Cross-Dehydrogenative Coupling of Heterocyclic Scaffolds with Unfunctionalized Aroyl Surrogates by Palladium(II) Catalyzed C(sp2)-H Aroylation through Organocatalytic Dioxygen Activation

Article abstract of DOI:10.1021/acs.joc.7b00226

Cross-dehydrogenative coupling of biorelevant heterocyclic scaffolds with arylmethanes for aroylation during Pd(II)-catalyzed C(sp²)-H activation has been achieved through dioxygen activation by NHPI. Mass spectrometry and ¹H NMR based kinetic isotope effect studies revealed C-H bond activation as the rate-determining step. Radical scavenging experiments indicated a radical pathway. The ¹H NMR of an aliquot of reaction mixture and in situ trapping with 2-aminothiophenol revealed the formation of aldehyde during aerobic oxidation of the arylmethanes. The reaction has broad scope for different variations of the aroyl source and the directing group that includes benzothiazole, benzooxazole, pyridine, quinoxaline, pyrimidine, and azoarene. The benzylic methylene moiety was found to be the source of the aroyl carbon with the benzyl ether moiety being the most preferred followed by the carbonyl group of aryl aldehyde and the aryl methane. However, the ease of availability of aryl methanes makes them the most attractive as an aroyl source. A time dependent selective mono- and bis-aroylation can be achieved. The 1,3-diarylpyrimidines exhibited regioselective aroylation of the 2-phenyl moiety irrespective of the absence or presence of any substitutent (electron withdrawing or electron donating) in the 3-phenyl moiety. For unsymmetrical azoarenes, selective aroylation took place in the phenyl moiety bearing the substituent.

Full text of DOI:10.1021/acs.joc.7b00226

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Article
Cross Dehydrogenative Coupling of Heterocyclic Scaffolds with
Unfunctionalised Aroyl Surrogates by Palladium(II) Catalyzed
C(sp2)-H Aroylation through Organocatalytic Dioxygen Activation
Bhavin Viththlbhai Pipaliya, and Asit K Chakraborti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00226 • Publication Date (Web): 16 Mar 2017
Downloaded from http://pubs.acs.org on March 16, 2017
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The Journal of Organic Chemistry
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Cross Dehydrogenative Coupling of
Heterocyclic Scaffolds with Unfunctionalised
Aroyl Surrogates by Palladium(II) Catalyzed
C(sp2)-H Aroylation through Organocatalytic
Dioxygen Activation
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Bhavin V. Pipaliya and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India.
CORRESPONDING AUTHOR FOOTNOTE Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160
062, Punjab, India. Fax: 91-(0)-172 2214692; Tel: 91-(0)-172 2214683; E-mail:
akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
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ABSTRACT.
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Pd(OAc)2 (5 mol%)
DG
DG
H
OrPd(OPiv)2(5 mol%)
CH3
Ar
NHPI (20 mol%), O2,
80 °C, 2.5- 8h
O
6
Ar
53-76%
7
8
9
Directing Group (DG): Benzothiazole, Benzoxazole, Pyridine,
Pyrimidine, Quinoxaline, Azobenzene
Salient features: O2 as oxidant, low catalyst loading, shorter time,
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versatile DGs, arylmethanes as aroyl surogates
Cross dehydrogenative coupling of bio-relevant heterocyclic with arylmethanes for aroylation
during the Pd(II)-catalysed C(sp2)-H activation has been achieved through dioxygen
1
activation by NHPI. Mass spectrometry and H NMR based kinetic isotope effect studies
revealed C-H bond activation as the rate determining step. Radical scavenging experiments
indicated radical pathway. The 1H NMR of an aliquot of reaction mixture and in situ trapping
with 2-aminothiophenol revealed formation of aldehyde during aerobic oxidation of the
arylmethanes. The reaction has broad scope for different variation of the aroyl source and the
directing group that include benzothiazole, benzooxazole, pyridine, quinoxaline, pyrimidine,
and azoarene. The benzylic methylene moiety was found to be the source of the aroyl carbon
with the benzyl ether moiety being the most preferred followed by the carbonyl group of aryl
aldehyde and the aryl methane. However, the ease of availability of aryl methanes makes
them most attractive as aroyl source. A time dependent selective mono- and bis-aroylation can
be acvhevde. The 1,3-diarylpyrimidines exhibited regioselective aroylation of the 2-phenyl
moiety irrespective of the absence or presence of any substitutent (electron withdrawing or
electron donating) in the 3-phenyl moiety. For unsymmetrical azoarenes, selective aroylation
took place in the phenyl moiety bearing the substituent.
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INTRODUCTION
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Cross dehydrogenative coupling (CDC) is the most attractive strategy for C-C bond
formation via C-H activation.1 The recent progress on directing group (DG) assisted
aroylation2 represent a newer version of CDC. In this context we were fascinated to explore
benzazoles as DGs due to their versatile therapeutic potential towards antitumor,3a antibiotic,3a
anti-leishmanial,3b anti-inflammatory,3c anti-tubercular3d activities.
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We observed that most of the reported procedures2 used functionalised coupling partners as
the aroyl surrogate e.g., aldehyde, benzyl alcohol, benzylic ether, mandelic acid, α-
oxocarboxylic acids, benzylamine, benzyl bromide, etc. Although a few reports used non-
functionalised coupling partner (e.g., arylmethanes),2b the use of bio-relevant DGs (e.g.,
benzazoles) are limited4 which, however, involved the use of functionalized aroyl surrogates
(e.g., aldehyde, benzyl alcohol, styrene, phenyl acetylene, and 2-acetoxy acetophenone) and
only one report with aryl methanes.4f Most of these reported aroylation reactions use large
amounts (1.5-10 equiv) of TBHP or 2 equiv of transition metal salt as the oxidising agent.
Scheme 1. The Pd-catalyzed aroylation of C(sp2)-H bond.
a) Literature report:
Limitations
X
DG
H
DG
O
PdII
i) Excess use of oxidant
ii) Functionalised aroyl surrogates
iv) specific to a particular DG
Ar
TBHP
X = CHO, CH2OH, CH2Br, CH2NH2, CH(OH)CO2H, CH3,
COCOPh, COCH(OH)Ph, COCH2OAc, CH2OCH2Ph
b) This work:
Advantages
CH3
DG
DG
i) O2 as sole oxidant
PdII
NHPI, O2
ii) Applicable to versatile DGs
iii) Arylmethanes as aroyl surogates
iv) Low catalyst loading (5 mol%)
iv) Shorter time (2.5 h)
Ar
H
DG = Benzothiazole; Benzoxazole; Pyridine
O
Pyrimidine; Quinoxaline; Azobenzene;
Molecular oxygen is the ideal oxidant and has gained popularity in various reactions.5 The
only report on aroylation with arylmethanes using molecular oxygen involves the use of
pyridyl/O-methyl oxime as the DG at 100 °C for 24 h6 but there is no report on CDC of bio-
relevant benzazoles with arylmethanes using molecular oxygen as the oxidant. Herein we
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report bio-relevant heterocyclic scaffolds directed C(sp2)-H aroylation catalysed by Pd(II)
compounds for CDC with arylmethanes through organo-catalytic non-hem model of dioxygen
activation7 (Scheme 1).
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RESULTS AND DISCUSSION
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To find the best operative reaction condition, the CDC of 2-phenylbenzo[d]thiazole (1a)
with toluene (2a) was performed to form 3aa under different variation of the reaction
condition such as the use of varying amounts of different transition metal salts/complexes as
catalyst, different oxidants, various dioxygen activators, varied reaction time and temperature
etc (Table 1). These revealed the necessity to use 5 mol% of Pd(OAc)2 and N-
hydroxyphthalimide (NHPI) as the effective dioxygen activator required in 20 mol%. The
reaction need to be performed under aerobic condition, however, use of oxygen is more
effective than open air.
