Copper, Silver and Sodium Salt-Mediated Quaternization by Arylation: Syntheses of N-Heterocyclic Carbene Precursors and 6-H-Phenanthridine Derivatives

Article abstract of DOI:10.1002/asia.201600563

We have developed a Cu^II-, Ag^I-, and NaOTf-mediated intramolecular quaternization by arylation reactions to synthesize a variety of N-heterocyclic carbene (NHC) precursors with a benzene-fused backbone. The methodology also provides a convenient alternative route for the synthesis of 6-H-phenanthridine derivatives. A novel silver–NHC complex was prepared by treatment of Ag₂O with the free carbene, which was in situ prepared from the deprotonation of a representative quinazolinonium salt.

Full text of DOI:10.1002/asia.201600563

DOI: 10.1002/asia.201600563
Communication
Arylation
Copper, Silver and Sodium Salt-Mediated Quaternization by
Arylation: Syntheses of N-Heterocyclic Carbene Precursors and 6-
H-Phenanthridine Derivatives
Wenqi Shen,[a] Jing Li,[a] Caiyun Zhang,[a] Min Shi,[a, b] and Jun Zhang*[a]
Abstract: We have developed a CuII-, AgI-, and NaOTf-
mediated intramolecular quaternization by arylation reac-
tions to synthesize a variety of N-heterocyclic carbene
(NHC) precursors with a benzene-fused backbone. The
methodology also provides a convenient alternative route
for the synthesis of 6-H-phenanthridine derivatives. A
novel silver–NHC complex was prepared by treatment of
Ag2O with the free carbene, which was in situ prepared
from the deprotonation of a representative quinazolinoni-
um salt.
Figure 1. Selected NHCs A–D and targeted NHC E, and the method for the
preparation of the NHC precursors of known N-methyl quinazolinone NHCs.
Over the last twenty years, much attention has been paid to
the precursors of a new kind of enamino-amido carbenes D.[6]
the N-heterocyclic carbenes (NHCs) due to their widespread
and remarkable applications as ligands in organometallic catal-
ysis and as organocatalysts.[1] Among the vast majority of
NHCs, those bearing a benzene-incorporated backbone have
been developed for a broad range of use in both carbene
chemistry and catalysis. Five-membered benzimidazolylidene A
(Figure 1) has been found in many applications for organome-
tallic catalysis.[2] Six-membered 3,4-dihydroquinazolin-2-yli-
denes B reported by our group showed high efficiency in both
Rh-catalyzed arylation of carbonyl compounds and Pd-cata-
lyzed Suzuki cross-coupling reaction.[3] Recently, Bielawski,
Cꢀsar, and Lavigne et al. have developed the novel six-mem-
bered diamidocarbenes C bearing bulky N-aryl substituents,
such as mesityl (Mes) or 2,6-diisopropylphenyl (Dipp). C is
more electrophilic compared to typical NHCs, and favor the NÀ
H and CÀH bond activation, reversibly fixing CO, coupling to
isonitriles, and [2+1] cycloaddition of olefins, aldehydes, al-
kynes, and nitriles.[4,5] We have also reported a metal-catalyzed
amidiniumation of alkynyl formamidines for the synthesis of
We envisioned that incorporating a benzene ring into the ami-
docarbene backbone would provide NHC additional stability
and exhibit unprecedented electronic property, thereby show-
ing a distinct reactivity behavior. Keeping this in mind, we
design herein NHC E with a quinazolinone core bearing bulky
N-aryl substituents, such as Mes or Dipp. The N-methyl coun-
terpart of E has been reported by Ganter and co-workers,[7] but
the last quaternization step of the previous method for the
synthesis of the NHC precursors suffered from using powerful
methylation reagents, such as methyltriflate or Me3O.BF4, thus
only allowing access to those NHCs of type F with a small N-
methyl group. Placing sterically bulky N-aryl substituents on
the NHCs could render decomposition pathway of carbene un-
favorable and increase the stability of NHC-supported metal
catalysts. The synthesis of N,N’-disubstituted NHCs bearing hin-
