Palladium-Catalyzed Allylic Amidation with N-Heterocycles via sp3 C-H Oxidation

Article abstract of DOI:10.1021/acscatal.6b01818

An atom-economic direct intermolecular allylic amidation of electron-deficient tautomerizable N-heterocycles is reported via allylic C-H activation of terminal olefins with a PdCl₂ catalyst. The reaction did not require any activators (base or Lewis acid) or external ligands and proceeded with high chemo- (N vs O), regio- (linear vs branched), and stereoselectivity (E vs Z) for a variety of N-heterocycles and terminal olefins. Mechanistic investigation and stoichiometric studies validate the sulfoxide-ligand-assisted allylic C-H bond cleavage to form a π-allylpalladium intermediate in the reaction pathway. Excellent selectivity was observed during intermolecular competition demonstrating the differential nucleophilicity of N-heterocycles and differential susceptibility of allyl C-H bond cleavage to form π-allylpalladium complexes directly from terminal olefins.

Full text of DOI:10.1021/acscatal.6b01818

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Article
Palladium-Catalyzed Allylic Amidation
with N-Heterocycles via sp3 C-H Oxidation
Sandeep R. Vemula, Dinesh Kumar, and Gregory R Cook
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01818 • Publication Date (Web): 01 Jul 2016
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ACS Catalysis
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Palladium-Catalyzed Allylic Amidation with N-Heterocycles via sp3
C-H Oxidation
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Sandeep R. Vemula, Dinesh Kumar, Gregory R. Cook*
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108-6050, USA
E-mail: gregory.cook@ndsu.edu
ABSTRACT: An atom economic direct intermolecular allylic amidation of electron deficient tautomerizable N-
heterocycles is reported via allylic C-H activation of terminal olefins with a PdCl2 catalyst. The reaction did not require
any activators (base or Lewis acid) or external ligands and proceeded with high chemo (N-vs-O)-, regio (linear-vs-
branch)-, and stereoselectivity (E-vs-Z) for a variety of N-heterocycles and terminal olefins. Mechanistic investigation and
stoichiometric studies validate the sulfoxide ligand assisted allylic C-H bond cleavage to form a π-allylpalladium interme-
diate in the reaction pathway. Excellent selectivity was observed during intermolecular competition demonstrating the
differential nucleophilicity of N-heterocycles and differential susceptibility of allyl C-H bond cleavage to form π-
allylpalladium complexes directly from terminal olefins.
KEYWORDS: palladium catalysis, allylic amidation, sp3 C-H activation, N-heterocycles, terminal olefins.
N-Heterocycles constitute an important structural class
of chemical substances, particularly among the natural
products, biologically active structures and medicinally
relevant compounds.1 Consequently their diverse func-
tionalization is highly significant.2 The Pd-catalyzed
allylic substitution (Tsuji-Trost reaction) has been in-
strumental to obtain structural diversity via formation
of C-C and C-X (X = N, O & S) bonds, however, it gener-
ally necessitates the pre-functionalization of allyl sub-
strates to prepare leaving groups capable of oxidative
addition with Pd(0).3 Further, performing such substitu-
tions generates a stoichiometric amount of acidic waste,
requiring additional treatment for its removal, and low-
ers the overall efficiency (Scheme 1). While much effort
has been devoted to improve the reaction to avoid pre-
activation and utilize allyl alcohols directly,4 a more
direct and sustainable approach is functionalization via
direct activation of a C-H bond.
Allylic sp3 C−H bond functionalization has emerged
as a highly valuable strategy for structural modification.5
During the past decade, Pd(II)-catalysis has enabled
allylic C−H oxygenation,6 amination,7 alkylation,8
carbonylation,9 silylation,10 fluorination,11 borylation,12
and dehydrogenation.13 Although these recent advances
have helped address basic synthetic problems, the direct
alkenylation of notorious electron deficient N-
heterocycles remains a challenge. Further, multiple
product pathways in the case of tautomerizable hetero-
cycles presents question of chemo- and regioselectivity.