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Table 1. The effect of oxidants and various dioxygen activators on the Pd(OAc)2-catalysed
CDC of 1a with 2a to form 3aa.a
Oxidantb Activator
(equiv)
Yield
(%)c
Entry
Catalyst (mol%)
Time (h)
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Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Air
Air
Air
Air
Air
Air
Air
Air
NHPI (1)
NHPI (1)
NHSI (1)
HOBt (1)
NHQI (1)
NHPI (0.5)
NHPI (0.4)
NHPI (0.3)
12
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12
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12
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12
62
64
0
0
0
64
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64
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Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (2.5)
Air
Air
Air
Air
Air
NHPI (0.2)
BQ (0.2)
12
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12
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12
20
12
12
64
0
1
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10
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HQ (0.2)
0
AIBN (0.2)
BPO (0.2)
0
0
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O2 balloon NHPI (0.2)
O2 balloon NHPI (0.2)
75
73
65
44
56
Air
NHPI (0.2)
O2 balloon NHPI (0.1)
O2 balloon NHPI (0.2)
aReaction conditions: 2-phenylbenzothiazole 1a (1.0 mmol) was treated with toluene
2a (2.0 mL) under different conditions at 110 °C for different time period. bAir: reaction
was performed in open air; O2 balloon: the reaction was performed under oxygen
c
atmosphere using a balloon filled with oxygen. Isolated yield of 3aa. NHSI: N-
Hydroxysuccinimide; HOBt: 1-Hydroxybenzotriazole; NHQI: 6-hydorxy-5H-
pyrrolo[3,4-b]pyridine-5,7(6H)-dione; BQ: Benzoquinone; HQ: Hydroquinone; AIBN:
Azobisisobutyronitrile; BPO: Benzoyl peroxide.
Among the various Pd(II) compounds used (Table 2, entries 1-9) the best result was
obtained with Pd(OAc)2 with Pd(OPiv)2 as the next best catalyst. The other transition metal-
based catalysts were ineffective (Table 2, entries 10-15).
Table 2. The effect of different Pd-compounds and other transition metal-derived
salts/complexes for CDC of 1a with 2a to form 3aa under oxygen (balloon) in the presence of
NHPI (20 mol%).a
Yield (%)b
Entry
Catalyst
Pd(OAc)2
Pd(OPiv)2
PdCl2
1
2
3
73
70
trace
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Pd2(dba)3
trace
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0
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Pd(dba)2
6
Pd(PPh3)4
Na2PdCl4
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0
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Pd(OCOCF3)2
Pd(OH)2/C
0
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9
0
.
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Cu(OAc)2 H2O
0
.
Co(OAc)2 H2O
0
.
Fe(OAc)2 H2O
0
[RuCl2 (p-cymene)]2
0
Ni(PCy3)2Cl2
0
.
NiCl2 6H2O
0
aReaction conditions: 2-phenylbenzothiazole 1a (1.0 mmol) was
treated with toluene 2a (2.0 mL) in the presence of different transition
metal-derived catalyst (5 mol%) and NHPI (20 mol%) at 110 OC for 12
h under oxygen atmosphere using a balloon filled with oxygen.
bIsolated yield of 3aa.
Further studies on passing oxygen gas into the reaction mixture (O2 bubbling) instead of
performing the reaction under oxygen atmosphere using a balloon filled with oxygen, using
varying amounts of 2a in various organic solvent rather than using 2a as the solvent (Table 3)
led to two reaction conditions: (A) treatment of the benzazole with the arylmethane (2
mL/mmol of benzazole) at 80 °C for 2.5 h under oxygen bubbling in the presence of NHPI
(20 mol%) and Pd(OAc)2 (5 mol%); (B) treatment of the benzazole with 5 molar equivalent of
the arylmethane in PhCl (2 mL/mmol of benzazole) at 80 °C for 2.5 h under oxygen bubbling
in the presence of NHPI (20 mol%) and Pd(OAc)2 (5 mol%). Thus, passing (bubbling) oxygen
gas into the reaction mixture rather than using oxygen gas under balloon provided advantages
in reducing the reaction time from 12 h to 2.5 h as well as the reaction temperature from 110
°C to 80 °C.
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Table 3. The effect of the varying amounts of 2a, other organic solvents for the Pd(OAc)2-
catalysed CDC of 1a with 2a to form 3aa.a
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Temp (oC)
Yield (%)b
Entry 2a (amt)
Solvent
2a
Time (h)
2.5
1
As solvent
As solvent
As solvent
As solvent
5.0 mmol
2.5 mmol
5.0 mmol
5.0 mmol
5.0 mmol
5.0 mmol
5.0 mmol
5.0 mmol
10.0 mmol
2.5 mmol
5.0 mmol
110
110
80
76
59c
75
45
70
53
0
2
2.5
2a
3
2.5
2a
4
60
2.5
2a
5
PhCl
PhCl
PhF
PhCF3
DCE
80
2.5
6
80
2.5
7
80
2.5
8
80
2.5
Trace
29
0
9
80
2.5
10
11
12
13
14
15
1,4-Dioxane 80
2.5
MeCN
DMSO
Noned
Noned
Noned
80
80
80
80
80
2.5
0
2.5
0
2.5
62
49
37
2.5
2.5
aReaction conditions: 2-phenylbenzothiazole 1a (1.0 mmol) was treated with toluene
2a (5 mmol or as specified) in the presence of Pd(OAc)2 (5 mol% except for entry 2),
NHPI (20 mol%) various solvent at the specified temperature for different time period
b
in open vessel while bubbling oxygen gas into the reaction mixture. Isolated yield of
3aa. cThe reaction was carried out using 2.5 mol% of Pd(OAc)2.dNo solvent was used.
The scope of the C(sp2)-H aroylation was next examined with respect to structurally diverse
2-arylbenzo[d]thiazoles7 using 2a as the aroyl source (Table 4).
Table 4. Scope with respect to structural variation of 2-arylbenzothiazole (1).a
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aReaction condition A: 1 (1 mmol) was treated with 2a (2 mL) in the presence of Pd(OAc)2 (5
mol%) and NHPI (20 mol%) at 80 oC under O2 bubbling for 2.5 h (yield of the isolated product
b
c
d
given). Reaction for 6 h. Reaction for 8 h. The yield obtained from the reaction of pre-
formed 3aa with 2a for 3 h.
The 2-(3'-bromophenyl)benzothiazole exhibited excellent regioselectivity for aroylation at
the less hindered ortho-position of the 2-aryl moiety to form 3da. For 2-(2'-
naphthyl)benzothiazoles, the peri hydrogen of the naphthyl group directs benzoylation at the
3'-position of the naphthyl moiety to form 3ja. Benzothiazoles bearing halogen (Br, Cl, F) and
electron donating (Me, OMe) substituents at the para-position of the 2-aryl group gave 3ea,
3fa, 3ga, 3ha, and 3ia in 68-74% yields. There appears to be no influence on the
regioselectivity and reaction time/yield of the electronic effect of the substituent present either
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on the benzothiazole or on the 2-aryl moiety. However, the influence of the steric effect can
be realised in regioselective formation of 3da and 3ja. The presence of Br at the ortho-
position of the 2-aryl moiety is not compatible as the corresponding debrominated product
3aa was formed in 68% yield. However, the corresponding ortho-chloro derivative gave the
desired product 3ka in 65%.8 These results and the fact that the meta and para Br substituents
remained unperturbed suggest chelation assisted oxidative addition of Pd(OAc)2 to the ortho
C-Br bond.9 Substitution of OCH3 at the ortho-position of the 2-aryl moiety provided 3la in
69% yield but required longer reaction time (6 h) due to the steric effect. Excellent time-
dependent selcectivity towards the formation of the mono- and bis-aroylated products was
observed. In all cases the reaction of the 2-arylbenzothiazole 1 with the arylmethane 2 led to
the exclusive formation of the corresponding mono-aroylated product in performing the
reaction for 2.5 h. However, performing the reaction for longer period aforded the bis-
aroylated products. Thus, the treatment of 1a and 1e with 2a for 8 h afforded 3ma and 3na in
71 and 65 % yields, respectively. It was presumed that the bis-aroylated product 3ma resulted
from a sequential reaction pathway: formation of the mono-aroylated product 3aa by the
reaction of 1a with 2a followed by further reaction of the in situ generated 3aa with 2a to
form the bis-aroylated product 3ma. Thus, when pre-formed 3aa was subjected to the reaction
with 2a for 3 h the bis-aroylated product 3ma was obtained in 70% yield. Therefore, selective
formation of the mono- and bis-aroylated products could be controlled by the reaction time.