dered aryl groups is highly desirable and remains more chal-
lenging.[1]
Aimed to construct the scaffold of E, we expected an intra-
molecular quaternization by arylation of N-substituted forma-
midines could probably be a practical method. Although pri-
mary and secondary amines can be arylated by aryl halides
using either a palladium or copper catalyst in the presence of
a base, the arylation of N-containing functional groups with no
NÀH, such as N-substituted heteroarenes and imines, remains
challenging (Scheme 1).[8] For example, quaternization by aryla-
tion of N-substituted imidazoles required a strongly electron-
deficient aryl source, such as 2,4-dinitrochlorobenzene or
aryne.[9] Recently, You, Gao et al. reported a CuII-catalyzed
direct quaternization by arylation of N-substituted imidazoles
to form imidazolium salts using either excess arylboronic acids
[a] W. Shen, J. Li, C. Zhang, Prof. Dr. M. Shi, Dr. J. Zhang
Key Laboratory for Advanced Materials and Institute of Fine Chemicals
School of Chemistry&Molecular Engineering
East China University of Science and Technology
130 Mei Long Road, Shanghai 200237 (China)
E-mail: zhangj@ecust.edu.cn
[b] Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600563.
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Table 1. Intramolecular quaternization by arylation of formamidine 1a.[a]
Entry
Reagent[equiv]
Additive
T [oC]
Yield [%][b]
1
2
3
4
5[c]
6
7
8
Cu(OTf)2 (3.0)
CuBr2 (3.0)
–
–
–
–
160
160
160
160
120
160
160
160
160
160
140
120
120
140
140
140
82
43
trace
62
trace
50
77
57
81
50
51
20
trace
32
36
Cu(OAc)2·H2O(3.0)
Cu(OTf)2 (2.0)
Cu(OTf)2 (3.0)
Cu(OTf)2 (0.1)
Cu(OTf)2 (0.1)
AgOTf (1.0)
AgOTf (0.05)
NaOTf (2.0)
NaOTf (2.0)
NaOTf (2.0)
NaOTf (2.0)
NaOTf (1.0)
NaOTf (3.0)
NaOTf (2.0)
–
AgOTf (1.0)
NaOTf (2.0)
–
9
NaOTf (2.0)
10
11
12
13[c]
14
15
16[d]
–
–
–
–
–
–
–
Scheme 1. Intramolecular arylation of amines and quaternization by aryla-
tion.
or diaryliodomium salts.[10] For a benzimidazole, the method
only allows quatermization with a less bulky phenyl group
(Scheme 1a).
67
[a] Reaction conditions: 1a (0.09 mmol), DMSO (4 mL), and 5.5 h. [b] Iso-
lated yields. [c] DMF(4 mL). [d] 12 h.
Since 2011, we have established several novel methods for
the preparation of various azolium salts as NHC precursors,
starting from functionalized formamidines.[11] Herein, we pres-
ent CuII-, AgI-, and NaOTf-mediated intramolecular quaterniza-
tion by arylation to synthesize a variety of NHC precursors with
a benzene-fused backbone (Scheme 1c). The NaOTf-mediated
such transformation represents a novel transition-metal-free
method. The methodology also provides a convenient alterna-
tive route for the synthesis of 6-H-phenanthridine derivatives,
most of which are bioactive natural alkaloids[12] and medically
relevant compounds,[13] and exhibit a diverse range of biologi-
cal and pharmaceutical activities.[14]
tion using a silver salt as additive instead of using excess
Cu(OTf)2. Gratifyingly, 2a was isolated in moderate yield in the
presence of catalytic Cu(OTf)2 and stoichiometric AgOTf
(entry 6). The observation inspired us to employ NaOTf to re-
place the transition-metal salt AgOTf. Interestingly, using cata-
lytic Cu(OTf)2 and stoichiometric NaOTf smoothly gave 2a in
77% yield (entry 7). In the absence of Cu(OTf)2, stoichiometric
AgOTf led to a decrease in yield (entry 8). Using catalytic
AgOTf and two equiv of NaOTf also afforded 2a in a good
yield of 81% (entry 9). Surprisingly, even without the activation
of transition-metal salt, NaOTf itself still worked for the trans-
formation. In the presence of two equivalents of NaOTf, 2a
can be obtained in 50% yield (entry 10). Running the reaction
at lower temperature of 1408C gave 2a in a similar yield (en-
tries 10 and 11). However, further lowering the reaction tem-
perature led to a considerable decrease in yield (entry 12).