In this communication, we report the first direct allylic
C−H amidation reaction employing tautomerizable N-
heterocycles. This protocol does not require any pre-
activation of allyl substrates or exogenous ligands or
additives, and proceeds with high chemo-, regio-, and
stereoselectivity.
Traditional Tsuji-Trost Reaction
stoichiometric
preactivation
NuH
cat.
R
OH
R
X
R
Nu
X = Cl, OAc,
OCOMe, etc.
WASTE
H-X WASTE
Allylic C-H Activation
NuH
Scheme 2. Preliminary investigation using White’s ami-
cat.
Sustainable
Atom Economical
nation protocol
R
R
Nu
We initially examined the utility of the amination
protocol reported by White7d,7e for the reaction of (4H)-
quinazolone 1a with allylbenzene 2a (Scheme 2). How-
ever, no allylic amidation to form 3a/3b was observed
under these conditions. Inclusion of known activators
such as Bronsted base (DIPEA) or Lewis acid
[(salen)Cr(III)Cl] did not afford any improvement. Vari-
H2
Scheme 1. Classical Tsuji-Trost reaction vs. allylic C-H
activation
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Page 2 of 8
ation in the reaction temperature or solvents was also with DMBQ (1.5 equiv) in DMSO (1M) at 100 °C was op-
1
2
3
4
5
6
7
ineffective (see SI). Additionally, no products of C-O
allylation were observed either. Thus we carried out a
systematic investigation of different Pd-catalysts, sol-
vents, and oxidants to find optimal conditions for this
challenging intermolecular allylation of 1a (see Table 1
and SI).
timal to produce 3a in 92% isolated yield with excellent
chemo- and regio- and stereoselectivity (Scheme 3). Im-
portantly, these conditions are relatively simple and do
not require additional metal Lewis acid7e or base7d addi-
tives for optimization. Further, no Wacker-type oxida-
tive products such as 3-(1-benzyl-vinyl)-3H-quinazolin-
4-one and/or benzyl methyl ketone were observed.
8
9
Table 1. Investigation of Pd-catalysts, solvents, and oxi-
dants for the allylic amidation of 1a with 2a.a*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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O
O
Catalyst (10 mol%)
NH
N
Ph
Ph
+
Oxidant (2 equiv),
Solvent (1M),
100 °C, 24 h
N
N
3a
Scheme 3. Optimized conditions for allylic amidation of
1a
2a
Oxidant Yield (%)b
1a
Entry Catalyst
Solvent
tracesc
13d
90
0c
Encouraged by initial results using allylbenzene 2a,
structurally different terminal olefins were investigated
to demonstrate the generality of intermolecular direct
allylic amidation of quinazolinone using our protocol
(Table 2). A wide scope of either commercially available
or readily accessible terminal olefins smoothly under-
went allylic C−H amidation reaction with 1a in high
yield and excellent chemo (N-vs-O)-, regio (linear-vs-
branch)-, and stereoselectivity (E-vs-Z). It is significant
to note that the reaction was seemingly insensitive to
the electronic feature of the aryl moiety of the olefin
substrates as both electron-donating (4b and 4c) and
electron-withdrawing (4d) substituted allyl benzenes
reacted smoothly with high yields. Fluorinated (4e and
4f), heteroaryl (4h and 4i), napthyl (4j) and sensitive
piperonyl moieties (4g) were found suitable affording
high yields of desired products. Aliphatic terminal ole-
fins (4k – 4m) reacted smoothly, however slightly lower
yields were obtained.
