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Ag2CO3/TFA-Catalyzed Intramolecular Annulation Approach to Imidazo[1,2-

c][1,3]oxazin-5-one Derivatives

Article  in  Organic & Biomolecular Chemistry · February 2022

DOI: 10.1039/D1OB02352G

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DOI: 10.1039/D1OB02352G

Organic & Biomolecular Chemistry Accepted Manuscript

ARTICLE

Ag2CO3/TFA-Catalyzed Intramolecular Annulation Approach to

Imidazo[1,2-c][1,3]oxazin-5-one Derivatives
Received 00th January 20xx,
Published on 21 January 2022. Downloaded by UNIVERSITE DE TOURS on 1/30/2022 8:54:27 PM.

Accepted 00th January 20xx Abdelkarim El Qami,a, b Badr Jismy,*a Mohamed Akssira,b Johan Jacquemin,a Abdellatif Tikad*c and
Mohamed Abarbri*a
DOI: 10.1039/x0xx00000x

A series of 2,7-disubstituted 3-methylimidazo[1,2-c][1,3]oxazin-5-one were synthesized in good yields via Ag2CO3/TFA-

mediated an intramolecular annulation of N-Boc-2-alkynyl-4-bromo(alkynyl)-5-methylimidazoles. This methodology was
carried out in the presence of a catalytic amount of silver carbonate and trifluoroacetic acid in dichloroethane at 60 °C. In
all experiments, only the six-membered ring product was obtained since the possible five-membered compound was not
observed, proving the highly regioselectivity of this approach. A complementary computational study was performed in
order to rationalize the mechanism of 6-endo-dig heterocycles formation. In addition, 2-bromo-3-methyl-7-
phenylimidazo[1,2-c][1,3]oxazin-5-one was used as a building block to synthesize a small library of new 2-substituted
imidazo[1,2-c][1,3]oxazin-5-one derivatives through Suzuki, Sonogashira and Heck cross coupling reactions.

Introduction endo-dig cyclizations (Figure 1b). The third method used to promote
the lactonisation is carried out in the presence of an electrophile
During the last two decades, the intramolecular annulation of 2-
such as ICl, NIS, I2, Br2, p-NO2PhCl, PhSeCl…etc; giving access to
alkynylbenzoates, via activation of carbon-carbon triple bond, has
C3,C4-difunctionalized isochromenones (Figure 1c).38–44
emerged as a powerful tool and an effective process for the
synthesis of isochromenone frameworks. These heterocycles Methods promoted intramolecular cyclizations of 2-alkynylbenzoates:
represent an important class of natural lactones having a wide (a) Acid catalysis,12,13,15-21 (b) Transition metal-catalysis,14,22-37
(c) E+ sources38-44f
range of biological and pharmacological activities.1–11 Several (a) Brnsted acids
O O
natural isocoumarins have been synthesized involving the TFA, PTSA, etc.
O
OR1
regioselective 6-endo-dig cyclization, as a key step, in their total (b) Lewis acids O + O
Pd, Au, Ag, etc.
syntheses, such as Thunberginol A,12 Scoparine A and B,13 (-)- R2
R2
R2
R1 = alkyl (c) E+ sources E E
Citreoisocoumarin, (-)-Citreoisocoumarinol, (-)-12-epi-
R2 = alkyl, aryl E = Cl, Br, I, SR3
Citreoisocoumarinol and (-)-Mucorisocoumarins A and B.14 Metal-catalyzed cyclization of Alkynyl O-alkyl(benzyl)carbamates :
Synthetically, the asymmetrical activation of the Csp-Csp bond of 2- Ph3PAuCl (6 mo%) O
Boc R
alkynylbenzoates to trigger intramolecular cyclization has been [d]45 AgNTf2 (18 mo%) BnO
N O
N
BnO DCM, rt, 1 h
accomplished by three main methods. The first one was performed 11 examples
R = H, alkyl, aryl R
using a catalytic amount of Brønsted acid such as TFA,13,15,16 PTSA17– 14-93%
19 or TfOH12,20,21 leading to the formation of 5- or 6-membered Ph3PAuCl (3 mo%)
[e]46 Cu(OTf)2 (15 mol%)
N
lactones (Figure 1a). The second method involves the transition- N Toluene, reflux, 1 h
Cbz R R = C4H9, 83% O O R
metal catalysts including Au,14,22–24 Ag,25–27 Pt,28,29 In,30 B,31,32 Cu,33– R = Ph, 75%
35 and Fe36,37 providing a competition between 5-exo-dig and 6-
[f]47 R HAuCl4 (5 mol%)
N N R
EtOH, rt, 1-34 h
Boc O
17 examples
R = alkyl, aryl O
52-90%
N
N
a. Laboratoire de Physico-Chimie des Matériaux et des Electrolytes pour l’Energie [g]50 ZnCl2 (1.5 equiv.)
R
N R
(PCM2E), EA 6299. Université de Tours, Faculté des Sciences et Techniques. N DCM, 40 °C, 3 h
Boc O
Avenue Monge Faculté des Sciences, Parc de Grandmont, 37200 Tours, France. 15 examples O
E-mail: mohamed.abarbri@univ-tours.fr. R = alkyl only 30-85%
b. Address here Laboratoire de Chimie Physique et de Chimie Bioorganique, URAC
O
Boc
N [Ag]
22. Université Hassan II de Casablanca, Faculté des Sciences et Techniques de [h] This work R2 N O
R1
Mohammedia. B.P. 146, 28800 Mohammedia, Morocco. N conditions N
c. Laboratoire de Chimie Moléculaire et Substances Naturelles. Université Moulay
R1 R2
1 2
Ismail, Faculté des Sciences. B.P. 11201, Zitoune, Meknès, Morocco. 1 R2 = Br, alkynyl
R = alkyl, aryl
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any Figure 1. Known procedures for cyclization of 2-alkynylbenzoates
supplementary information available should be included here]. See
and alkynyl O-alkylcarbamates.
DOI: 10.1039/x0xx00000x