The scope with various substituted arylmethanes was next evaluated (Table 5) under
condition B. The aroylation is compatible with halogens irrespective of its nature and
position. The reaction with ethyl benzene and isobutyl benzene gave 3aa as the only product
in 65 and 60% yields, respectively, suggesting the benzylic carbon as the preferred site to
generate the carbonyl moiety.
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Table 5. Scope with respect to structural variation of arylmethanes (2).a
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aReaction condition B: 1a (1 mmol) was treated with the arylmethane (5 mmol, 5 equiv) in
PhCl (2.0 mL) in the presence of Pd(OAc)2 (5 mol%), NHPI (20 mol%) at 80 °C under O2
bubbling for 2.5 h. The yield of the isolated product mentioned against each example.
The applicability of the aroylation protocol was extended to other DGs (Table 6). The 2-
arylbenzoxazoles10 4a and 4b underwent CDC with 2a and p-xylene (2b) to afford 5aa, 5ab,
and 5ba in 65, 67, and 67% yields, respectively. The treatment of the azobenzene 4c, 2-
phenylpyridine 4e and the 2,3-diphenyl quinoxaline 4f11 with 2a afforded 5ca, 5ea, and 5fa in
53, 77, and 64% yields, respectively. The selective monoaroylation mark the specific
advantage of the present work. Thus, although the benzoylation of 4e has been reported6 to
form 5ea (80%) along with the corresponding bis-benzoylated product in 5% yield, repetition
on our hand afforded 5ea (30%) and the bis-benzoylated product (46%). In case of 4c and 4f
only one of the two phenyl groups underwent benzoylation. For the unsymmetrical
azobenzene 4d the selective aroylation with 4-chlorotoluene (2m) was observed in the
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electron rich phenyl ring to afford 5dm. The pyrimidine 4f contains two phenyl groups and
represents a perfect example of regioselectivity. Selective aroylation took place at the 2-
phenyl ring of 2,4-diphenylpyridine 4g giving 5ga as the only product in 69% yield. Increase
or decrease of electron density at the 4-phenyl ring did not have any effect on the
regioselective outcome as the reaction of 4-(4'-nitrophenyl)-2-phenylpyrimidine 4h and 4-(4'-
methoxyphenyl)-2-phenylpyrimidine 4i afforded 5ha and 5ia in 62 and 60% yields,
respectively, indicating selective activation of the C(sp2)-H bond of the 2-phenyl ring.
Table 6. Scope of other directing groups.a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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31
32
33
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35
36
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a4 (1 mmol) was treated with 2 (2 mL) in the presence of Pd(OAc)2 (5 mol%) and
NHPI (20 mol%) at 80 oC under O2 bubbling for 3 h (yield of the isolated product
given). bReaction with 5 mmol of 2a/2m in PhCl (2 mL). cYield obtained from the
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reaction of 5ia with 2a for 3 h. dYield obtained from the reaction of 4i with 2a for
8 h.
1
2
3
4
5
6
7
8
9
The influence of differential electronic effect of the substituent present in the 2-phenyl
and 4-phenyl ring in reversing the regioselectivity towards the 4-phenyl ring was investigated.
The pyrimidine derivative 5ia bearing electron rich 4-phenyl and electron deficient 2-phenyl
moieties on aroylation with 2a gave 5ja in 71% yield indicating the ability of the pyrimidine
moiety in directing aroylation at the 2-phenyl ring. However, 5ja was obtained in 63% yield
when the reaction of 4i with 2a was performed for 8 h. This further demonstrated that a time
dependent selective mono- and bis-aroylation can be achieved.
10
11
12
13
14
15
16
17
18
19
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59
60
The aroylation product 5dm on reductive cyclisation afforded a liver(X) receptor agonist12
(Scheme 2) with distinct advantages over existing reports13 in avoiding use of excessive
oxidant, additional ligand, and base in minimizing generation of wastes.
Scheme 2. Synthesis of liver(X) receptor agonist (6)
To demonstrate good scale-up capability, a gram scale reaction was carried out during the
treatment of 1a (1.47g, 7 mmol) with 2a that afforded the desired product 3aa in 70 and 68%
yields under reaction conditions A and B, respectively.
The applicability of other aroyl surrogates was examined under the condition B (Table 7).
The treatment of 1a with 5 molar equiv of each of benzaldehyde14 and benzyl alcohol in PhCl
at 80 °C under O2 bubbling for 2.5 h afforded 3aa in 67 and 61% yields, respectively. The
best result (84% yield in 2.5 h) was obtained using dibenzyl ether. Others such as benzyl
amine, mandelic acid, benzil, and benzoyl acetone gave 3aa in inferior yields (25-51%). The
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use of 4-phenyl-2-butanone formed 3aa as the only product (32% yield) and further indicated
the benzylic carbon as the preferred source of the aroyl carbonyl.
Table 7. Scope of aroyl surrogates.a
1
2
3
4
5
6
7
8
9
Pd(OAc) (5 mol%)
NHPI (20 mol%)
2
Aroyl
source
3aa
1a +
O bubbling, Ph-Cl,
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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48
49
50
51
52
53
54
55
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59
60
o
80 C
Yield (%)b
Entry
1
Aroyl source
Equiv
5.0
5.0
2.5
5.0
5.0
2.5
5.0
5.0
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
Time (h)
2.5
PhCH3
70
41
51
67
45
56
86
86
84
61
26
0
2
1.5
3
2.5
4
PhCHO
Bn2O
2.5
5
1.5
6
2.5
7
2.5
8
1.5
9
2.5
10
11
12
13
14
15
16
17
18
PhCH2OH
PhCH2NH2
PhCH2Cl
2.5
2.5
2.5
PhCH(OH)COOH
PhCOCOPh
2.5
29
0
2.5
PhCOCH(OH)Ph
PhCOCH2COCH3
Ph(CH2)2COCH3
PhCN
2.5
51
25
32
0
2.5
2.5
2.5
aReaction conditions: 1a (0.5 mmol), aroyl source, Pd(OAc)2 (5 mol%), NHPI
(20 mol%), chlorobenzene (1.0 mL), O2 bubbling at 80 oC. bIsolated yield of 3aa.
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The above results reflect that aroylation is more facile using dibenzyl ether is used as the
aroyl source. However, no major difference (in terms of product yield and reaction time)
could be observed for aroylation using toluene and benzaldehyde as the aroyl source. Thus, to
assess the distinct difference on the ease of aroylation using benzyl ether, aryl aldehyde, and
aryl methane as the aroyl source the following inter- and intra-molecular competition studies
(Schemes 3 and 4) were performed.
1
2
3
4
5
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During the intermolecular competitions 1a was treated with (i) 5 equiv of each of p-xylene
(2b) and dibenzyl ether; (ii) 5 equiv of each of 2b and 4-methoxybenzaldehyde; and (iii) 5
equiv of each of 2b and 4-bromobenzaldehyde (Scheme 3). In all of these cases a mixture of
aroylated products corresponding to the respective aroyl source were formed and could not be
isolated in pure form. Therefore, a quantitative estimation of the corresponding aroylated
product was obtained mass spectrometrically15 by subjecting an aliquot portion of the reaction
mixture to ESI/MS analysis and determining the ion current16 of the mass peak of the
corresponding sodium adduct (M+Na+). The ratio of the ion current provided the relative
amount of formation of the corresponding product. The results reflected that the dibenzyl
ether and aldehyde are more effective/reactive aroyl source compared to arylmethanes.
