Palladium(II)/N-heterocyclic carbene-catalyzed direct C-H acylation of heteroarenes with N-acylsaccharins

Article abstract of DOI:10.1021/acs.orglett.7b02877

N-Acylsaccharin represents a facile acyl group transfer agent to heteroarenes in the presence of Pd(II)/NHC complexes appended with a pyrene unit. Catalytic acylation of heteroarenes was enhanced by the noncovalent interaction between the pyrene unit and

Full text of DOI:10.1021/acs.orglett.7b02877

Letter
pubs.acs.org/OrgLett
Palladium(II)/N‑Heterocyclic Carbene-Catalyzed Direct C−H Acylation
of Heteroarenes with N‑Acylsaccharins
Shanmugam Karthik and Thirumanavelan Gandhi*
Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, Tamil Nadu 632014, India
S
* Supporting Information
ABSTRACT: N-Acylsaccharin represents a facile acyl group
transfer agent to heteroarenes in the presence of Pd(II)/NHC
complexes appended with a pyrene unit. Catalytic acylation of
heteroarenes was enhanced by the noncovalent interaction
between the pyrene unit and substrates. High functional group
tolerance, broad substrate scope, and moderate to good yields of
2-acylated azoles are added features of this method.
zoles, especially 2-substituted azoles (aryl and acyl), are an
important structural motif prevalent in biological systems,
demanding prefunctionalized substrates.11 Amides could be an
excellent choice as an electrophile as they are ubiquitous in
Nature, which governs the biological, materials, and structural
properties.12 However, using amides as a functional group
transfer agent is impaired due to the resonance stabilization,
resulting from the orbital overlap between the nitrogen lone pair
(nN → π*CO) and the antibonding orbital of the carbonyl
group.12a Recently, a trendsetting contribution by Garg et al.
unveiled the utility of the stable and rigid amides as electrophilic
coupling partners with the intervention of transition metal
catalysts.13 Strategically, the C(O)−N bond is activated by using
twisted amides, which interrupt the resonance stabilization and
pave the way for oxidative addition of transition-metal catalysts
and subsequent elusive organic transformations.14
A
pharmaceuticals, agriculture, and functional materials.1,2 Of late,
transition-metal-catalyzed organic transformations have emerged
as one of the attractive and practical methods for forging C−C
bonds which lead the way for the direct C-2 functionalization of
azoles.3 Besides the conventional synthesis4 of 2-substituted
azoles, other recent methods include the palladium-catalyzed
carbonylative cross-coupling reaction (Figure 1a),5 decarbox-
Szostak and co-workers efficiently exploited the amides
bestowed with geometrical distortion in many of the catalytic
cross-coupling reactions.15 In addition, amides proved to be a
good acylating agent by reacting with aryl boronic acid,13b,15a,16
organozinc halides,17 alcohols,13a and cyclic and acyclic amines.18
N-Functionalized saccharin, in particular, acted as an excellent
functional group transfer agent (resonance energy 2.0 kcal/
mol)19 for acylation,20 aryloxycarbonylation,21 formylation,22
and thiolation.23 Accordingly, N-functionalized saccharin has
gained impetus as an electrophilic transfer agent owing to its
interesting traits: it is economical, easily accessible, and shelf-
stable. Its geometric distortion enhanced the activation of the
C(O)−N bond. Recently, our group has developed a method
comprising tailor-made Pd−NHC catalyst bearing naphthali-
mide and bis-naphthalimide wingtip substituents on an NHC
ligand promoting regioselective heteroannulation of tertiary
propargyl alcohols and o-haloanilines to form 2-alkenylindoles.24
Herein, we report a general and convenient synthesis of 2-
acylazoles catalyzed by air-stable Pd−NHC complexes (attached
with pyrene wingtip substituents) by the reaction of azoles with
N-acylsaccharin via challenging amide C(O)−N bond activation.
Figure 1. Synthesis of 2-acylated azoles: previous (a−d) and (e) this
work.
ylative cross-coupling approach (Pd (Figure 1b)6 Ni7 and Co8
catalyzed), cycloetherification method (Figure 1c),9 and C−H
functionalization via isocyanide insertion (Figure 1d).10 Never-
theless, most of the reported methodologies suffer from certain
drawbacks such as uptake of CO, harsh reaction conditions,
longer reaction time, assembly of multicomponents, and
Received: September 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Initially, we set out to explore the effective Pd catalyst.
Headway was made by designing and synthesizing a series of
pyrene-based Pd−PEPPSI catalysts D1−D5 with wingtip
substituents such as ar-alkyl and alkyl groups (Figure 2).