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ARTICLE Journal Name

Despite all results reported using the above-mentioned Figure 2. Some examples of Bioactive compounds containing
View Article Online
methods to activate the triple bond at the ortho position of imidazo[1,2-c][1,3]oxazin-5-one skeleton and derivatives.
DOI: 10.1039/D1OB02352G

the carboalkoxy group, their extension to alkynyl O-tert-

butylcarbamates, as starting materials, remains very

Organic & Biomolecular Chemistry Accepted Manuscript

It should be noted that imidazo[1,2-c][1,3]oxazin-5-one derivatives
complicated.
are an important subclass of fused heterocycles due to their wide
In general, when a tert-butoxycarbonyl is attached to a nitrogen
range of pharmacological and biological properties, including
atom, its reactivity under harsh conditions is limited to undergo an
fungicidal (Figure 2a),51 BRD4-inhibitory and anti-proliferation
intramolecular cyclization with alkyne because of the cleavage of C-
(Figure 2c),52 Cytotoxic (Figure 2d),53 CDK2/cyclin E (Figure 2e),54
N bond. For this reason, we decided to develop new mild conditions
and mGlu5 PAM activity (Figure 2f).55 In addition, imidazo[1,2-
to boost the reactivity of this triple bond and induce intramolecular
c][1,3]oxazin-5-one derivatives have been reported recently as
cyclization with tert-butoxycarbonyl to construct new polycyclic
recognition sites for detection of phosgene (highly toxic gas) in the
heterocycles without the deprotection of the Boc group as a side
Published on 21 January 2022. Downloaded by UNIVERSITE DE TOURS on 1/30/2022 8:54:27 PM.

