnerable to changes in the tautomeric
composition, the reaction of 1a with allyl alcohol 2d was
performed in different solvents (see Table 2 & SI-Table 3). No
significant difference of the reaction media on selectivity was
observed, however in solvents like MeOH, EtOH, TFE, and
NO2Me, the formation of 3a1 was detected along with 3a2. The
use of DMSO and DMC was found optimal, however DMC was
chosen as the solvent of choice for further studies due of its
favorable properties for sustainability (renewable, low toxicity
and biodegradability).7
traces
traces
traces
20
traces
traces
0
0
0
0
0
9
10
11
12
13
14
15
16
17
0
0
0
0
Zirconocene
a1a (0.5 mmol) was treated with 2d (2 equiv, 1 mmol) in DMC (1 mL) at 100 °C in
presence of different transition metal catalysts (10 mol%) for 12 h. bBased on GC-
MS. cIsolated yield of 3a2.
Table 4: Investigation of different ligands on the selectivity control during the
reaction of 1a with 2d in DMC under Pd(PPh3)4 catalysis.a
Table 2: Investigation of solvent effect on the selectivity control during the
reaction of 1a with 2d in under Pd(PPh3)4 catalysis.a
Entry
Ligand
% Conversionb
3a1 3a2 3a3
Yield (%)c
3a2
Entry
Solvent
% Conversionb
Yield (%)c
1
2
3
4
5
6
7
8
9
PCy3
P(o-tol)3
TFP
dppp
BPhen
DPFF
XPhos
(DHQD)2AQN
TEP
0
0
0
3
4
0
0
5
5
96
87
91
70
88
95
86
93
82
0
0
0
0
0
0
0
0
0
85
76
78
67
92
83
72
84
70
3a1 3a2 3a3
3a2
1
2
3
4
5
6
7
8
MeOH
EtOH
TFE
1,4-Dioxane
THF
DMF
DMSO
PhMe
PhH
DCE
DMC
9
5
2
0
0
0
0
0
0
0
0
5
0
60
90
97
97
37
93
96
83
89
79
100
46
93
0
0
0
0
0
0
0
0
0
0
0
0
0
47
78
81
84
25
82
85
70
75
67
92
29
80
a1a (0.5 mmol) was treated with 2d (2 equiv, 1 mmol) in dimethyl carbonate (1
mL) at 100 °C in presence of Pd(PPh3)4 (10 mol%) and different ligands (20 mol%)
for 12 h. bBased on GC-MS. cIsolated yield of 3a2.
9
10
11
12
13
MeNO2
MeCN
The selection of allyl alcohol 2d for these and subsequent
studies was made for sustainability reasons8 as performing
such substitutions with activated allyl substrates generates
2 | J. Name., 2012, 00, 1-3
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stoichiometric amounts of waste and allyl alcohol forms water
as the only by-product. It also negated the need for additional
steps to prepare the allyl reagents.8b
O
N
N
3a2
The predominant formation of 3a2 irrespective of
conditions tested (allylating reagent, base, solvent, catalyst,
and ligand) indicated the possible intermediacy of 3a1 and/or
3a3. These could be formed first and undergo rearrangement
to form the final product, 3a2. To investigate this, 3a1 and 3a3
were prepared by an independent route or prepared in-situ9
and subjected to Pd(0) catalysis in DMC at 100 °C. A smooth
conversion of 3a1 into 3a2 was observed, however 3a3 failed to
react (see scheme 1 & SI page S12). This transformation could
proceed via a thermal or Lewis acid catalyzed [3,3]-sigmatropic
rearrangement.10 This was ruled out by the heating of 3a1 in
DMC at 100 °C for 12 h with or without a Lewis acid [In(OTf)3].
3a1 was recovered intact indicating the exclusive role of the
Pd-catalyst in allylic disposition from 3a1 to 3a2 (see scheme 1
& ESI-Table 9).11
PdII
Pd0
O
N
PdII
O
N
OH
N
N
2d
PdII
PATH B-2
Pd0
PATH B-1
B
O
H2O
PATH A
N
O
N
PdII
PATH B
N
NH
OH
3a1
O
N
A
H2O
1a
NH
1a
Scheme 2: Possible routes for the formation of 3a2
To investigate allylic rearrangement via Path B-1 or Path B-
2, the crotyl derivative was prepared and examined under
4
Interamolecular allyl migration from preformed 3a1/ 3a3
the reaction conditions. If the rearrangement were to occur via
Path B-1, a mixture of regioisomeric products would be
expected. Alternatively, if the reaction proceeds through Path
B-2, only the branched product would result. We observed the
formation of a mixture of regioisomers 5a and 5b (92:8; GC-
MS) demonstrating the ionization pathway B-1 was operative
(scheme 3).