Scheme 3. Intermolecular competition during aroylation of 1a with dibenzyl ether,
arylmethane, and aryl aldehydes as the aroyl surrogates.
condition B
3aa
3ab
+
:
1a 2b
(i)
+
+ Bn2O
CHO
4.5
1
condition B
condition B
(ii)
3aj
3ab
+
1a
2b
:
3.9
1
OMe
CHO
3af
3ab
+
(iii)
1a 2b
:
4.2
1
Br
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For intramolecular competition studies (Scheme 4) 1a was treated with (i) of p-
tolualdehyde, (ii) 4-benzyloxy toluene, (iii) 4-benzyloxybenzaldehyde under reaction
condition B that would represent competitive aroylation involving aryl methane vs aryl
aldehyde, aryl methane vs benzyl ether, and aryl aldehyde vs benzyl ether, respectively. In
each case the corresponding product was isolated and characterised. The results obtained
suggest aryl aldehyde as the preferred aroyl source over the aryl methane but benzyl ether is
the most preferred aroyl source compared to both aryl methane and aryl aldehyde. However,
the readily availability of arylmethanes make them a preferred choice as the aroyl surrogate.
Scheme 4. Intramolecular competition during aroylation of 1a with 4-methylbenzaldehyde, 4-
benzyloxytolune, and 4-benzyloxybenzaldehyde as the aroyl surrogates.
1
2
3
4
5
6
7
8
9
10
11
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CHO
S
N
S
N
condition B
O
Me
R
1a
3ab, 70%
Me
S
N
S
N
condition B
O
O
1a
Ph
R = Me; 3aa, 63%
3aa
Ph
R = CHO;
, 65%
Anticipating that the aroylation proceeds through C‐H activation, kinetic isotope effect
(KIE) studies were carried out. In two separate experiments 1a and 1a-d2 were treated with 2a
in the presence of Pd(OAc)2 (5 mol%) at 80 °C under O2 bubbling. A quantitative estimation
of the corresponding aroylated product 3aa/3aa-d was made by determination of ion current17
of the mass peak of the corresponding sodium adduct (M+Na+) by subjecting an aliquot
portion of the reaction mixture, withdrawn after specified time interval to ESI/MS analysis
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(Table 8). The ratio of the ion current provided the kH/kD values that reflected the kinetic
isotope effect and provided evidence for C‐H activation.
Page 16 of 45
1
2
3
4
5
6
Table 8. Determination of kH/kD by ESI/MS.a
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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c
kH/kD
entry
time (h)
ion current of [M+Na+] peak
3aa (X)b
3aa-d (Y)b
0.65 ×107
0.40 ×107
0.22 ×107
0.57 ×107
1
2
3
4
0.5
1.0
1.5
2.0
2.25 ×107
1.17 × 107
0.77 × 107
1.45 × 107
2.11
1.87
2.24
1.62
a1a (0.5 mmol) and 1a-d2 (0.5 mmol) were separately treated with 2a (1 mL) and after
b
the specific time 10 µL of the reaction mixture was subjected to ESI‐MS analysis. The
c
area of the ion peak of the sodium adduct of the benzoylated product. The kH/kD is
represented by the ratio X/Y.
1
Intermolecular competition experiments, monitored through H NMR reflected more
pronounced KIE (kH/kD 2.91-3.62) (Table 9).
Table 9. Determination of kH/kD by NMR.a
c
3aa (X) b
3aa-d (Y)b
kH/kD
3.62
3.36
2.91
Entry
Time (h)
0.75
1
2
3
85
84
82
15
16
18
1.0
1.5
aThe mixture of 1a (0.5 mmol) and 1a-d2 (0.5 mmol) was treated with 2a
(1 mL) in the presence of Pd(OAc)2 (5 mol%) and NHPI (20 mol%) at 80
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The Journal of Organic Chemistry
°C under O2 bubbling (1 atm). bThe ratio of the product was determined by
NMR. cThe relative rate (kH/kD) is represented by the ratio X/Y
1
2
3
In order to get further mechanistic insight, the mixture of 2a/Bn2O and NHPI (20 mol%)
was heated at 80 °C under O2 (bubbling) for 2 h in the absence of any Pd catalyst followed by
treatment of the reaction mixture with 2-aminothiophenol for further 1 h to furnish 1a in 67
and 79% yields, respectively, (Scheme 5). In situ formation of benzaldehyde from 2a was also
confirmed by subjecting an aliquot of the crude reaction mixture of 2a and NHPI (20 mol%)
4
5
6
7
8
9
10
11
12
13
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1
under O2 bubbling after 2 h to H NMR analysis after distilling off the excess of 2a. The
remaining reaction mixture was diluted with EtOAc (5 mL), washed with water (2 X 5 mL),
dried with Na2SO4, and concentrated under vacuum. The resultant crude product in toluene (2
mL) on being treated with 2-aminothiophenol afforded 1a in 65%. This indicates in situ
formation of benzaldehyde as aldehydes are known to form benzothiazoles on reaction with 2-
aminothiophenols.7
Scheme 5. Evidence for in situ formation of aldehyde.
The addition of TEMPO (1.5 equiv) to the Pd(OAc)2 (5 mol%) catalysed reaction of 1a with
2a in the presence of NHPI (20 mol%) at 80 °C under O2 (bubbling) for 2.5 h did not produce
any significant amount of 3aa. This suggests the involvement of radical pathway for the
aroylation.
The Pd(OAc)2 (5 mol%) catalysed reaction of 1a with 2a in the presence of NHPI (20
mol%) at 80 °C under N2 (balloon) for 12 h did not produce any significant amount of 3aa
indicating the essentiality of molecular oxygen for this oxidative coupling reaction.
Based on these studies and precedent literature reports6,17 a plausible mechanistic pathway is
proposed (Scheme 6). The first step involves the generation of the phthalimide-N-oxyl (PINO)
radical from NHPI and dioxygen. The in situ generated PINO radical abstracts hydrogen
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radical from the arylmethane to form the benzylic radical I which subsequently reacts with
dioxygen to form the benzyl peroxyradical II (Scheme 6)17b which disproportionates to the
aldehyde and hydroxyl radical. The generated hydroxyl/PINO radical would abstract the
hydrogen radical from the aldehyde group to form the acyl radical III.18,14 The in situ formed
aldehyde may also undergo acyl radical formation in the presence of molecular oxygen.19 The
Pd(OAc)2 coordinates with the benzazole through the nitrogen atom and activates the ortho C-
H bond of the 2-aryl moiety. The chelation-directed C-H bond activation is followed by the
(acetate) ligand-assisted proton abstraction20 through a six-membered chair-like transition
state in IV to the cyclo-palladated complex V. The lack of catalytic efficiency of PdCl2 as
well as Na2PdCl2 could be due to the poor basicity (and hence H-B formation ability) of the
chloride anion. In case of Pd(dba)3 and Pd(dba)2 as the ligand attains psuedoaromatic
character involving the d orbital of the Pd(II) it is unable to form the chair-like transition state
to abstract the ortho aryl proton. On similar reason Pd(PPh3)4 is also ineffective. On the other
hand, in Pd(OPiv)2 the pivalate anion can take part in forming the chair-like transition state to
abstract the ortho arylproton due to its basicity (hydrogen bond acceptor ability) and hence
exhibited catalytic efficiency comparable to that of Pd(OAc)2. The inability of Pd(OCOCF3)2
to promote the reaction is supportive of the proposal on ligand-assisted abstraction of the
ortho-aryl proton as the trifluoroacetate anion is less basic. The poor H-B accepting ability of
the carbonyl oxygen of the trifluoroacetate anion is not conducive for formation of the six-
membered chair-like transition state leading to the analogous complex IV (Scheme 6).