solution and gas phases (Figure 2b).56

reaction. Since 2007, gold catalysis has been described as a new
mild synthetic alternative to activate alkynyl O-tert-
butylcarbamates having N-benzyloxy group, providing selectively
Results and discussion
the 6-endo-dig cyclized products (Figure 1d).45 However, this
In order to prepare a library of new imidazo[1,2-c][1,3]oxazin-5-one
strategy has been scarcely explored and only reserved to specific
heterocycles, N-Boc-4-bromo-5-methyl-2-phenylethynylimidazole
substrates such as N-Boc-6-alkynyl-3,4-dihydro-2H-pyridine46
1a was studied as a model and subjected to some annulation
(Figure 1e) and N-Boc-2-alkynylindole47 derivatives (Figure 1f).
process conditions which were already described in the
Recently, new benzimidazoxazinone derivatives were synthesized
literature.25,37,46,49,50,57–64 Compound 1a, which is a suitable
using ZnCl2-promoted deprotective heterocyclization of N-Boc-2-
substrate to undergo intramolecular annulation, was prepared
alkynylbenzimidazoles (Figure 1g).50 Considering the importance of
following our recent procedure involving regioselective Sonogashira
developing efficient catalytic approaches for the synthesis of new
cross coupling reaction of N-Boc-2,5-dibromo-4-methylimidazole.48
heterocycles, we report herein a silver-catalyzed intramolecular
Initially, the zinc catalyst (ZnCl2) was used in dichloromethane at
oxacyclization of N-Boc-2-alkynyl-4-bromo(alkynyl)-5-
40 °C but it was found to be totally inert, since the starting material
methylimidazole 1 to form new 3-methylimidazo[1,2-c][1,3]oxazin-
was completely recovered after 48 hours (Table 1, entry 1). When
5-one derivatives 2 (Figure 1h).
DCE was employed as a solvent instead of DCM, the desired
O
O
product 2a was observed in very low yields (Table 1, entries 2-3).
O N N
Afterwards, the oxacyclization of imidazole 1a was examined with a
N O N
N O F variety of Lewis acids, such as FeCl3, BF3.OEt2 and AgSbF6.
N O
N
O O Unfortunately, in all cases the starting material was fully converted
(a) (b) S to the deprotected imidazole 3a (Table 1, entries 4-6). As the
Et N F
H
(c) annulation process involved the formation of the carbenium ion
O
O species, we decided to perform the reaction under acidic
N NH conditions. Thus, the addition of p-toluenesulfonic acid (0.3 equiv.)
N NH F
O
N
N in dichloroethane at 60 °C for 24 hours triggered the cyclization,
(d) (e) N N and the desired compound 2a was formed in 19% yield along with
O N 81% of deprotected imidazole 3a (Table 1, entry 7). Replacing
(f) AgSbF6 by AgOTf improved slightly the 2a/3a ratio from (19:81) to
CN
(50:50) (Table 1, entry 8).

Table 1. Optimization of Oxacyclization Reaction Conditions

O Cat (equiv.) O
OtBu O H
Additive (equiv.) N N
N N O + Br O + Ph
Ph Br N
Solvent, T (°C), Br N
N N Ph
Br Time 2'a Ph
1a 2a 3a
(not observed)

Ratio (%)a
Entry Solvent Catalyst (equiv.) Additive (equiv.) T (°C) Time (h)
2a/3a/1a
149,50 DCM ZnCl2 (1.2) - 40 48 0/0/100
2 DCE ZnCl2 (1.2) - 40 16 33/67/0
3 DCE ZnCl2 (1.2) - 60 12 25/75/0
437 DCM FeCl3 (1) - 25 96 0/100/0
557–59 DCE BF3.OEt2 (1) - 25 24 0/100/0
660 MeOH AgSbF6 (0.1) - 25 28 0/100/0

2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

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Journal Name ARTICLE

7 DCE AgSbF6 (0.1) p-TsOH (0.3) 60 24 19/81/0 View Article Online

825 DCE AgOTf (0.1) p-TsOH (0.3) 60 48 50/50/0
DOI: 10.1039/D1OB02352G
9 DCE AgOTf (0.1) p-TsOH (1) 60 2 17/83/0
10 DCE AgOTf (0.1) p-TsOH (0.3) 100 16 14/86/0

Organic & Biomolecular Chemistry Accepted Manuscript

11 DCE AgOTf (0.1) TFA (2) 60 24 83/17/0
12 DCE AgOTf (0.1) TFA (1) 60 24 6/94/0
13 DCE Ag2CO3 (0.1) TFA (1) 60 12 50/0/50
14 DCE Ag2CO3 (0.1) TFA (0.5) 60 12 5/0/95
15 DCE Ag2CO3 (0.1) TFA (2) 60 6 100b/0/0
16 DCE Ag2CO3 (0.1) - 60 72 0/0/100
17 DCE Ag2CO3 (0.1) p-TsOH (1) 60 72 0/100/0
18 DCE - p-TsOH (1) 60 72 0/100/0
1961 DCE - TFA (1) 60 12 0/0/100
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20 DCE - TFA (2) 60 72 0/0/100