O
O
O
N
N
N
N
catalyst
+
DMC, 100 °C, 12 h
N
N
3a2
3a1
3a3
Catalyst
Pd(PPh3)4
In(OTf)3
K2CO3
93%
0%
0%
0%
0%
0%
0%
0%
None
O
PdII
O
O
N
O
N
O
N
N
N
N
N
catalyst
DMC, 100 °C, 12 h
+
N
PATH B-1
N
5a
5b
N
3a2
98 : 2
+
Pd0
3a1
3a3
O
N
PdII
O
Catalyst
Pd(PPh3)4
N
N
0%
0%
O
N
B
N
O
N
N
Interamolecular allyl migration from in-situ generated 3a1
O
O
N
PdII
O
N
1) BOP/Et3N, rt
Dry THF
4
N
Pd(PPh3)4
N
PdII
PATH B-2
N
3a1
N
1a
+
only
DMC, 100 °C,
12 h
2)
N
OH
3a3
3a2
72%
Scheme 1: Investigation of intramolecular allyl migration
C
5b
Scheme 3: Validation of Path B-1 / B-2
0%
With detailed investigation of factors influencing the
selectivity control and mechanistic insight rationalizing the
Possible mechanistic pathways for the allylation of 1a with
chemo-selectivity, next we explored the feasibility of
a
allyl alcohol are presented in Scheme 2. In all cases the first
step is likely the oxidative addition of Pd(0) into the allylic
alcohol bond to form an allylpalladium hydroxide intermediate
generalized green allylation protocol with optimized conditions
using cinnamyl alcohol 2da (see Table 5).
(A). Direct N-allylation of 1a with loss of water would form the
Table 5: Effect of different reaction parameters on the (PPh3)4Pd-catalyzed
allylation of 1a with 2da.a
observed product 3a2 (Path A). Alternatively, O-allylation could
occur to form 3a1 as an intermediate (Path B). This could re-
OH
ionize to form intermediate
B that could produce the product
O
3a2 (Path B-1). Alternatively, exogenous Pd(II) could catalyze a
stepwise [3,3]-sigmatropic rearrangement to produce the final
product (Path B-2). It should be noted that Path B-1 may be
indistinguishable from Path A.
Pd(PPh3)4 (X mol%)
N
N
Ph
Ph
OH
+
DMC, Temp (°C)
N
N
1a
2da
3b
Entry
catalyst
(mol%)
equiv
(2da)
Temp.
(°C)
Time
(h)
Yield
(%)b
1
2
3
0.5
1
2.5
2
2
2
100
100
100
24
24
24
12
28
63
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OH
O
N
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5.0
10
15
2
2
2
1
100
100
100
100
100
100
rt
24
24
24
24
24
24
24
24
24
24
4
90
90
90
72
90
90
traces
32
51
90
51
69
90
N
N
Ph
N
17
1q;
3;
82
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
Ph
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
N
OH
OH
N
O
N
N
18
18
1r;
1s;
3s;
3t;
84
89
50
80
O
N
N
Ph
100
100
100
100
100
N
N
8
12
16
Ph
N
OH
OH
N
O
90
19
1t;
3u;
86
a1a (0.5 mmol) was treated with 2da under different reaction conditions in DMC
(1 mL). bIsolated yield of 3b.
Ph
N
N
N
O
The scope of tautomerizable heteroarenes was examined
first. As summarized in Table 6, a wide range of 4-hydroxy
quinazolines bearing alkyl, cycloalkyl, aryl, heteroaryl, and
styryl moieties were reacted with cinnamyl alcohol 2da
affording excellent yield of N-allylated products (entries 1-15).
A wide range of functional groups (-OMe, -NMe2, -NO2, -CN, -
Cl, CF3, -CHO, -COMe, -OCH2O-) were tolerated well, validating
the robustness of protocol. The applicability of this protocol
was further extended to other biologically relevant
tautomerizable heteroarenes. Gratifyingly, N-cinnamylation of
a variety of heteroarenes proceeded well with excellent yields
(entries 16-23).12
N
20
21
22
1u;
1v;
1w;
3v;
3w;
3x;
90
90
86
Ph
N
N
OH
OH
O
S
S
Ph
N
N
O
O
O
OH
O
Ph
O
N
N
N
O
Ph
N
Ph
23
1x;
3y;
86
aTautomerizable heteroarenes (0.5 mmol) were treated with 2da (1.2 equiv, 0.6
mmol) in DMC (1 mL) at 100 °C in the presence of Pd(PPh3)4 (5 mol %) for 12 h.
bIsolated yield.