Scheme 6. Proposed mechanism for C(sp2)-H aroylation.
1
2
3
4
5
6
7
8
9
10
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(+II)
O
O
O
O
1a
1
2
3
4
5
6
7
8
Me
Pd
Me
Ph
(+II) O
O
O
O
Me
Pd
Me
N
S
O
N
S
C
-
3aa
n
o
H
e
9
v
i
i
a
c
Me
O
t
a
t
O
c
10
11
12
13
t
i
v
u
n
Me
i
1a
a
d
t
m
e
i
o
O
Ph
i
l
r
O
n
N OH
e
(+II)Pd
N
O
O
H
S
N
Me
NHPI
O
14
15
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17
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20
21
22
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60
O
Pd(+III)
H.
S
O
O
2,
O
Ph
IV
S
N
O
n
O
-
o
i
t
(+IV) Pd
Me
Or
o
Me
l
a
c
O
d
y
N O
a
c
l
l
O
a
O
Ph
o
a
p
O
VIb
Pd
PINO
O
x
d
i
AcOH
d
a
t
i
v
S
N
(+II)
N
O
e
d
i
(+III)
t
io
n
Pd
O
Me
S
V
O
O
Ph
VIa
Ph
III
NHPI
H2O
OH
O
2,
O O
PINO
O2
PhCHO
2a
+
Ph
PhCH2
II
I
2a
To demonstrate that the deprotonation of the ortho aryl proton in IV does not take place by
external base a few additional experiments were performed. Thus, the PdCl2-catalysed
reaction of 1a with 2a that did not afford any significant amount of 3aa under method A was
performed separately by adding KOAc (5 mol%) alone as well as along with 5 mol% of 18-C-
6. Thus, external base is not involved in the abstraction of the ortho proton of the 2-aryl
moiety. The complex V undergoes oxidative addition to III to form the intermediate
Pd(III)/Pd(IV)21 species VIa/VIb which on reductive elimination by new C-C bond formation
is converted to the aroylated product and the Pd(II) catalyst is regenerated and re-enters into
the catalytic cycle.
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In conclusions, cross dehydrogenative coupling of arylmethanes with bio-relevant
heterocycles has been achieved for Pd(II)-catalysed C(sp2)-H aroylation through
organocatalytic dioxygen activation. Mass and NMR spectrometry based kinetic isotope effect
studies revealed C-H bond activation as the rate-determining step and radical scavenging
experiment established radical pathway to generate aroyl radical as the actual aroylation
species formed by aerial oxidation of the arylmethanes through organocatalytic activation of
molecular oxygen. Excellent selectivity was observed in forming the mono- and the bis-
aroylated produtcs through a time dependent reaction. The exclusive formation of the mono-
aroylated product took place for a shorter reaction period (2.5 – 3 h) while performing the
reaction for longer period (~ 8 h) gave the bis-aroylated product which, however, can also be
obtained by further aroylation of the corresponding pre-formed mono-aroylated compound. A
representative application of this newly developed synthetic methodology on C(sp2)-H
aroylation via organocatalytic dioxygen activation has been demonstrated through the
preparation of liver(X) receptor agonist. The use of molecular oxygen as the oxidant,
arylmethanes as unfunctionalised aroyl surrogates, lesser catalyst loading, and the
applicability with diverse directing groups mark the distinct advancements in catalytic C(sp2)-
H aroylation.
1
2
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5
6
7
8
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17
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EXPERIMENTAL SECTION
1
13
General: H and C NMR spectra were recorded on a 400 MHz NMR spectrometer in
CDCl3 with a residual undeuterated solvent (CHCl3 at 7.26/77.0) using TMS as an internal
standard. Chemical shifts (δ) are given in ppm and J values are given in Hz. 13C NMR spectra
were fully decoupled and were referenced to the middle peak of the solvent CDCl3 at 77.00
ppm. Splitting patterns were designated as s, singlet; d, doublet; dd, doublet of doublet; dt,
doublet of triplet; td, triplet of doublet; t, triplet; m, multiplet. The IR spectra were recorded
either on KBr pellets (for solids) or neat (for liquids) on a FTIR spectrometer. High resolution
mass spectra (HRMS) were obtained using the electron spray ionization (ESI) technique and
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TOF mass analyzer. Melting points were measured using a melting point apparatus and were
uncorrected. ESI/MS spectra were recorded on advance mass spectrometer with ion trap mass
analyzer. Open column chromatography and thin layer chromatography (TLC) were
performed on silica gel (60-120 mesh and fluorescent silica gels, respectively). Evaporation of
solvents was performed under reduced pressure, using a rotary vacuum evaporator.
All the commercially available chemicals were used without further purification. Starting
material 1b-1j,7 4a-4b,10 4d,22 and 4f,11 were synthesized according to literature protocol.
Liver receptor agonist (6) from 5dm was synthesized using reported methodology.23
General procedure for the Pd(OAc)2 catalyzed Cross-dehydrogenative coupling of 2-
arylbenzo[d]thiazole (1) with arylmethane (2) (reaction of 1a with 2a to form 3aa)
(Condition A):
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5
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60
The magnetically stirred mixture of 2-phenylbenzo[d]thiazole (1a) (211 mg, 1.0 mmol),
Pd(OAc)2 (11.2 mg, 5 mol%) and NHPI (33 mg, 20 mol%) in toluene (2a) (2.0 mL) was
o
heated at 80 C (oil bath temp) for 2.5 h (TLC) while O2 gas (cylinder outlet pressure 10 psi)
was bubbled (passed) into the reaction mixture. The reaction mixture was cooled to rt and
diluted with EtOAc (50 mL), washed with brine (3 × 5 mL), dried (anh Na2SO4), filtered, and
concentrated under rotary vacuum evaporation. The crude reaction mixture was purified by
column chromatography on silica gel (60-120 mesh size) using 4% EtOAc in hexane as eluent
to afford 2-(benzo[d]thiazol-2-yl)phenyl)(phenyl)methanone 3aa (236 mg,75%) as yellowish
o
solid; mp: 82-83 C; IR (KBr) νmax: 3059, 2923, 1608, 1596, 1508, 1448, 1432, 1314, 1263,
1
1151, 1072, 967, 927, 759, 703 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 7.97-7.95 (m,
1H), 7.81-7.78 (m, 4H), 7.66-7.61 (m, 2H), 7.58-7.56 (m, 1H), 7.43-7.38 (m, 2H), 7.32 (t, J =
7.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 197.6, 165.3, 153.5, 139.7, 137.8, 135.3,
132.7, 132.1, 130.3, 130.2, 129.6, 129.2, 128.9, 128.2, 126.1, 125.3, 123.4, 121.4; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C20H13NOSNa 338.0616; found 338.0630. Identical
with those of an authentic sample.4d
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Phenyl(2-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenyl)methanone (3ba): Yellowish
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2
3
o
solid (268 mg, 70%); mp: 127-128 C; IR (KBr) νmax: 3062, 2926, 1673, 1596, 1511, 1452,
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5
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1422, 1329, 1267, 1149, 1124, 1076, 1055, 965, 931, 840, 767, 708, 671, 637 cm-1; 1H NMR
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(CDCl3, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.98-7.92 (m, 2H), 7.81 (d, J = 7.6 Hz, 2H), 7.70-
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7.64 (m, 2H), 7.58-7.55 (m, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.38-7.34 (m, 2H); C NMR
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(CDCl3, 100 MHz) δ (ppm): 197.2, 167.6, 153.0, 139.9, 138.7, 137.5, 133.0, 131.5, 130.8,
130.3, 129.9, 129.4, 129.0, 128.7, 128.4, 122.1, 121.7 (J = 3.0 Hz), 120.5 (J = 4.0 Hz);
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H12F3NOSNa 406.0489; found 406.0496.