1
Pd(OAc)2
Pd(TFA)2
PdCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
DMBQ
2
3
4
5
6
7
8
9
(PPh3)2PdCl2
(PhCN)2PdCl2
[PdCl(allyl)]2
Pd(dppf)Cl2
55
57
0c
IPrPd(allyl) Cl
White Catalyst
13
traces
0c
10 PdCl2
11 PdCl2
12 PdCl2
13 PdCl2
14 PdCl2
15 PdCl2
16 PdCl2
17 PdCl2
18 PdCl2
19 PdCl2
20 PdCl2
21 PdCl2
22 PdCl2
MTBE
THF
0c
0c
0c
0c
0c
0c
0c
DCE
1,4-Dioxane DMBQ
PhMe
DMC
DMBQ
DMBQ
DMBQ
BQ
DME
Table 2. Intermolecular allylic amidation with different
terminal alkenes.a,b,c
DMSO
DMSO
DMSO
DMSO
DMSO
45
46
O
O
MBQ
PdCl2 (10 mol%)
NH
R
N
R
+
Duroquinone48
DMBQ (1.5 equiv),
DMSO (1 M),
100 °C, 24 h
N:O >99%
L:B >99%
E:Z >99%
N
N
4m
1a
4a
-
Oxone
MnO2
59
29d
O
O
O
OCH3
N
N
N
a1a (0.2 mmol) was treated with 2a (0.3 mmol, 1.5 equiv)
under different reaction conditions. Isolated yield. Start-
ing 1a was found intact. dUnreacted 1a was recovered intact.
*For detail, see the ESI-Table S3-S7.
N
O
CF3
N
O
X
N
OCH3
b
c
4d, 81%
4g, 86%
4a, X = Me; 88%
4b, X = OMe; 89%
4c, 87%
O
F
F
F
F
O
O
N
N
N
N
N
F
N
O
F
N
O
4e, 91%
4f, 75%
Although Pd(OAc)2 was completely ineffective, we
were delighted to discover the use of PdCl2,
(PhCN)2PdCl2, and [PdCl(allyl)]2 in the presence of 2,6-
dimethylbenzoquinone (DMBQ) using DMSO as solvent
provided encouraging results. A survey of solvents using
PdCl2 as catalyst showed that the reaction was highly
sensitive to the reaction media. No transformation was
observed in other tested solvents (entries 10-17, Table 1).
2,6-Dimethoxy-1,4-benzoquinone (DMBQ) was found to
be the most efficient oxidant, thus providing the highest
yield 85% (entries 18-22, Table 1). A full optimization
study (see ESI) revealed the use of 10 mol% of PdCl2
O
S
N
N
S
N
N
N
N
O
4h, 90%
4i, 84%
4j, 87%
O
O
N
Ph
N
N
N
N
4k, 57%
4l, 73%
4m, 51%
aReactions were conducted at 0.2 mmol scale. b1H NMR
analysis of the crude reaction mixture determined the ratio
c
of E/Z and L/B selectivity. GC-MS analysis of the crude
reaction mixture determined the ratio of N/O.
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ACS Catalysis
We next examined the scope of N-heterocycles as
quinazolinone or steric hindrance of the amide N-H16
using additives might alter the outcome of the reaction.
However, when carried out in the presence of different
additives such as AgOTf, DIPA, DBU, Cs2CO3, AcOH or
TfOH, the reaction was completely shut down (Table 4).
With DIPEA and TEA present, only the exclusive for-
mation of 3a was observed. Of particular note, no signif-
icant effect of ligands was observed on the chemoselec-
tivity. Selective formation of 3a (>94%, N/O) was ob-
served in presence of phosphine ligands (PPh3, PCy3),
amino acid ligand (Ac-Gly-OH), and N-heteocyclic car-
bene ligand N,N’-bis(2,6-diisopropylphenyl)imidazol-2-
yliedene (IPr) (Table 4).