2146,62,63 DCE AuClPPh3 (0.1) TFA (1) 60 72 0/40/60
2264 DCE CyJohnPhosAuCl (0.1) TFA (1) 60 72 0/56/44
23 DCE ZnCl2 (0.1) TFA (2) 60 72 0/100/0
24 DCE Ag2CO3 (0.05) TFA (2) 60 72 75/0/25
aThe ratio of mixture (2a/3a/1a) was calculated from the crude 1H NMR spectrum. bCompound 2a was isolated in

80% yield after purification by silica-gel column chromatography.

Under the same conditions, the use of a stoichiometric amount mol%), the reaction is not complete despite stirring at 60 °C for 72
of p-TsOH affected completely the formation of desired product 2a (Table 1, entry 24).
since its yield decreased to 17% while the yield of byproduct 3a Having established the required conditions for efficient
increased to 83% (Table 1, entry 9). Performing the reaction at 100 cyclization, a wide variety of N-Boc-2-alkynyl-5-
°C seems beneficial for the deprotection reaction at the expense of bromoimidazoles were then examined (Scheme 1).
the annulation (Table 1, entry 10). To our delight, using
O
trifluoroacetic acid (2 equiv.) instead of p-TsOH improved OtBu Ag2CO3 (0.1 equiv.) O

significantly the yield of cyclized product 2a to 83% accompanied N TFA (2 equiv.) N O

R Br
with 17% of 3a (Table 1, entry 11). In order to avoid the formation Br N DCE, 60 °C, 6 h N R
of side product 3a and as TFA is the most acid used in the literature 1a-l 2a-l
for the deprotection of the Boc group; its amount has been then
O O O
reduced. Surprisingly, when the reaction was carried out with one
N O N O N O
equivalent of TFA the percentage of 2a in the mixture decreased to Br Br Br
N N N
6% while 3a increased to 94%, indicating that AgOTf plays a critical
role in the formation of byproduct 3a (Table 1, entry 12). Replacing 2a, 80% 2b, 83% OMe 2c, 81% Cl

AgOTf by Ag2CO3 confirmed this result since 50% of starting O O

O
material was converted to the desired compound 2a without the
N O N O Cl N O F
Br
formation of any trace of 3a (Table 1, entry 13). By reducing the Br
N
Br
N N
amount of TFA (0.5 equiv.), the yield of the target heterocycle 2a
was considerably decreased (Table 1, entry 14). Gratifyingly, the 2d, 86% 2e, 66% 2f, 77%
Cl
combination between Ag2CO3 and two equivalents of TFA
O O O
dramatically accelerated the transformation and allowed the fully
N O F N O N O
conversion of the starting material to the desired compound 2a Br Br Br
N N N
N
which was obtained in good isolated yield (80%), after purification
by silica-gel column chromatography (Table 1, entry 15). When the 2g, 86%
F
2h, 69% 2i, 70% N

reaction was conducted without additive in the presence of Ag2CO3,

O O O
only starting material was completely recovered (Table 1, entry 16).
N O N O
No trace of the expected compound 2a was observed when p-TsOH Br Br Br
N O
N N
was used instead of TFA (Table 1, entry 17), indicating that p-TsOH N
S
is responsible of the deprotection of the Boc group. This result was 2j, 87% 2k, 50% 2l, 80%
confirmed by performing the reaction without catalyst and under O O
acidic conditions (p-TsOH or TFA) (Table 1, entries 18-20). It is N O N O
noteworthy that the combination between TFA and other catalysts N Ph N Ph
such as AuClPPh3, CyJohnPhos AuCl and ZnCl2 did not promote the 2ma, 0% 2na, 0%
cyclization since only the deprotection of Boc group was observed aOnly deprotected products were obtained.
(Table 1, entries 21-23). By reducing the amount of Ag2CO3 (5