Table 6: Cinnamylaion of biologically relevant heteroarenes.a
O
X
OH
Allylation of 1a with a variety of allyl alcohols having
α-, β-,
Pd(PPh3)4 (5 mol%)
N
Ph
N
or γ-substitution proceeded well to produce the allylated
Ph
OH
+
products in excellent yields (Table 7).13 With regards to
regioselectivity, allylation with cinnamyl alcohol 2da or 1-
phenylprop-2-en-1-ol 2db resulted in exclusive formation of
the linear product (>99%; GC-MS) whereas a 94:6 isomeric
Y
Y
DMC, 100 °C
X
X = Y = C or N
Entry
T-heteroarenes
Products
Yield (%)b
OH
O
X
X
ratio (linear:branched) was observed in the case of 2dc or 2dd
.
N
N
Ph
The reaction of 1a with 2-butene-1,4-diol 2dh, produced the
dienamine 6d in excellent yield. This could serve as model
reaction for a generalized one-step synthesis of dienamines,
alkenyl oxide/sulfide and conjugated dienes, valuable synthons
for pharmaceutical and materials applications. This
methodology was found to be advantageous in terms of
substrate scope, functional group tolerance and the use of
additives or other promoters.14
N
R
N
R
1
2
3
4
5
6
7
8
9
1a; X = H; R = H
3b; X = H; R = H
3c; X = H; R = Me
3d; X = H; R = Cy
3e; X = H; R = Ph
3f; X = H; R = furyl
3g; X = H; R = styryl
3h; X = Cl; R = H
3i; X = OMe; R = H
90
91
85
88
84
72
84
90
82
1b; X = H; R = Me
1c; X = H; R = Cy
1d; X = H; R = Ph
1e; X = H; R = furyl
1f; X = H; R = styryl
1g; X = Cl; R = H
1h; X = OMe; R = H
1i; X = NO2; R = H
3j; X = NO2; R = H
Table 7: Pd-catalyzed reaction of 1a with different allyl alcohols.a
OH
O
N
N
N
Ph
OH
N
Pd(PPh3)4 (5 mol%)
N
Allyl alcohol
+
Product
Yield (%)b
R
R
DMC, 100 °C
10
11
12
13
14
15
1j; R = NMe2
1k; R = CF3
1l; R = CN
1m; R = C(O)H
1n; R = C(O)Me
1o; R = -OCH2O-
3k; R = NMe2
3l; R = CF3
3m; R = CN
3n; R = C(O)H
3o; R = C(O)Me
3p; R = -OCH2O-
85
86
85
90
85
83
N
EntryAllyl alcohol
Product
1
2
2d;
3a2;
3b;
91
90
OH
O
N
N
Ph
16
1p;
3q;
81
2da;
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To gain insight into the relative reactivity of allylic alcohols
in the allylation reaction, an equimolar mixture of 2d and 2da
,
2d and 2-cyclohexeneyl alcohol 2df, and 2da and 2df was
treated with 1a (Scheme 5). Selective incorporation of allyl
group took place in preference to cinnamyl and 2-
cyclohexeneyl, however in the case of competition between
2da and 2df, selective incorporation of cinnamyl group took
place in preference to 2-cyclohexeneyl indicating a distinct
difference in reactivity with either allylpalladium formation or
nucleophilic addition to the allyl complex.
3
4
2db;
2dc;
3b;
5a;
88
O
N
N
82c
OH
N
O
81c
86
N
5
6
2dd;
2de;
5a;
6a;
O
O
N
Ph
N
OH
OH
1a
1a
Ph
OH
+
+
+
+
N
N
3a2; 61%
3b; 39%
2da
2d
2d
O
O
7
2df;
6b;
78
N
N
O
Ph
OH
N
N
N
Ph
OH
3a2; 98%
6b; 2%
2df
N
Ph
Ph
8
9
2dg;
2dh;
6c;
71
82
O
O
N
Ph
1a
N
OH
Ph
OH
+
+
N
N
3b; 4%
2df
6b; 96%
2da
6d;
Scheme 5. Intermolecular competitions study involving two different allyl
alcohols for a given tautomerizable heteroarenes (1a).
a1a (0.5 mmol) was treated with allyl alcohol (1-1.5 equiv) in DMSO (1 mL) at 100
°C in the presence of Pd(PPh3)4 (5 mol %) for 12 h. bIsolated yield. cE/Z mixture
(10:1). A small amount of the branched regioisomer (not shown) was also formed
(94:6 linear: branched).
