Vinylene carbonate: Beyond the ethyne surrogate in rhodium-catalyzed annulation with amidines toward 4-methylquinazolines

Article abstract of DOI:10.1039/d1cc00882j

In this paper, we developed a rhodium-catalyzed annulation of vinylene carbonate with amidines, leading to 4-methylquinazolines with moderate to excellent yields. This procedure proceeded by sequentialortho-acylation and annulation, where vinylene carbonate served as the acetylation reagent rather than the ethyne surrogate.

Full text of DOI:10.1039/d1cc00882j

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Vinylene carbonate: beyond the ethyne surrogate
in rhodium-catalyzed annulation with amidines
toward 4-methylquinazolines†
Cite this: Chem. Commun., 2021,
57, 3929
Received 16th February 2021,
Accepted 6th March 2021
Chang Wang, Xiaodong Fan, Fan Chen, Peng-Cheng Qian* and Jiang Cheng
*
DOI: 10.1039/d1cc00882j
rsc.li/chemcomm
In this paper, we developed a rhodium-catalyzed annulation of Scheme 1). In the aforementioned works, vinylene carbonate
vinylene carbonate with amidines, leading to 4-methylquinazolines takes part in a formal [4+2] annulation.
with moderate to excellent yields. This procedure proceeded by sequen-
In this work, we developed a rhodium-catalyzed annulation of
tial ortho-acylation and annulation, where vinylene carbonate served as amidine with vinylene carbonate, leading to 4-methylquinazolines
the acetylation reagent rather than the ethyne surrogate.
with moderate to excellent yields, where vinylene carbonate served
as the acylation reagent rather than an acetylene surrogate,
Quinazolines are a class of fused heterocycles with special proceeding with a formal [5+1] annulation (eqn (4), Scheme 1).
biological activity which are widely present in natural Herein, we wish to report our study on it.
products.1 In addition, they have attracted widespread
We initiated our investigation by exploring the reaction of
attention for their excellent medicinal properties,2 serving as amidine 1a (0.1 mmol) and vinylene carbonate 2a (0.3 mmol)
antitumor,3 antiviral,4 antituberculosis5 and antineural6 in THF under N2 atmosphere at 80 1C for 12 h (Table 1).
reagents (Scheme 1). As such, many excellent works on the Disappointingly, [RuCl2(p-cymene)2]2, [Cp*Co(CO)I2] and
construction of quinazoline frameworks have been reported,7 Rh2(OAc)4 resulted in no reaction (entries 1–3). To our delight,
which mainly start with ortho-difunctionalized substrates, such the desired product 3a was isolated with a 9% yield in the
as 2-aminoacetophenone,8 2-aminobenzylamine,9 and 2-bromo- presence of [Cp*RhCl2]2 (5 mol%) and Cu(OAc)2 (3 equiv., entry
benzylamine.10 However, most of them require harsh reaction 4). Afterwards, among the additives tested, AgOAc (20%) was
conditions, including the presence of strong acids and bases. superior to Ag2CO3 (17%), AgSbF6 (12%) and AgI (o5%, entries
Moreover, in the case of achieving products with complexity and 5–8). The solvent also had an effect on the reaction. DCM (33%)
diversity, it is difficult to achieve poly-substituted ortho- was superior to acetone (27%), THF (20%) and toluene (14%,
difunctionalized substrates. Therefore, the development of entry 8). The reaction efficiency was further improved by
practical and facile synthetic methods starting from mono- adding acids or bases as co-additives (30–64%, 1 equiv., entries
functionalized substrates remains an urgent goal for organic 9–13) and PivOH was the best (64%, entry 13). Importantly, in
chemists.
the presence of both PivOH (1 equiv.) and NaIO4 (0.5 equiv.),
Vinylene carbonate is known as a novel oxidizing acetylene the yield further increased to 72% (entry 14).
or ethynol surrogate in annulation leading to new cyclic frame-
With the optimized conditions in hand, the range of
works. Tanaka et al. report excellent work on the annulation of amidines with aryl substituents on the amino was studied, as
1,6- and 1,7-diynes with vinylene carbonate, where the vinylene shown in Fig. 1. Importantly, various substrates possessing
carbonate serves as an ethynol surrogate (eqn (1), Scheme 1).11 substituents at the para- (3c, 39%; 3d, 51%; 3e, 67%; 3f, 64%;
Afterward, Miura et al.12 independently develop the application 3g, 59%; 3h, 75%), meta- (3ah, 56%), and ortho- (3j, 77%)
of vinylene carbonate as an acetylene surrogate in the positions of the phenyl ring all reacted well under the standard
synthesis of isocoumarins, isoquinolinones and pyridinones. procedures. As expected, some functional groups, such as
Next, Zhang et al.13 also report similar work (eqn (2) and (3), methyl (3d, 51%), methoxy (3c, 39%), halogen (3e, 3f, 3h, 3l
and 3j, 56–77%) and tert-butyl (3g, 59%) were compatible under