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3

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Scheme 1. Ag2CO3/TFA-Mediated Annulation of N-Boc-2-alkynyl-4- View Article Online

bromo-5-methylimidazoles 1a-l. O
OtBu
DOI: 10.1039/D1OB02352G
Ag2CO3 (0.1 equiv.) O
N TFA (2 equiv.)
1 N O
All starting materials 1b-l were prepared from the R
DCE, 60 °C, 6 h
R2
N

Organic & Biomolecular Chemistry Accepted Manuscript

N R1
corresponding N-Boc-2,5-dibromo-4-methylimidazole, as 4a-l
R2 5a-l
described for 1a, by regioselective Sonogashira cross-coupling
reaction.48 Symmetrical alkynes R1 = R2

The cyclization was found to be compatible with a wide range O O

of R groups in substrate 1 such as alkyl, cycloalkyl, aryl and N O N O
MeO
heteroaryl, containing electron-donating or -withdrawing N N
substituents.
5a, 85% 5b, 67% OMe
As illustrated in Scheme 1, when R = 4-methoxyphenyl, as an
O
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O
electron-donating group, at the para position, 1b was easily
Cl N O N O
cyclized, giving access to the desired compound 2b in 83%
N N
yield. Imidazoles bearing an electron-withdrawing groups such Cl
5f, 86%
as a chlorine group at para, meta or ortho positions 1c-e, 5c, p-Cl, 67%
5d, m-Cl, 88%
underwent annulation successfully leading to the 5e, o-Cl, 91% O
corresponding products 2c (81%), 2d (86%) and 2e (66%). As
N O
observed, the reaction efficiency was impacted by the steric
N
hindrance of the ortho-position. Starting materials containing
5g, 93%
fluorine atoms on the aromatic ring R = 2-fluorophenyl and R =
Unsymmetrical alkynes R1  R2
2,4-difluorophenyl were found to be compatible with this
intramolecular cyclization [2f (77%) and 2g (86%)]. O O

N O N O
MeO tBu
After the good results obtained with different R = aryls, this N N
Ph Ph
cyclization was extended to imidazole containing ethynylheteroaryl. 5h, 69% 5i, 61%
Interestingly, the presence of heteroaryl goups such as 2-pyridyl, 3- O Cl O
pyridyl and 3-thienyl on the triple bond was also tolerated under N O N O
Cl
optimized oxacyclization conditions and the expected heterocycles N Ph N Ph
were isolated in good yields [2h (69%), 2i (70%) and 2j (87%)]. 5j, 70% 5k, 76%
O
The cyclization of substrate bearing aliphatic group such as
phenylethyl works well affording the expected product 2l in 80% N O
S N
yield. However, when R = cyclohexyl, the yield of product 2k did not Ph
5l, 70%
exceed 50%, which could be explained by the relatively low
reactivity of the corresponding starting material. In all experiments,
the 6-endo-dig cyclization product 2 was found to be the sole Scheme 2. Oxacyclization of symmetrical and unsymmetrical 2,4-
isolated product, and compound 5-exo-dig 2’ was not observed. dialkynylated imidazoles 4a-I.
This result could be explained by the fact that the N-Boc-2-
alkynylimidazole structure is very rigid which spontaneously Interestingly, symmetrical 2,4-dialkynylated imidazoles 4f-g
underwent internal nucleophilic attack by the favorably positioned containing aliphatic alkynes (cyclohexyl and butyl) were successfully
tert-butoxy group close to the alkyne. underwent cyclization in excellent yields [5f (86%) and 5g (93%)].
In order to extend the scope and limitation of this annulation, For unsymmetrical 2,4-dialkynylated imidazoles 4h-l, all of the
symmetrical and unsymmetrical 2,4-dialkynylated imidazoles 4a-l corresponding imidazooxazinones 5h-l were obtained with yields
(bearing different R1 and R2 groups; prepared following our recent ranging from 61 to 76%, whatever the nature of aromatic or
procedure by regioselective and double Sonogashira cross coupling heteroaromatic alkynes.
reactions48) were subjected to the optimized reaction conditions
(Scheme 2). An interesting feature of our approach is the fact that the
As shown in Scheme 2, when R1 = R2 = Ph, the intramolecular generated 2-bromo-7-substituted 3-methylimidazo[1,2-
annulation was performed properly and the imidazooxazinone c][1,3]oxazin-5-one 2 can be further functionalized by using various
heterocycle 5a was isolated in 85% yield. Good results were also cross-coupling reactions. First, we decided to study the Suzuki-
obtained with substrates containing a substituted aryl on the triple Miyaura65–69 cross-coupling between imidazooxazinone 2a and p-
bond, either electron-donating [methoxy; 5b (67%)] or electron- methoxyphenylboronic acid. Thus, the reactivity of the bromine at
withdrawing chlorine group at para, meta or ortho positions [5c C-2 position seems to be tricky since the use of classical Suzuki
(67%), 5d (88%) and 5e (91%), respectively], indicating that this cross-coupling conditions proved unsatisfactory because of the
cyclization is not affected by steric hindrance. carbamate function sensitivity under basic conditions (for the
optimization conditions, see Table S1 in ESI).