DMSO was also proven to be a better solvent than DMF in the
NaOTf-promoted cyclization of 1a (entry 13). Either increasing
or decreasing the amount of NaOTf gave 2a in lower yields
(entries 14 and 15). Better result was achieved with a prolonged
reaction time (67% yield; entry 16, Table 1).
The copper-promoted arylation of anilines has been well es-
tablished for more than a century as the classical Ullmann cou-
pling reaction. We started our investigation by reacting excess
Cu(OTf)2 with bromophenyl-substituted formamidine 1a, pre-
pared by the acylation of N,N’-bis(2,6-diisopropylphenyl)-formi-
midamide with 2-bromobenzoic acid in the presence of dicy-
clohexylcarbodiimide (DCC) and 4-dimethylaminopyridine
(DMAP) (Table 1). Cu(OTf)2 (3 equiv) was proven to be efficient
to promote the reaction to the desired quinazolinonium salt
2a in DMSO (Table 1, entry 1). Both iodophenyl- and chloro-
phenyl-substituted formamidine led to disappointing result
(Table S1 in the Supporting Information). The structure of 2a
was unequivocally confirmed by X-ray diffraction analysis (Fig-
ure S1 in the Supporting Information). Other copper salts were
also examined, but exhibited poor reactivity or no reactivity to-
wards the process (entries 2 and 3). Reducing the amount of
Cu(OTf)2 led to a lower yield (entry 4). When using DMF instead
of DMSO as solvent only trace 2a was obtained (entry 5). Silver
salts have been used as additives in many transition-metal-cat-
alyzed reactions, in which a silver salt reacts with a transition-
metal-halide intermediate to form a catalytically more active
species.[15] Therefore, we further investigated the transforma-
Using the established methods, the generality and scope of
this new synthetic protocol was investigated (Scheme 2). Upon
the activation of either three equivalents of Cu(OTf)2 or
Cu(OTf)2(cat.)/AgOTf, quinazolinonium salts 2b–2d, pyrimidi-
nonium salt 2e, 3,4-dihydroquinazolinium salts 2 f and 2g, and
benzoimidazolium salts 2h and 2i could be prepared. Either
AgOTf/NaOTf or NaOTf can promote the quaternization by ary-
lation to prepare quinazolinonium salts 2b and 2c and pyrimi-
dinonium salt 2e; However, they both could not promote the
syntheses of 3,4-dihydroquinazolinium salts 2 f and 2g, and
benzoimidazolium salts 2h and 2i. Even using three equiva-
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Scheme 3. Syntheses of 6-H-phenanthridine derivatives.
hyde condensation. Gratifyingly, under the activation of
three equivalents of Cu(OTf)2, in the presence of mesityl ani-
line, aldehyde 10 underwent cyclization to give desired phe-
nanthridinium salt 2k in 74% yield [Eq. (2)]. Using NaOTf as
promoter led to a decrease in yield.