1
2
3
4
5
6
7
8
nucleophile in the direct amidation of allylbenzene (Ta-
ble 3). Differently substituted quinazolinones14 reacted
well to produce high yields with excellent chemo-, re-
gio- and stereoselectivity. Both electron-withdrawing
(5a) and electron-donating (5b) quinazolinones worked
well. Further, more hindered 2-substituted substrates
allylated with high efficiency (5c – 5f). We envisioned
that such an amidation strategy could be extended be-
yond the quinazolinone nucleus to other biologically
relevant heterocycles with varying nucleophilicity. As
shown in Table 2, we were delighted to discover that N-
heterocycles such as phthalazine (5g), pyrimidine (5h),
pyrazine (5i), and pyridines (5j - 5m) all reacted well
with excellent yields and high chemo-, regio- and stere-
oselectivities under optimized conditions. This demon-
strates the versatility of our methodology to afford a
range of allylated heterocycles. Thus the reaction scope,
particularly for the heterocycle, is highly impressive. It
is noteworthy to mention the excellent N-vs-O selectivi-
ty for the pyridinone and pyrazinone nucleophiles as
high selectivity is often times very difficult to achieve
due to the labile nature of oxo-hydroxy tautomeric equi-
libria. It is interesting to note that these heterocycles
produced trace amounts of byproducts resulting from
O-allylation and regioisomeric allylation (linear and
branched products). However, selectivity remained very
high.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Table 4. Investigation of additives effect on the PdCl2-
catalylyzed the allylic C-O bond formation.a
O
NH
O
N
Ph
PdCl2 (10 mol%)
Additive (20 mol%)
N
1a
N
3a
+
+
3b
+
DMBQ (1.5 equiv),
DMSO (1M),
100 °C, 24 h
Ph
3c
2a
Entry
Additive
Convb
3a: 3b: 3cc,d 3a/Yield (%)e
1
AgOTf
DIPA
DBU
0f
0f
0f
25g
26 g
0f
0f
0f
25 g
77
7 g
0f
N/A
N/A
N/A
N/A
15
2
N/A
3
N/A
4
DIPEA
TEA
100: 0: 0
100: 0: 0
N/A
5
15
Table 3. Intermolecular allylic amidation with different
N-heterocycles. a,b,c
6
Cs2CO3
AcOH
TFA
N/A
N/A
N/A
16
7
N/A
O
O
R2
R2
8
N/A
PdCl2 (10 mol%)
NH
R1
Ph
N
Ph
+
DMBQ (1.5 equiv),
DMSO (1 M),
100 °C, 24 h
N
R1
N
9
10
11
12
13
14
15
PPh3
100: 0: 0
98: 2: 0
100: 0: 0
N/A
2a
N : O
= >99
5a - 5m
L : B = >99
E : Z = >99
PCy3
62
O
N
O
N
O
Bphen
bpy
rac-BINAP 0f
N/A
N/A
N/A
68
O
N
MeO
Ph
N
Ph
Cl
Ph
N
Ph
N
N
Ph
N
CH3
5a, 88%
5b, 86%
5c, 89%
5d, 82%
N/A
O
N
O
N
O
O
Ac-Gly-OH 85
96: 4: 0
N
Ph
Ph
N
Ph
N
N
Ph
IPr
54
95: 5: 0
41
N
N
5e, 81%
5f, 83%
5g, 76%
5h, 74%
a1a (0.2 mmol) was treated with 2a (0.3 mmol, 1.5 equiv)
N(Me)2
CF3
N : O = >99
L : B = >99
E : Z = >99
N : O = 92 : 8
L : B = 95 : 5
E : Z = >99
under optimized conditions in presence of different addi-
b
1
O
O
N
O
O
N
O
tives (20 mol%). Based on H NMR of the crude reaction
mixture with respect to 1a. c1H NMR analysis of the crude
reaction mixture determined the ratio of E/Z and L/B selec-
N
Ph
Ph
N
Ph
Ph
N
Ph
N
Br
CF3
CH3
d
5i, 71%
5j, 71%
5k, 70%
5l, 72%
5m, 74%
tivity. GC-MS analysis of the crude reaction mixture de-
e
f
N : O = 98 : 1
L : B = 96 : 4
E : Z = >99
N : O = 93 : 7
L : B = 97 : 3
E : Z = >99
N : O = 94 : 6
L : B = 95 : 5
E : Z = >99
N : O = 91 : 9
L : B = >99
E : Z = >99
N : O = 97 : 3
L : B = 92 : 8
E : Z = >99
termined the ratio N/O selectivity. Isolated yield. Starting
1a was found intact. gUnreacted 1a was recovered intact.