Table 1. Optimization of the Reaction Conditions
b
entry
base
catalyst
additive
solvent yield (%)
THF
1
K2CO3
K2CO3
Na2CO3
NaOt-Bu
KOt-Bu
Et3N
2
Pd(OAc)2/PPh3
THF
15
3
Pd(OAc)2/PPh3
THF
4
Pd(OAc)2/PPh3
dioxane
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
CHCl3
DMF
5
Pd(OAc)2/PPh3
6
Pd(OAc)2/PPh3
20
25
30
20
15
35
55
62
78
7
Et3N
Pd(OAc)2/PPh3
TBAB
8
Et3N
Pd(OAc)2/PCy3
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
9
Et3N
Pd(OAc)2/XPhos
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
DBU
Et3N
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Et3N
Pd(OAc)2/IPr
Et3N
Pd(OAc)2/C1
Figure 2. Structures of carbene ligands and synthesized pyrene based
Pd−NHC catalysts.
Et3N
Et3N
D1
D1
D1
D1
D1
D1
D1
D1
D1
D2
D3
D4
D5
Et3N
Pyrene-substituted azolium salts C1−C5 were prepared by
treating the 1-(pyren-1-yl)-1H-imidazole with various ar-alkyl/
alkyl halides. Subsequently, palladation of C1−C5 with PdCl2
furnished D1−D5 complexes which were characterized by
multinuclear NMR and HRMS (see the Supporting Information
(SI)). The molecular structure of D1 was determined by X-ray
crystallography, and the Pd−Ccarbene distance was found to be
1.973(9) Å (see the SI). The catalytic efficacies of D1−D5 were
examined in acylation of heteroarenes by direct C−H bond
functionalization reaction. We commenced our investigation by
choosing benzoxazole 1a as a coupling partner and N-
benzoylsaccharin 2a as an electrophilic source for the benzoyl
group to form 2-benzoylated benzoxazole 3aa in the presence of
a well-examined palladium catalyst system (Pd(OAc)2/PPh3)
and K2CO3 as a base in THF at 65 °C for 16 h (Table 1).
Delightfully, the desired product 3aa was observed, but in low
yield (15%). Predictably, 3aa was not observed in the absence of
palladium salts (entries 1−2). To improve the yield of 3aa, we
screened phosphine ligands (PCy3 and XPhos), bases (Na2CO3,
NaO-t-Bu, KO-t-Bu, Et3N, and DBU), additives (TBAB and
DMAP), and solvents (THF, 1,4-dioxane, and MeCN) (entries
3−10). Combination of Et3N, DMAP, and MeCN improved the
yield of the acylation reaction to 35% (entry 11). When IPr was
employed in lieu of the phosphine system, it gave 55% yield with
Et3N as base and DMAP as an additive in MeCN at 65 °C for 16
h (entry 12). This result prompted us to evaluate our synthesized
Pd−NHCs D1−D5. Meanwhile, use of the ligand C1 with
Pd(OAc)2 under the same conditions improved the yield of 3aa
to 62% (entry 13). Interestingly, D1 proved to be the best
catalyst for acylation of heteroarenes (78%) (entry 14). No
product was observed in the case of nonpolar solvents such as
toluene and chloroform, whereas polar aprotic solvents were
found to be effective (in the order of MeCN > DMF > DMSO)
(entries 15−18). Changes in the time, temperature, and catalytic
loading from 16 to 24 h (entry 19), 65−85 °C (entries 20 and
21), and 5−2.5 mol % (entry 22), respectively, deters the yield of
3aa. Consistently, D2−D5 (entries 23−26) was outperformed
by D1 in the acylation of heteroarenes.
Et3N
38
Et3N
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
c
Et3N
60
d
Et3N
72
e
Et3N
70
66
f
Et3N
Et3N
55
65
69
60
Et3N
Et3N
Et3N
a
1a (1.0 equiv), 2a (1.1 equiv), base (1.5 equiv), catalyst (5 mol %),
additive (0.1 equiv), solvent (0.1 M), 65 °C, 16 h. Entries 1−10:
b
ligand (10 mol %). Entries 11 and 12: ligand (6 mol %). Percentage
c
d
e
f
of yields as isolated. For 24 h. 75 °C. 85 °C. 2.5 mol % of D1. IPr:
[1,3-bis(2,6-diisopropyl phenyl)-1H-imidazol-3-ium] chloride, C1: [3-
benzyl-1-(pyren-1-yl)-1H-imidazol-3-ium] bromide, TBAB: tetrabuty-
lammonium bromide, DMAP: 4-(dimethylamino)pyridine.
could be synthesized (Scheme 1). Reaction of saccharin with N-
acyl moieties bearing electron-donating substituents 3aa−ad
proceeds smoothly as compared to electron-withdrawing 3ae−
al. Interestingly, 2-acylation of azoles was extended to thiophenyl
3am and 2-naphthyl derivatives 3an. Substituents such as OMe,
OEt, F, Cl, Br, CN, and NO2 were well tolerated under the
reaction conditions. Functional groups such as −CN25 and
−NO226 known for its directing effect did not further participate
in the C−H activation process.