Scheme 2. Intramolecular quaternization by arylation of formamidines 1b–
1k.[a] Method A: Cu(OTf)2 (3.0 equiv), DMSO, 1608C, 5.5 h. Method
B: Cu(OTf)2 (0.1 equiv), AgOTf (1.0 equiv), DMSO, 1608C, 5.5 h. Method C:
AgOTf (0.05 equiv), NaOTf (2.0 equiv), DMSO, 1608C, 5.5 h. Method D: NaOTf
(2.0 equiv), DMSO, 1408C, 12 h.
lents of Cu(OTf)2, benzoimidazolium salt 2i was obtained in
a very low yield, probably due to the steric hindrance of N-aryl
substituent. Both Cu(OTf)2 and NaOTf showed reactivity in the
intramolecular quaternization by arylation to prepare phenan-
thridinium salts 2j and/or 2k. The structure of 2d was con-
firmed by X-ray crystallography (Figure S2 in the see Support-
ing Information).
With the novel quinazolinonium salts in hand, we investigat-
ed the reactivity of their corresponding NHCs towards sulfur. In
practice, the representative salt 2b, was selected as the start-
ing material. The free carbene, which was in situ prepared
from the deprotonation of 2b by KN(SiMe3)2 (KHMDS), was
treated with S8, affording the desired thione 11, the structure
of which has been confirmed by NMR and HRMS analyses
[Eq. (3)]. The 13C NMR signal for C=S appears at d=175.2 ppm
for 11. The ability of the new NHC to ligate transition-metal
fragment was also evaluated. Using a classic method, silver–
NHC complex 12 was isolated, from the reaction between qui-
nazolinonium salt 2a and Ag2O, as an air stable white solid
[Eq. (4)]. Both mass and NMR spectra confirmed the formation
of the bisNHC silver complex, in which HRMS evidence indi-
cates that one silver atom is associated with two quinazoli-
none rings in 12.
We also applied our novel methodology to the synthesis of
natural alkaloid trisphaeridine 6-H-phenanthridine deriva-
tives.[16] NaOTf was proven to be a better promoter than
Cu(OTf)2 in the cyclization of imine 3 to afford phenanthridini-
um salt 4, which is a precursor for the synthesis of alkaloids, bi-
colorine (6) and N-methyl crinasiadine (7) (Scheme 3). Typically,
bicolorine is prepared by the N-methylation of trisphaeridine.
Our methodology provides a more convenient route for the
preparation of bicolorine. Our method was also successfully
used for the direct synthesis of natural alkaloid trisphaeridine 9
in 40% yield [Eq. (1)].
We preliminarily investigated the practical synthesis of phe-
nanthridinium salts directly starting from aldehydes instead of
using imines, which are typically prepared by the amine/alde-
In conclusion, we presented the CuII- and AgI-mediated intra-
molecular quaternization by arylation to synthesize a variety of
NHC precursors with a benzene-fused backbone. The transfor-
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a novel transition-metal-free method. The methodology also
provides a convenient alternative route for the synthesis of
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a representative quinazolinonium salt.
Acknowledgements
Financial support from Shanghai Pujiang Talent Program
(11J1402500) and the National Natural Science Foundation of
China (21171056) is greatly acknowledged.
Keywords: copper · nitrogen heterocycles · phenanthridines ·
silver · sodium
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Manuscript received: April 24, 2016
Accepted Article published: May 23, 2016
Final Article published: && &&, 0000
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COMMUNICATION
Arylation
Wenqi Shen, Jing Li, Caiyun Zhang,
Min Shi, Jun Zhang*
CuII-, AgI-, and NaOTf-mediated intra-
molecular quaternization by arylation
reactions to synthesize a variety of N-
heterocyclic carbene (NHC) precursors
with a benzene-fused backbone has
been developed (see scheme). The
methodology also provides a convenient
alternative route for the synthesis of 6-
H-phenanthridine derivatives.
&& – &&
Copper, Silver and Sodium Salt-
Mediated Quaternization by Arylation:
Syntheses of N-Heterocyclic Carbene
Precursors and 6-H-Phenanthridine
Derivatives
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