(2-(5-Chlorobenzo[d]thiazol-2-yl)phenyl)(phenyl)methanone (3ca): Yellowish solid (247
o
mg, 71%); mp: 107-108 C; IR (KBr) νmax: 3059, 2926, 1671, 1596, 1509, 1450, 1432, 1286,
1267, 1151, 1074, 965, 929, 902, 794, 768, 704, 676, 637 cm-1; 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.60 (m, 1H), 7.80-7.78 (m, 3H), 7.71 (d, J = 8.5 Hz, 1H), 7.68-7.62 (m, 2H), 7.57-
7.55 (m, 1H), 7.47-7.43 (m, 1H), 7.37-7.33 (m, 2H), 7.29 (dd, J = 8.5, 2.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ (ppm): 197.3, 167.3, 154.2, 139.8, 137.6, 133.5, 132.8, 132.2, 131.7,
130.6, 130.2, 129.7, 129.3, 128.9, 128.3, 125.9, 123.1, 122.1; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C20H12ClNOSNa 372.0226; found 372.0233.
(2-(Benzo[d]thiazol-2-yl)-4-bromophenyl)(phenyl)methanone (3da): Off white solid (272
o
mg, 69%); mp: 104-105 C; IR (KBr) νmax: 3061, 2925, 1670, 1596, 1581, 1449, 1434, 1378,
1313, 1278, 1260, 1151, 977, 925, 829, 760, 703, 672, 654 cm-1; 1H NMR (CDCl3, 400 MHz)
δ (ppm): 7.08 (d, J = 1.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 2H), 7.74-7.71 (m, 3H), 7.40 (d, J = 8.2
13
Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.31-7.27 (m, 3H); C NMR
(CDCl3, 100 MHz) δ (ppm): 196.6, 163.5, 153.3, 138.4, 137.4, 135.4, 134.0, 133.2, 132.9,
132.4, 130.4, 129.2, 128.3, 126.4, 125.7, 124.2, 123.6, 121.5; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C20H12BrNOSNa 415.9721; found 415.9717.
(2-(Benzo[d]thiazol-2-yl)-5-bromophenyl)(phenyl)methanone (3ea): Yellowish solid (276
o
mg, 70%); mp: 123-124 C; IR (KBr) νmax: 2924, 1769, 1596, 1501, 1448, 1383, 1258, 1108,
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The Journal of Organic Chemistry
1052, 749 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.84 (d, J = 8.3 Hz, 1H), 7.82-7.77 (m,
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5H), 7.68 (d, J = 1.9 Hz, 1H), 7.46-7.38 (m, 2H), 7.36-7.31 (m, 3H); C NMR (CDCl3, 100
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5
6
7
8
MHz) δ (ppm): 195.8, 164.0, 153.4, 141.2, 137.2, 135.2, 133.2, 133.0, 131.7, 130.9, 129.2,
128.4, 126.3, 125.6, 124.9, 123.5, 121.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C20H12BrNOSNa 415.9708; found 415.9721.
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(2-(Benzo[d]thiazol-2-yl)-5-chlorophenyl)(phenyl)methanone (3fa): Yellowish solid (273
o
mg, 68%); mp: 135-136 C; IR (KBr) νmax: 3057, 2924, 1672, 1596, 1522, 1449, 1346, 1314,
1275, 1260, 1157, 1093, 967, 750, 705, 645 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.90
(d, J = 8.4 Hz, 1H), 7.81-7.78 (m, 4H), 7.62 (dd, J = 8.3, 2.2 Hz, 1H), 7.53 (d, J = 2.1 Hz,
13
1H), 7.45-7.38 (m, 2H), 7.37-7.30 (m, 3H); C NMR (CDCl3, 100 MHz) δ (ppm): 195.9,
164.0, 153.4, 141.1, 137.2, 136.7, 135.2, 133.0, 130.8, 130.5, 130.2, 129.2, 128.9, 128.4,
126.3, 125.5, 123.5, 121.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H12ClNOSNa
372.0226; found 372.0236.
(2-(Benzo[d]thiazol-2-yl)-5-fluorophenyl)(phenyl)methanone (3ga): Yellowish gummy
(233 mg, 70%); IR (neat) νmax: 3060, 2918, 1672, 1596, 1581, 1482, 1449, 1404, 1314, 1276,
1
1261, 1209, 1098, 980, 860, 841, 759, 709 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 7.93
(dd, J = 8.6, 5.5 Hz, 1H), 7.78-7.75 (m, 4H), 7.42-7.23 (m, 7H); 13C NMR (CDCl3, 100 MHz)
δ (ppm): 195.9, 164.8-162.2 (JFC = 253 Hz), 164.1, 153.4, 142.0 (JFC = 7.0 Hz), 137.2, 135.2,
133.0, 131.8 (JFC = 9.0 Hz), 129.2, 128.4, 126.2, 125.4, 123.4, 121.4, 117.2 (JFC = 22 Hz),
116.2 (JFC = 23.0 Hz); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H12FNOSNa
356.0521; found 356.0533.4f
(2-(Benzo[d]thiazol-2-yl)-5-methylphenyl)(phenyl)methanone (3ha): Off white solid (240
o
mg, 73%); mp: 103-104 C; IR (KBr) νmax: 3066, 2922, 1670, 1592, 1578, 1515, 1486, 1452,
1
1433, 1314, 1267, 1209, 1176, 976, 817, 753, 705, 645, 620 cm-1; H NMR (CDCl3, 400
MHz) δ (ppm): 7.82 (d, J = 8.0 Hz, 1H), 7.70-7.74 (m, 4H), 7.41 (d, J = 7.9 Hz, 1H), 7.37-
13
7.31 (m, 3H), 7.30-7.25 (m, 3H), 2.47 (s, 3H); C NMR (CDCl3, 100 MHz) δ (ppm): 197.8,
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165.4, 153.5, 140.9, 139.7, 137.9, 135.2, 132.6, 130.8, 129.5, 129.4, 129.4, 129.2, 128.2,
126.0, 125.1, 123.3, 121.3, 21.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H15NOSNa
352.0772; found 352.0787.4d
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(2-(Benzo[d]thiazol-2-yl)-5-methoxyphenyl)(phenyl)methanone (3ia): Yellowish solid
9
o
(255 mg, 74%); mp: 88-89 C; IR (KBr) νmax: 3048, 2923, 1668, 1598, 1484, 1399, 1311,
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1218, 1100, 1030, 964, 938, 761, 709, 620 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 7.90
(d, J = 8.6 Hz, 1H), 7.81-7.75 (m, 4H), 7.41 (t, J = 7.3 Hz, 1H), 7.37-7.26 (m, 4H), 7.15 (dd, J
13
= 8.6, 2.6 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H); C NMR (CDCl3, 100 MHz) δ (ppm): 197.3,
165.0, 161.2, 153.5, 141.3, 137.6, 135.0, 132.7, 131.2, 129.2, 128.2, 126.0, 125.0, 124.6,
123.1, 121.3, 115.9, 113.9, 55.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H15NO2SNa
368.0721; found 368.0728.4f
(3-(Benzo[d]thiazol-2-yl)naphthalen-2-yl)(phenyl)methanone (3ja): Yellowish solid (270
o
mg, 74%); mp: 119-120 C; IR (KBr) νmax: 3060, 2925, 1664, 1596, 1497, 1430, 1381, 1260,
1105, 956, 884, 754, 747, 728, 701 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.44 (s, 1H),
8.06 (s, 1H), 8.06-8.03 (m, 1H), 7.97-7.95 (m, 1H), 7.85-7.82 (m, 4H), 7.70-7.64 (m, 2H),
13
7.44-7.36 (m, 3H), 7.36-7.31 (m, 3H); C NMR (CDCl3, 100 MHz) δ (ppm): 197.2, 165.6,
153.6, 138.2, 137.0, 135.2, 133.4, 133.2, 132.6, 130.1, 129.9, 129.4, 129.3, 128.5, 128.5,
128.4, 128.3, 128.2, 126.1, 125.3, 123.4, 121.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C24H15NOSNa 388.0772; found: 388.0786.