aReactions were conducted at 0.2 mmol scales. b1H NMR
analysis of the crude reaction mixture determined the ratio
The observed high chemoselectivity for N-allyaltion
with 1a and other N-heterocycles could result from an
initial O-allylation followed by an allylic rearrangement
(Scheme 4). This could proceed via a thermal17 or Lewis
acid catalyzed [3,3]- sigmatropic rearrangement18 or a
Pd(II)-catalyzed allylic migration.19
To investigate this further, the proposed O-allylated
intermediate 6 was independently prepared20 and sub-
jected to various conditions. A concerted (thermal or
Lewis acid-promoted) [3,3]-sigmatropic rearrangement
was ruled out as the starting material 6 remained intact
c
of E/Z and L/B selectivity. GC-MS analysis of the crude
reaction mixture determined the ratio N/O selectivity.
The appearance of trace amounts of O-allylated
products with other heterocycles prompted us to inves-
tigate their formation from quinazolinone 1a in hopes of
optimizing an alternative reaction pathway. We envi-
sioned alteration of the tautomeric equilibrium15 of the
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upon heating in DMSO at 100 °C for 24 h with or with-
however in only trace amount (<5%, GC-MS).22 The pos-
sibility of an allyl cation intermediate produced by qui-
none-mediated oxidation of olefin (Path-C)23 was ruled
out, as DMBQ could not fulfill the allylic amidation in
1
2
3
4
5
6
7
8
out a Lewis acid catalyst present. In contrast, when
treated with a Pd(II) catalyst under conditions opti-
mized for the allylic amidation reaction, 6 was exclu-
sively converted to the rearranged branched product 7b
with no formation of linear 7a. As only the branched
regioisomer was obtained, reionization of the allylic
species to form the bis-allyl complex A (Scheme 4, Path
A) does not appear to be operating. This rearrangement
most likely occurred via Path B by a stepwise amino-
palladation to form B followed by elimination to pro-
duce 7b. While these observations demonstrate that a
Pd(II)-catalyzed allylic rearrangement from 6 is possi-
ble, it is unlikely to be an intermediate in the C-H acti-
vation/allylic amidation process since the linear N-
allylated product 3a was formed exclusively in the latter
process.
the absence of PdCl2.
Ph
H
1a
Ph
Pd
9
Ph
Pd(II)
Ph
Nu
Path-D
Path-A
Pd
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
Pd
NH-H
1a
L
DMBQ
DMBQ
PdH
Pd(0)
OH
3a
3a
HO
1a
Nu
Ph
Pd
Ph
L
CH3
Nu-H (1a)
Pd(II) DMBQ
O
O
N
CH3
O
CH3
O
optimized
Pd(II)-catalyzed
conditions
Pd(0)
Cl
Path-B
HO
N
N
N
+
N
N
Path-C
7b
6
7a
0%
Ph
100% (GC-MS)
Ph
H
Pd(0)
Pd
Cl
O
N
CH3
Ph
PdII
O
Scheme 5: Possible catalytic cycles
CH3
N
N
7a
+
O
N
Path-A
N
CH3
PdII
NH
PdCl2 (10 mol%)
Ph
+
No products
O
CH3
DMBQ (1.5 equiv),
DMSO (1M),
100 °C, 24 h
O
1a
8
N
N
O
N
CH3
PdCl2 (10 mol%)
N
Ph
N
[A]
Ph
7b
DMBQ (1.5 equiv),
DMSO (1M),
100 °C, 24 h
N
8; 12%, GCMS
2a
8
PdII
CH3
O
CH3
O
N
6
PdCl2 (10 mol%)
Ph
Ph
Ph
Path-B
N
N
DMBQ (1.5 equiv),
DMSO (1M),
100 °C, 24 h
2a; 0%, GCMS
N
7b
[B]
O
O
N
PdCl2 (10 mol%)
NH
Ph
Scheme 4. Investigation of allylic migration for ob-
served chemoselectivity
Cl
+
+
DMBQ (1.5 equiv),
DMSO (1M),
100 °C, 24 h
N
O
N
9
1a
1a
3a, < 5 % (GCMS)
In order to further elucidate the mechanism, we