Encouraged by this finding, we further examined the substrate
scope of azoles. Both electron-donating 3ba−fa and electron-
withdrawing 3ga substituents on azoles are compatible with the
reaction conditions, resulting in moderate yields. Gratifyingly,
this optimized protocol of acylation could be successfully
employed to N-methylbenzimidazoles 3ha−ja and benzothia-
zoles 3ka−ma. However, longer reaction time and increase in
catalyst loading is required to furnish the desired products
(Scheme 2). Inspired by the work of Peris et al.27 and our own
recent report,24 we envisioned the role of pyrene wingtip
substituents on Pd−NHCs, which could promote the acylation
of azoles. This anomalous enhancement in the catalytic reaction
could be attributed to noncovalent interaction between (π−π
Having established the new catalytic system, substrate scope
for acylation was examined and a variety of 2-acylated azoles
B
DOI: 10.1021/acs.orglett.7b02877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
stacking) the appended pyrene moiety and substrates. To
corroborate the aforementioned concept, we have introduced π-
stacking additives, namely phenanthrene and pyrene, to the
acylation reaction and followed the reaction by GC (see the SI).
In addition, to ascertain the presence of the π−π interactions
between pyrene with D1, UV−vis absorption studies were
performed in chloroform at room temperature. Notably, an
increase in the absorption of pyrene was observed with an
increment in concentration of D1, which supports the formation
of donor−acceptor complex (D−A).28 To substantiate the
higher reactivity of N-benzoylsaccharin, 1a was reacted with 4
and 5 under the optimized reaction conditions. Understandably,
both proved to be poor electrophilic acyl transfer reagents
(Scheme 3a,b). Furthermore, this reaction was found to be
Scheme 1. Scope of Amides in Pd−NHC-Catalyzed Direct C−
a,b
H Acylation with Benzoxazole
Scheme 3. Control Experiments for Pd−NHC-Catalyzed
Direct C−H Acylation
a
1a (1 equiv), 2a (1.1 equiv) Et3N (1.5 equiv), D1 (5 mol %), DMAP
b
(0.1 equiv), MeCN (0.1 M), 65 °C, 16 h. Isolated yields.
Scheme 2. Scope of Azoles in Pd−NHC Catalyzed Direct C−
a,b
H Acylation
scalable under optimized conditions (Scheme 3c). Applicability
of this protocol was realized by employing 2-acylated azoles as a
valuable precursor for the synthesis of important organic
derivatives (Scheme 4). On the basis of previous literature
Scheme 4. Synthetic Diversification of 2-Acylated Derivatives
reports,29 we proposed the plausible mechanism of Pd−NHC-
catalyzed acylation of azoles. Acyl palladium complex B was
generated by oxidative addition of N-acylsaccharin to an
activated palladium complex A. The base removes the acidic
proton from 1a and generates the intermediate C. Eventually, C
undergoes reductive elimination to form the desired product 3aa
(Scheme 5).
In summary, an efficient method for the acylation of
heteroarenes by direct C−H bond functionalization using
pyrene-based Pd−NHC catalyst D1−D5 has been developed.
Various benzoxazoles, a few examples of benzothiazole, and N-
methylbenzimidazole were selectively converted into the
corresponding 2-acylated products in high selectivity with
synthetically useful yield. Functional group tolerance and
broad substrate scope provide an attractive approach to access
a
1a (1 equiv), 2a (1.1 equiv), Et3N (1.5 equiv), D1 (5 mol %), DMAP
b
c
(0.1 equiv), MeCN (0.1 M), 65 °C, 16 h. Yields are isolated. D1 (7.5
mol %), 24 h. D1 (10 mol %), 36 h.
d
C
DOI: 10.1021/acs.orglett.7b02877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02877.
■
S
Detailed experimental procedures and spectral data for all
compounds (PDF)
Crystallographic data for compound D1 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: velan.g@vit.ac.in.
ORCID
Thirumanavelan Gandhi: 0000-0002-0461-5155
Notes
(20) Cui, M.; Wu, H.; Jian, J.; Wang, H.; Liu, C.; Daniel, S.; Zeng, Z.
Chem. Commun. 2016, 52, 12076.
The authors declare no competing financial interest.
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2015, 51, 12574.
(23) Xu, C.; Ma, B.; Shen, Q. Angew. Chem., Int. Ed. 2014, 53, 9316.
(24) Panyam, P. K. R.; Gandhi, T. Adv. Synth. Catal. 2017, 359, 1144.
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4533. (b) Dutta, U.; Modak, A.; Bhaskararao, B.; Bera, M.; Bag, S.;
Mondal, A.; Lupton, D. W.; Sunoj, R. B.; Maiti, D. ACS Catal. 2017, 7,
3162.
ACKNOWLEDGMENTS
■
This work is supported by the CSIR, India [01(2815)/14/EMR-
II], and Seed Grant, VIT University, Vellore. S.K. acknowledges
UGC, India, for JRF [no. F.2-4/2011(SA-I) dated 22 July 2014].
We thank VIT-SIF and IITM-SAIF for instrument facilities. We
thank Dr. C. M. Nagaraja at IIT Ropar for assistance with the
single-crystal XRD.
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Org. Lett. XXXX, XXX, XXX−XXX