(2-(Benzo[d]thiazol-2-yl)-3-chlorophenyl)(phenyl)methanone (3ka): Off white solid (227
mg, 65%); IR (KBr) νmax: 1732, 1668, 1448, 1314, 1280, 1235, 1134, 966, 760, 701 cm-1; 1H
NMR (CDCl3, 400 MHz) δ (ppm): 7.87 (d, J = 7.9 Hz, 1H), 7.82 (m, 1H), 7.69 (dd, J = 7.8,
1.5 Hz, 1H), 7.66-7.63 (m, 2H), 7.55-7.52 (m, 1H), 7.49 (dd, J = 7.6, 1.5 Hz, 1H), 7.41-7.31
(m, 3H), 7.27-7.23 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 195.7, 152.2, 142.9,
137.0, 136.0, 134.4, 134.1, 132.8, 132.0, 130.6, 129.9, 129.4, 128.1, 127.4, 126.0, 125.6,
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123.6, 121.3; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H12ClNOSNa 372.0226; found
372.0221.4f
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(2-(Benzo[d]thiazol-2-yl)-3-methoxyphenyl)(phenyl)methanone (3la): White solid (238
7
8
o
mg, 69%); mp: 148-149 C; IR (KBr) νmax: 2934, 1668, 1575, 1449, 1316, 1288, 1160, 1066,
9
974, 760, 701 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.80 (d, J = 7.4 Hz, 1H), 7.76-7.71
(m, 3H), 7.58 (t, J = 7.9 Hz, 1H), 7.35-7.21 (m, 6H), 7.16 (dd, J = 7.6, 1.0 Hz), 4.08 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ (ppm): 197.2, 160.4, 157.1, 151.4, 142.3, 138.2, 135.9, 132.0,
131.3, 128.7, 128.0, 125.6, 124.9, 122.9, 121.1, 120.9, 120.8, 112.7, 56.1; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C21H15NO2SNa 368.0721; found 368.0721.4d
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(2-(Benzo[d]thiazol-2-yl)-1,3-phenylene)bis(phenylmethanone) (3ma): Off white solid
o
(353 mg, 71%); mp: 129-130 C; IR (KBr) νmax: 3050, 1669, 1593, 1445, 1312, 1287, 1260,
1
1158, 1007, 788, 761, 712 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 7.78-7.71 (m, 8H),
7.58 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.32-7.25 (m, 5H), 7.21 (t, J = 7.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ (ppm): 196.8, 162.9, 152.6, 141.0, 136.8, 136.4, 133.2, 131.3,
130.4, 129.7, 129.6, 128.3, 126.0, 125.3, 123.4, 121.2; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C27H17NO2SNa 442.0878; found 442.0872.
(2-(Benzo[d]thiazol-2-yl)-5-bromo-1,3-phenylene)bis(phenylmethanone) (3na): Yellowish
o
solid (324 mg, 65%); mp: 124-125 C; IR (KBr) νmax: 3060, 2924, 1732, 1596, 1451, 1380,
1
1283, 1174, 1001, 758, 708 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 8.22 (d, J = 7.4 Hz,
2H), 7.96-7.94 (m, 2H), 7.87-7.82 (m, 3H), 7.75-7.71 (m, 3H), 7.58-7.54 (m, 3H), 7.42-7.38
(m, 1H), 7.32-7.27 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 195.1, 162.8, 162.1,
142.5, 136.3, 134.9, 134.8, 133.5, 132.9, 130.7, 129.6, 129.0, 128.9, 128.4, 126.1, 125.5,
125.3, 124.3, 124.0, 123.4, 121.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C27H16BrNO2SNa 519.9983; found 519.9978.
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General procedure for the Pd(OAc)2 catalyzed cross-dehydrogenative coupling of 1 with
arylmethanes (2) via C(sp2)-H bond activation (reaction of 1a with 2a to form to 3aa):
(Condition B):
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The magnetically stirred mixture of 2-phenylbenzo[d]thiazole (1a) (211 mg, 1.0 mmol), 2a
(531 µL, 5 mmol), Pd(OAc)2 (11.2 mg, 5 mol%) and NHPI (33 mg, 20 mol%) in PhCl (2.0
mL) was heated at 80 oC (oil bath temp) for 2.5 h (TLC) while O2 gas (cylinder outlet pressure
10 psi) was bubbled (passed) into the reaction mixture. The reaction mixture was cooled to rt
and diluted with EtOAc (50 mL), washed with brine (3 × 5 mL), dried (anh Na2SO4), filtered,
and concentrated under rotary vacuum evaporation. The crude reaction mixture was purified
by column chromatography on silica gel (60-120 mesh size) using 4% EtOAc in hexane as
eluent to afford 2-(benzo[d]thiazol-2-yl)phenyl)(phenyl)methanone 3aa (225 mg, 70%) as
yellowish solid that was identical (spectral data) with the authentic sample.
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(2-(Benzo[d]thiazol-2-yl)phenyl)(p-tolyl)methanone (3ab): Off white solid (243 mg, 74%);
mp: 103-104 oC; IR (KBr) νmax: 3066, 2922, 1670, 1592, 1578, 1515, 1486, 1452, 1433, 1314,
1
1267, 1209, 1176, 976, 817, 753, 705, 645, 620 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm):
7.82 (d, J = 8.0 Hz, 1H), 7.70-7.74 (m, 4H), 7.41 (d, J = 7.9 Hz, 1H), 7.37-7.31 (m, 3H), 7.30-
7.25 (m, 3H), 2.47 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 197.8, 165.4, 153.5, 140.9,
139.7, 137.9, 135.2, 132.6, 130.8, 129.5, 129.4, 129.4, 129.2, 128.2, 126.0, 125.1, 123.3,
121.3, 21.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H15NOSNa 352.0772; found
352.0787.4d
(2-(Benzo[d]thiazol-2-yl)phenyl)(m-tolyl)methanone (3ac): Yellowish oil (237 mg, 72%);
1
IR (neat) νmax: 2923, 1670, 1432, 1276, 1207, 967, 762, 729 cm-1; H NMR (CDCl3, 400
MHz) δ (ppm): 7.86 (d, J = 7.4 Hz, 1H), 7.74-7.69 (m, 2H), 7.57-7.50 (m, 3H), 7.46-7.44 (m,
2H), 7.30-7.27 (m, 1H), 7.24-7.18 (m, 1H), 7.13-7.07 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
(ppm): 197.8, 165.4, 153.5, 139.9, 138.0, 137.7, 135.4, 133.6, 132.2, 130.2, 130.1, 129.7,
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129.7, 128.9, 128.1, 126.8, 126.1, 125.3, 123.4, 121.4, 21.2; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C21H15NOSNa 352.0772; found 352.0761.4f
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(2-(Benzo[d]thiazol-2-yl)phenyl)(o-tolyl)methanone (3ad): White solid (240 mg, 73%); mp:
7
o
105-106 C; IR (KBr) νmax: 3058, 2925, 1664, 1593, 1500, 1456, 1378, 1254, 1160, 1122,
8
9
967, 924, 853, 754, 737, 662, 638 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.89 (d, J = 8.2
Hz, 1H), 7.87-7.84 (m, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.67-7.63 (m, 3H), 7.42 (td, J = 7.7, 1.2
Hz, 1H), 7.34-7.30 (m, 1H), 7.18-7.14 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 7.5 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 199.04, 165.7, 153.5, 141.0, 139.8, 137.6, 135.4,
132.5, 131.4, 131.2, 130.4, 130.3, 130.1, 129.9, 129.6, 126.1, 125.2, 124.9, 123.4, 121.4, 21.4;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H15NOSNa 352.0772; found 352.0784.