4 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

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R B(OH)2 (1.3 equiv.) 73 Once more, during the optimization of reaction conditions (See
View Article Online
Pd2(dba)3 (2.5 mol%) O
Table S2 in ESI), the use of Pd2(dba)3/XPhos as10.1039/D1OB02352G
DOI: a tandem catalyst
XPhos (10 mol%) N O
R plays a crucial role for the efficiency of this Csp-Csp2 cross-coupling
K3PO4 (2 equiv.) N
Toluene/H2O (10/1)
Ph (Scheme 3). Aromatic alkynes containing an electron-withdrawing

Organic & Biomolecular Chemistry Accepted Manuscript

110 °C, 1 h 6a R = 4-MeOPh, 93% or -donating groups reacted well and provided heterocycles 5a, 5h
6b R = 3-MeOPh, 89%
6c R = 2-MeOPh, 80% and 7a in good yields. 1-Hexyne as an aliphatic alkyne was also
6d R = (E)-Styryl, 94% found to be compatible with this coupling reaction conditions since
R (1.3 equiv.) O the desired compound 7b was obtained in 70% yield.
O
Pd2(dba)3 (5 mol%) After having successfully developed C-2-arylation and C-2-
N O
N O R alkynylation of imidazo[1,2-c][1,3]oxazin-5-one 2a via Suzuki-
Br XPhos (10 mol%) N
N Ph
Ph Et3N, 80 °C, 1 h Miyaura and Sonogashira cross couplings, respectively, using
2a 5a R = Ph, 85%
Pd2(dba)3/XPhos as a catalytic system, we focused on introducing
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R (2.5 equiv.)
Pd2(dba)3 (10 mol%)
XPhos (10 mol%)
K3PO4 (2 equiv.)
Toluene, 130 °C, 16 h
Scheme 3. Functionalization of 2a via Palladium catalyzed cross-
coupling reactions.
After several investigations, it was found that Pd2(dba)3 (2.5 mol%),
XPhos (10 mol%) and K3PO4 (2 equiv.) in a mixture of toluene/H2O
(10/1) at 110 °C were required for the reaction to go to completion
and to avoid any degradation (Table 2, entry 7). Under these
conditions, substrate 2a was successfully coupled with 2-, 3- and 4-
methoxyphenylboronic acids as well as (E)-styrylboronic acid,
affording the expected products 6a-d in excellent yields, after only
one hour (Scheme 3).
We were then interested in the functionalization of 2a with a
variety of alkynes involving Sonogashira cross-coupling reaction.70–
5h R = 4-MeOPh, 78%
7a R = 4-FPh, 81%
7b R = n-Bu, 70%
O was undertaken, in the presence of alkene (2.5 equiv.), Pd2(dba)3
N O
R N
6d R = Ph, 60%
8a R = CO2Me, 53%
8b R = 4-MeOPh, 76%
8c R = 4-ClPh, 55%
greater diversity by employing this catalyst in Heck cross-coupling
reaction (Scheme 3).74 Thus, the C-2-alkenylation of substrate 2a
(10 mol%), XPhos (10 mol%) and K3PO4 (2.5 equiv.) as the base in
Ph toluene at 130 °C for 16 h.
This protocol provided direct access to several new 2-alkenyl
imidazo[1,2-c][1,3]oxazin-5-one 8a-c and 6d in yields of 53 to 76%
(Scheme 3). Notably, styrene reacted moderately with 2a to afford
the desired compound 6d in 60% yield.
In addition, substituted styrene bearing an electron-donating group
such as a methoxy group at para position, coupled easily with 2a
giving the expected product 8b in 76% yield, whereas methyl
acrylate and 4-chlorostyrene that possesses electron withdrawing
groups, were less efficient [8a (53%) and 8c (55%)].
Theoretical calculation (Computational studies).
A mechanism for the formation of the target imidazooxazinone 2a
using Ag2CO3 and TFA is proposed in Scheme 4. All calculations were
done using TmoleX 19.