the reaction conditions with good yields. The naphthalene
analogue was a reaction partner, providing 3k with a 33% yield.
Institute of New Materials & Industry Technology, College of Chemistry & Materials
Engineering, Wenzhou University, Wenzhou, 325035, P. R. China.
Next, the range of amidines with substituents attached to
E-mail: jiangcheng@cczu.edu.cn, jiangcheng@wzu.edu.cn, qpc@wzu.edu.cn
the CQNH group was studied, as shown in Fig. 2. Generally, all
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc00882j
substrates reacted well to afford the corresponding products
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Table 1 Selected results of the screening for the optimized reaction
conditionsa
Entry Catalyst
Additives
Cu(OAc)2
Solvent Yieldb (%)
1
[RuCl2(p-
THF
n.r.
cymene)2]2
[Cp*Co(CO)I2]
Rh2(OAc)4
2
3
4
5
6
7
8
9
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
AgSbF6
AgI
THF
THF
THF
THE
THF
THF
THF
DCM 36
DCM 30
DCM 48
DCM 42
DCM 64
DCM 72
n.r.
n.r.
9
17
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
12
o5
AgOAc
20, 33c, 27d, 14e
AgOAc, LiOH
AgOAc, KIO4
AgOAc, NaIO4
AgOAc, HOAc
AgOAc, PivOH
AgOAc, PivOH
NaIO4
a
Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), [Cp*RhCl2]2
(5 mol%), indicated additives: Ag or Cu additive (3 equiv.), acid or base
additive (1 equiv.), NaIO4 (0.5 equiv.), solvent (2 mL), 80 1C, under N2 for
b
c
d
e
12 h Isolated yields. DCM. Acetone. Toluene.
Scheme 1 TM-catalyzed annulation of vinylene carbonate and
representative 4-methylquinazoline compounds.
with yields of 41–78%. The substrates possessing chloro
(3n, 41%) and trifluoromethyl (3o, 41%) groups in the phenyl
worked. In addition, substrates possessing both electron-donating
(3m, 72%; 3p, 68%; 3q, 61%) and electron-withdrawing (3n, 41%;
3o, 41%) groups were also suitable reaction partners under the
standard procedure. Notably, the procedure tolerated functional
groups such as cyclopropanyl (3r, 41%), 2-furanyl (3s, 78%),
2-thiophenyl (3t, 64%), cyclohexanyl (3u, 65%) and 1-naphthalenyl
(3v, 53%). Meanwhile, the tert-butyl analogue worked well,
providing the product 3w with a 75% yield. Disappointingly,
the methyl analogue failed to work under the standard
conditions (3l, trace).
To further increase the practicality of the reaction, this
procedure was applied to acquire polysubstituted quinazoline
(3x, 51%; 3y, 71%, eqn (1) and (2), Scheme 2). In a 1 mmol scale
reaction, 3a was isolated with an acceptable 64% yield. Fig. 1 The range of amidines with aryl substituents on the amino.
Reaction conditions:
1 (0.10 mmol), 2a (0.30 mmol), [Cp*RhCl2]2
Moreover, further functionalization was studied. 4-Aceoxymethyl
2-phenyl quinazoline 4 and 2,6-diphenyl quinazoline 5 were
isolated with yields of 53% and 91%, respectively (eqn (3) and
(4), Scheme 2).14
(5 mol%), AgOAc (3 equiv.), PivOH (1 equiv.), NaIO4 (0.5 equiv.), 80 1C,
DCM (2.0 mL), under N2 for 12 h, with isolated yields.
The intra- and inter-molecular KIEs were found to be 1.9 and
According to the literature,9,10 a tentative mechanism was
2.0, respectively (eqn (1) and (2), Scheme 3). Thus, the cleavage proposed (Scheme 4). Initially, the coordination of Rh(III) and
of the ortho-C–H bond may be the rate determining step during amidine produces a rhodacycle complex A, which takes part in
this transformation.
coordination and the insertion of a Rh–C bond into vinyl,
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Scheme 3 KIEs study.
leading to rhodacycle B. The rhodacycle B undergoes b-H
elimination to afford intermediate C and HRhCp* species.
Next, the insertion of HRhCp* in intermediate C, followed by
b-O elimination, results in the intermediate E. Then, inter-
mediate E undergoes protonolysis to afford intermediate F,
along with the regenerated catalyst and extrusion of CO2.
Finally, the desired product 3a was afforded through the
intramolecular condensation of intermediate G.
In conclusion, we have developed a rhodium-catalyzed
annulation between amidine and vinylene carbonate, leading
to 4-methylquinazoline with moderate to good yields.
Importantly, during this procedure, vinylene carbonate served
as the acylation reagent rather than the ethyne surrogate.
As such, this presents a facile and mild pathway leading to
complex and diverse 4-methylquinazolines.
Fig. 2 The substrate range of amidines with substituents attached to the
CQNH groups. Reaction conditions: 1 (0.10 mmol), 2a (0.30 mmol),
[Cp*RhCl2]2 (5 mol%), AgOAc (3 equiv.), PivOH (1 equiv.), NaIO4 (0.5 equiv.),
80 1C, DCM (2.0 mL), under N2 for 12 h, with isolated yields.
Scheme 2 Synthesis of polysubstituted 4-methylquinazoline and further
functionalization.
Scheme 4 A tentative mechanism.
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