investigated several oxidative amidation pathways. One
possibility is a pathway involving a Wacker-type ami-
dopalladation/β-hydride elimination (Scheme 5, Path-
A).21 However, when an internal olefin 1-phenylpropene
(8) was employed, no reaction ensued (Scheme 6). Fur-
ther, a Wacker oxidation usually results in attack of the
nucleophile at the secondary carbon over a primary car-
bon. As a control experiment, allylbenzene, in the ab-
sence of 1a, underwent isomerization to 8 under the
reaction conditions (~12%, GC-MS) suggesting that al-
lylbenzene is capable of undergoing C-H activation
through a Pd-allyl intermediate. Further, no isomeriza-
tion of 8 to 2a was observed. Thus, it is unlikely that the
oxidative amidation process proceeds through an ami-
dopalladation pathway. On the other hand, chloropal-
ladation could form an intermediate allylic chloride
(cinnamyl chloride, 9) and subsequent nucleophilic sub-
stitution via a standard Tsuji-Trost reaction (Path-B)
could ensue.3 In an independent study, treatment of 9
with 1a under the reaction conditions produced 3a,
DMBQ (1.5 equiv)
NH
Ph
Ph
No products
O
DMSO (1M),
100 °C, 24 h
N
2a
2a
Ph
H3C
CH3
S
Pd
PdCl2 (0.5 mmol)
Cl Pd Cl
S
Cl
Cl
DMBQ (1.5 equiv),
DMSO (0.5 mL),
100 °C, 3 h
+
Pd
H3C
CH3
O
A
Ph
B
Ph
O
N
Pd
Pd
1a
N
Ph
Cl
Cl
DMSO (1M),
DMBQ (1.5 equiv),
100 °C, 3 h
3a
Ph
B
Scheme 6. Mechanistic investigation
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On the basis of these mechanistic studies, a reason-
Scheme 7. Intermolecular competition study involving
two different heterocycles with variable nucleophilicity
for a given terminal olefin 2a.
1
2
3
4
5
6
7
8
able mechanism for the direct allylic amidation can be
envisioned (Scheme 5, Path-D) and is in line with simi-
lar allylic oxidation studies.5,6,7 It is likely that an inter-
mediate Pd-allyl species is a key intermediate in the
reaction. This could be formed via an electrophilic al-
lylic C-H bond cleavage mediated by a sulfoxide-assisted
Pd(II) catalyst. Nucleophilic attack of the nitrogen of N-
heteroarenes would form the allylated product 3a fol-
lowed by subsequent reoxidation of Pd(0) to Pd(II) by
DMBQ to complete the catalytic cycle.
An equimolar mixture of 1a & 1(2H)-phthalazinone 10,
1a & 4(3H)-pyrimidone 11, 1a & 2(1H)-pyrazinone 12, as
well as 1a & 2(1H)-pyridone 13 were treated with
equimolar amounts of 2a. Selective allylation of 1a took
place in preference to 10 and 12. However, the reverse
selectivity was observed in the case of 11. No particular
selectivity was observed in case of competition involving
1a and 13.
To gain insight into the relative reactivity of allyl
arenes in the allylation reaction, an equimolar mixture
of 2a & 4-allylanisol 2b, 2a & 1-allyl-4-(trifluoromethyl)
benzene 2c, 2a & 2-allylthiophene 2d and 2a & allylcy-
clohexane 2e was treated with 1a (Scheme 8). Selective
amidation of 2a took place in preference to 2b, 2d and
2e, however in the case of competition between 2a and
2c, selectivity favored toward 2c. The observed selectivi-
ties indicate the differential susceptibility of allylic C-H
bond cleavage to form “allylpalladium” and or the rela-
tive electrophilicity allyl complex toward nucleophilic
addition.