(2-(Benzo[d]thiazol-2-yl)phenyl)(3-chlorophenyl)methanone (3ae): Yellowish oil (227 mg,
65%); IR (neat) νmax: 3063, 2924, 1674, 1570, 1432, 1255, 1154, 967, 760 cm-1; mp: 88-89
oC; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.96 (m, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.79 (d, J =
7.6 Hz, 1H), 7.77 (t, J = 1.8 Hz, 1H), 7.70-7.60 (m, 3H), 7.57-7.55 (m, 1H), 7.42-7.37 (m,
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1H), 7.36-7.31 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H); C NMR (CDCl3, 100 MHz) δ (ppm):
196.2, 165.0, 153.4, 139.6, 139.0, 135.2, 134.4, 132.4, 132.0, 130.6, 130.5, 129.6, 129.5,
128.9, 128.9, 127.2, 126.3, 125.5, 123.4, 121.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C20H12ClNOSNa 372.0226; found 372.0225.4d
(2-(Benzo[d]thiazol-2-yl)phenyl)(4-bromophenyl)methanone (3af): Yellowish solid (216
o
mg, 74%); mp: 131-132 C; IR (KBr) νmax: 3055, 2928, 1669, 1585, 1482, 1397, 1365, 1265,
1
1068, 1010, 967, 922, 841, 752, 726, 699 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 7.97-
7.95 (m, 1H), 7.84-7.82 (m, 1H), 7.79-7.77 (m, 1H), 7.67-7.61 (m, 4H), 7.54-7.52 (m, 1H),
7.46-7.44 (m, 2H), 7.42-7.34 (m, 2H);13C NMR (CDCl3, 100 MHz) δ (ppm): 196.6, 153.4,
139.1, 136.7, 131.9, 131.7, 131.6, 130.6, 130.5, 130.5, 130.4, 129.6, 128.8, 127.8, 126.3,
125.5, 123.4, 121.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H12BrNOSNa 415.9703;
found 415.9721.4f
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(2-(Benzo[d]thiazol-2-yl)phenyl)(3-bromophenyl)methanone (3ag): Yellowish gummy
(193 mg, 66%); IR (neat) νmax: 3059, 2925, 1673, 1567, 1432, 1281, 1259, 1151, 1068, 968,
760, 728, 697, 673 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.95-7.92 (m, 2H), 7.81 (t, J =
8.3 Hz, 2H), 7.69-7.62 (m, 3H), 7.28-7.55 (m, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.42-7.31 (m,
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2H), 7.15 (t, J = 7.9 Hz, 1H); C NMR (CDCl3, 100 MHz) δ (ppm): 196.1, 165.0, 153.4,
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139.8, 138.9, 135.3, 135.2, 132.0, 131.8, 130.6, 130.5, 129.8, 129.6, 128.9, 127.6, 126.3,
125.5, 123.4, 122.5, 121.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H12BrNOSNa
415.9718; found 415.9721.
(2-(Benzo[d]thiazol-2-yl)phenyl)(2-bromophenyl)methanone (3ah): Yellowish solid (195
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mg, 67%); mp: 124-125 C; IR (KBr) νmax: 3060, 1672, 1581, 1430, 1294, 1252, 1025, 967,
929, 759, 729 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.03 (d, J = 8.2 Hz, 1H), 7.80-7.70
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(m, 3H), 7.66-7.59 (m, 2H), 7.43-7.39 (m, 2H), 7.33-7.29 (m, 2H), 7.06-6.98 (m, 2H); C
NMR (CDCl3, 100 MHz) δ (ppm): 195.9, 165.4, 153.5, 139.3, 138.9, 135.5, 134.1, 133.2,
131.8, 131.2, 131.1, 130.6, 130.3, 130.0, 126.5, 126.1, 125.3, 123.8, 121.5, 121.3; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C20H12BrNOSNa 415.9721; found 415.9708.
(2-(Benzo[d]thiazol-2-yl)phenyl)(4-iodophenyl)methanone (3ai): White solid (300 mg,
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68%); mp: 107-108 C; IR (KBr) νmax: 3060, 2924, 1671, 1580, 1456, 1431, 1390, 1276,
1261, 1151, 1055, 1007, 967, 761, 697, 669, 644 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm):
7.95 (m, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70-7.61 (m, 4H), 7.54-7.52
(m, 1H), 7.51-7.48 (m, 2H), 7.42-7.32 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 196.8,
165.0, 153.4, 139.1, 137.6, 137.3, 135.2, 131.9, 130.5, 130.4, 130.4, 129.6, 128.7, 126.3,
125.5, 123.4, 121.5, 100.6; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H12INOSNa
463.9582; found 463.9590.
(2-(Benzo[d]thiazol-2-yl)phenyl)(4-methoxyphenyl)methanone (3aj): White solid (258 mg,
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75%); mp: 128-129 C; IR (KBr) νmax: 1652, 1599, 1509, 1418, 1260, 1150, 1029, 970, 928,
764, 608 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.98 (d, J = 7.4 Hz, 1H), 7.86 (d, J = 8.1
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The Journal of Organic Chemistry
Hz, 1H), 7.82-7.77 (m, 3H), 7.65-7.58 (m, 2H), 7.52-7.50 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H),
7.32 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
(ppm): 196.2, 165.4, 163.3, 153.5, 140.1, 135.5, 132.0, 131.8, 130.7, 130.2, 129.9, 129.8,
128.6, 126.1, 125.2, 123.5, 121.4, 113.6, 55.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C21H15NO2SNa 368.0721; found 368.0733.4d
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(2-(Benzo[d]thiazol-2-yl)phenyl)(3,5-dimethylphenyl)methanone (3ak): Yellowish oil (240
mg, 70%); IR (neat) νmax: 3060, 2922, 1668, 1605, 1456, 1433, 1379, 1311, 1224, 1136, 1023,
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967, 863, 814, 763, 698, 674 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm): 7.98-7.97 (m, 1H),
7.85 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.53 (m, 1H), 7.42-
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7.38 (m, 3H), 7.33 (td, J = 7.6, 1.2 Hz, 1H); C NMR (CDCl3, 100 MHz) δ (ppm): 197.9,
165.5, 153.5, 140.1, 137.8, 137.7, 135.5, 134.5, 132.2, 130.1, 130.1, 129.7, 128.8, 127.3,
126.1, 125.2, 123.4, 121.4, 21.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H17NOSNa
366.0929; found 366.0931.4i
(2-(Benzo[d]thiazol-2-yl)phenyl)(2-bromo-3-methylphenyl)methanone (3al): Yellowish
oil (273 mg, 67%); IR (neat) νmax: 3061, 2927, 1676, 1432, 1291, 1238, 1026, 968, 761, 728,
668, 643 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.06 (d, J = 8.1 Hz, 1H), 7.81-7.76 (m,
3H), 7.67-7.62 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.5 Hz,
1H), 7.08 (d, J = 7.4 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ (ppm):
196.3, 165.8, 153.4, 139.9, 139.5, 139.3, 133.5, 132.7, 131.4, 130.9, 130.3, 130.2, 128.4,
126.2, 126.0, 125.2, 123.8, 126.6, 121.3; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C21H14BrNOSNa 429.9877; found 429.9893.
General procedure for the synthesis of starting material 2,4-diphenylpyrimidine (4g):
To the magnetically stirred mixture of acetophenone (2.5 mmol, 450 mg) and DMF-DMA
(357 mg, 3.0 mmol, 0.39 mL, 1.2 equiv) at 100 °C under N2 was added 1-methylimidazole
(MeIm) (2.5 mmol, 0.19 mL, 1 equiv) and the mixture was stirred until acetophenone was
completely consumed for 3 h; The mixture was subjected to rotary evaporation in vacuum to
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