O
O TSIIaendo TSII'aendo
N
H H
Ph H H
H H O
Br N O
O + H O O
O F3C OH F3C O
Ag+
N O N O N O
Path a N O Br Br + Ag
Br Br
N N Ph N Ph
N Ph Ph
Ag Ag H
O Ag
O a
TSIIIaendo 2a
N b
Ph H H
H H
Br N H H
Ag+
O O O
O
TSI O O + H
O F3C OH F3C O O
O N N
O N Ph
N Ph + Ag
Path b Ph Ph N
Br Ag Br N
N Br N
Br Ag Ag
TSIIIbexo 2'a
TSIIbexo TSII'bexo

Scheme 4. Projected computational catalytic cycle.

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 5

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DOI: 10.1039/D1OB02352G
Briefly, all structures were optimized in the gas phase and then in
Table 2. Partial Atomic Charges for alkyne substituent from
DCE with a convergence criterion of 10-8 Hartree, using density
Natural Population Analysis (NPA) of compounds 1a-l and 4a-l.
functional theory (DFT) calculations combining the resolution of

Organic & Biomolecular Chemistry Accepted Manuscript

identity (RI) approximation,75,76 within the Turbomole programme entry Comp. Charge Comp. Charge
package using the B3LYP function with the def2-TZVP basis set.77,78
α = +0.063 α = +0.061
Herein, these DFT calculations have been then performed 1 1a 4a
β = -0.043 β = -0.042
using a N-Boc-5-bromo-3-methyl-2-phenylethynylimidazole 1a
α = +0.066 α = +0.063
as a model substrate in DCE. This choice was motivated to 2 1b 4b
β = -0.057 β = -0.056
dress a direct comparison with experimental results and to
α = +0.058 α = +0.057
more thoroughly consider the reaction mechanism. In order to 3 1c 4c
β = -0.034 β = -0.034
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clarify the unique 6-endo cyclization selectivity of annulation,

α = +0.056 α = +0.056
the energy profiles of both cyclization manners [6-endo-dig 4 1d 4d
β = -0.028 β = -0.027
(path a, blue) or 5-exo-dig (path b, red)] display in Scheme 4
α = +0.055 α = +0.056
were computed and then compared with results shown in 5 1e 4e
β = -0.019 β = -0.018
Figure 3.
α = +0.054 α = +0.102
6 1f 4f
β = -0.025 β = -0.094
α = +0.051 α = +0.093
7 1g 4g
O
O
O
β = -0.023 β = -0.093
ΔE (kcal/mol) O N

TSI
N
Ph
Ph α = +0.042 α = +0.059
N Br N
Ag 8 1h 4h
O 48.5 Br Ag β = -0.016 β = -0.041
O TSII'bexo
N TSIIbexo
42.2 O α = +0.051 α = +0.060
Ph
39.8 9 1i 4i
Br N
Ag + N
O
Ph
β = -0.023 β = -0.041
Br N
Ag α = +0.060 α = +0.063
10 1j 4j
26.4 27.3 TSIIIbexo β = -0.042 β = -0.042
23.9
TSIIaendo TSII'aendo α = +0.109 α = +0.063
11 1k 4k
14.1
β = -0.096 β = -0.043
O O
N O TSIIIaendo
O
α = +0.093 α = +0.060
Br Br
N O
N
O
12 1l 4l
N Ph N Ph O
Ph β = -0.085 β = -0.042
Ag Ag Br N
0.0 N O
Br 2'a
N
1a
Ag
Ph
-5.4 Whatever the structure, NPA seems to highlight that the carbon
O
atom leading to the 6-endo-dig cyclization (denoted α, therein) is
O O