The reaction was also performed on a gram scale. 3-(3-
Phenyl-allyl)-3H-quinazolin-4-one 3b was obtained in 84%
yield, thus demonstrating the scalability and utility of this
protocol.
Anticipating differential nucleophilicity of aromatic-OH
and/or amide-NH among different heteroarenes, we
undertook a competition study and the results are illustrated
in Scheme 4. An equimolar mixture of 1a & 2-hydroxy pyridine
Conclusions
1p
1u
,
,
1a & 2-hydroxy phthalazine 1s
, 1a & 2-hydroxy quinoxaline
In conclusion, the present work reports the investigation of a
wide range of allylating reagents, solvents, metal catalysts, and
ligands for the chemo- and regioselective allylation of
heteroarenes bearing multiple interconvertible nucleophilic
sites. The process was developed as a generalized green
protocol for allylation of biologically relevant heteroarenes
with allyl alcohols using DMC as solvent with wide range of
functional groups tolerance. The differential nucleophilicity of
heteroarenes was examined through intermolecular
competition studies involving two different heteroarenes and
excellent selectivity was observed. Similarly, an excellent
selectivity was observed during intermolecular competition
involving two different allyl alcohols demonstrating the
differential ability of allyl alcohols to form allylpalladium
complexes and react with the nucleophile. The direct use of
allyl alcohol as an allylating reagent, DMC as solvent, the lack
of a requirement for additional additives/promoters, and the
feasibility of scale up represent a green protocol for the
selective allylation of medicinally relevant tautomerizable N-
heteroarenes and are an important addition to the tool box of
medicinal chemists.
1a & 2-hydroxy benzothiazole 1v as well 1a & 2-hydroxy
benzoxazole 1w was treated with equimolar amounts of 2da
.
,
Selective cinnamylayion of 1a took place in preference to 1p
1s, and 1u. However, the reverse selectivity was observed in
the case of 1v and 1w
.
O
OH
OH
O
N
N
Ph
Ph
N
N
N
Ph
6a
+
+
+
+
N
N
1p
1a
1a
3b; 82%
3q; 18%
OH
O
O
OH
N
N
N
Ph
N
6a
6a
6a
6a
+
+
+
+
N
N
N
3b; 95%
3t; 5%
1u
1t
Ph
OH
O
N
O
N
N
OH
N
N
N
N
Ph
Ph
Ph
N
N
N
3v; 26%
1a
1a
1a
3b; 74%
Ph
Ph
OH
O
N
S
N
S
N
OH
OH
O
O
+
N
N
1v
3w; 63%
3b; 37%
O
OH
N
O
N
N
+
N
O
N
1w
3b; 24%
3x; 76%
Scheme 4. Intermolecular competition study involving two different
tautomerizable heteroarenes with variable nucleophilicity for a given allyl
alcohol (2da).
Acknowledgements
We acknowledge the generous financial support of this work
from North Dakota State University.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Green Chemistry
Page 6 of 7
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DOI: 10.1039/C5GC01028D
ARTICLE
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General procedure for the cinnamylaion of tautomerizable
heteroarenes: In a glove box, to an oven dried 4 mL glass vial
equipped with a stirring bar, 4-hydroxy quinazoline 1a (0.731 g,
0.5 mmol), cinnamyl alcohol 2da (0.067 g, 0.5 mmol, 1 equiv), Pd
(PPh3)4 (0.029 g, 0.025 mmol, 5 mol%) followed by DMC (1 mL)
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Na2SO4 and concentrated under reduced pressure. The crude
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6
,
7
8
9
3b as white solid (0.118 g, 90%); 1H NMR (400 MHz, CDCl3):
δ
8.36 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.73-7.79 (m, 2H), 7.51-7.55
(m, 2H), 7.26-7.39 (m, 5H), 6.68 (d, J = 15.8 Hz, 1H), 6.32-6.39
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6 | J. Name., 2012, 00, 1-3
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Green Chemistry
View Article Online
DOI: 10.1039/C5GC01028D
Graphical abstract
Highly chemo- and regioselective allylic substitution with tautomerizable
heteroarenes
Dinesh Kumar, Sandeep R. Vemula, Gregory R. Cook*
Department of Chemistry and Biochemistry
North Dakota State University
Fargo, North Dakota 58108-6050 United States
E-mail: gregory.cook@ndsu.edu
Investigation and exploration of chemo- and regioselective allylic substitution with
tautomerizable heteroarenes under variable conditions with mechanistic insight and substrate
scope.