9
10
11
12
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In a proof of concept study, the stoichiometric reac-
tion, excluding nucleophile 1a, in DMSO was performed
1
and monitored by H NMR. A dimeric π-allylpalladium
chloride complex-B was observed, confirming the allylic
C-H bond cleavage. When 1a was then treated with 1a
under the optimized reaction conditions, formation of
3a was observed with similar yields and regioselectivi-
ties. In the absence of DMSO (using dioxane as solvent),
the formation of dimeric π-allylpalladium chloride com-
plex-B was not observed, suggesting the sulfoxide liga-
tion to PdCl2 was essential to effect Pd-mediated allylic
C-H cleavage to form a monomeric π-allylpalladium
intermediate that is detected in the form of dimeric
complex-B. Single crystal X-ray structures of the sulfox-
ide ligated PdCl2 (complex-A)24 and dimeric π-
allylpalladium chloride complex-B were obtained to
confirm their formation.25 Treatment of the preformed
complex-B with 1a in presence of DMBQ in DMSO re-
sulted the formation of 3a quantitatively.
It is important to note that no base was required for
these intermolecular reactions. The quinone was shown
to play a vital role as a proton acceptor as well as the
oxidant. However, the possibility of chloride playing the
role as base to deprotonate the N-heterocycle could not
be ruled out. The addition of stoichiometric base signif-
icantly attenuates this reaction, most likely by interfer-
ing with the electrophilic C-H cleavage step of the cata-
lytic cycle.
Anticipating differential nucleophilicity of amide-
NH among different heterocycles, we undertook a com-
petition study and the results are shown in Scheme 7.
Scheme 8. Intermolecular competitions study involving
two different terminal olefins for a given heterocycles 1a.
The allylic amidation reaction could be carried out
on a gram scale without significant reduction in yield
(3a, 88%), demonstrating the scalability of this protocol
(Scheme 9).
Scheme 9. Demonstration of gram scale reaction
In summary, we have developed
a
general
Pd(II)/sulfoxide-catalyzed allylic C-H activation method
for the direct intermolecular amidation of terminal ole-
fins with tautomerizable heterocycles (quinazoline,
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9258. (i) Kumar, D.; Vemula S. R.; Cook, G. R. Green
phthalazine, pyrimidine, pyrazine, and pyridine) with
1
2
3
4
5
6
7
8
Chem. 2015, 17, 4300-4306.
excellent chemo-, regio-, and stereoselectivity. This op-
erationally simple method proceeded with high sub-
strate generality under uniform conditions (catalyst,
solvent, temperature) offering a valuable tool to obtain
structurally diverse N-heterocycles amenable for medic-
inal chemistry applications.
5) For selected reviews of allylic C−H functionalization:
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ASSOCIATED CONTENT
9
Supporting Information. Detailed experimental proce-
dures, spectral data, and CIF file for reported single crys-
tals. This material is available free of charge via the Internet
at http://pubs.acs.org.
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11
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Org. Lett. 2009, 11, 2707-2710. (b) Fraunhoffer, K. J.; White,
M. C. J. Am. Chem. Soc. 2007, 129, 7274-7276. (c) Liu, G.;
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E.; J. Am. Chem. Soc. 2003, 125, 6056-6057. (b) Piera, J.;
Närhi, K.; Bäckvall, J. -E. Angew. Chem. Int. Ed. 2006, 45,
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AUTHOR INFORMATION
Corresponding Author
Department of Chemistry and Biochemistry, North Dakota
State University, Fargo, North Dakota 58108-6050,United
States
ACKNOWLEDGMENT
We acknowledge the generous financial support of this
work from North Dakota State University. We thank NSF
CRIF (CHE-0946990) for funding a departmental X-ray
diffractometer and Dr. Angel Ugrinov for solving XRD
structures.
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Pd(II) cat., [Ox]
R
R
NHet
+
H2
H
5
6
7
8
+
Sustainable
O
O
N
O
O
O
NH
NH
NH
N
NH
NH
Atom economic
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N
N
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R = aryl/hetroaryl/napthyl/alkyl/cycloalkyl
8
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