N N O
-15.5 always positively charged while each local charge on the carbon
Ph Br
Br N N Ph 2a atom leading to the 5-exo-dig cyclization were negatively charged
H
(denoted β).
In addition, geometric parameters, computed N−C(O) rotational
Figure 3. Energy reaction profile for the oxacylization pathway of barriers and charges have been also investigated to understand why
compound from selected starting material to products. compound 2m and 2n are not cyclized (Scheme 1). Table 3
summarizes bond lengths (entries 1−4), parameter θ (entry 5),
All the transition states (TSII aendo - TSIII aendo) and product for the 6- dihedral angle (entry 6), calculated N−C(O) rotational barriers
(entries 8−9) and partial atomic charges on the carbons of the triple
endo-dig oxacyclization (path a, blue) shows a lower energy level
bond (entry 10).63
than corresponding states following the 5-exo-dig (path b, red). This
result clearly indicates that the cyclization steps for the endo-mode
Table 3. Select Geometric Parameters,a Computed N−C(O)
are favoured not only thermodynamically but also kinetically due to
Rotational Barriersb and NPA on triple bond of compounds 2a,
their aromatic character.
2m and 2n
Furthermore, our mechanistic hypothesis was also confirmed
thanks to the charge distribution of carbon atoms in the carbon- entry parameter value of 2a value of 2m value of 2n
carbon triple bonds, which seems to be critical in determining the
resulting cyclization. In fact, the natural population analysis of 1 N−C(O) 1.429 1.425 1.427
carbons in the alkyne group of all compounds described therein 2 C(O)−O 1.333 1.335 1.332
were computed in DCE as reported in Table 2. 3 N−C1 1.413 1.417 1.414
4 N−C5 1.401 1.400 1.390
Briefly, this NPA highlights a similar electronic character on the
5 θ 359.974 359.991 359.968
carbons of the triple bond of all compounds 1a-l and 4a-l (Table 2).
6 τ 208.787 151.221 171.046
7 ε 128.011 128.207 131.290

6 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

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Journal Name
8 ΔE N-C(O) 4.5 5.4 7 General procedure for the regioselective oxacyclization (2a-l, 5a-l).
9 ΔG N-C(O) 2.05 n.d.c n.d.c
α = +0.063 α = +0.048 α = +0.060
10 charge
β = -0.043 β = -0.038 β = -0.039
aBond
lengths and angles are reported in Å and degrees,
respectively. bCalculated ΔG and ΔE values reported in kcal/mol.
cn.d. not determined.
A close examination of parameters shown in Table 3, reveals that
the bond lengths for compounds 2a, 2m and 2n are similar (entries
1−4). The nature of the amide nitrogen is further described using
the parameter θ, indicating that this nitrogen has similar character
for all studied compounds (entry 5). The dihedral angles are
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significantly different, revealing a greatly increased twist angle for
compound 2a (entry 6). The rotational barrier of the amide 2a is
much smaller than those of compounds 2m and 2n (ΔE N-C(O) = 4.5
kcal/mol for 2a vs 5.4 kcal/mol and 7 kcal/mol for 2m and 2n,
respectively; entry 8).
As discussed in previous sections, the bigger torsion angle τ
and the smaller rotational barrier ΔE N-C(O) are responsible
for the high reactivity of the amide 2a contrary to compounds
2m and 2n which undergo a Boc deprotection systematically.
More details for theoretical calculations are given in the
supporting information along with cartesian coordinates of all
studied compounds (see Supplementary material section).
Experimental
General information
All reactions were carried out under argon atmosphere using
anhydrous solvents purchased from ThermoFisher Scientific stored
under Argon and over activated 3Å sieves. All reagents were used
as received from their suppliers. Reactions were monitored by thin-
layer chromatography (TLC) analysis using silica gel (60 F254) plates,
and all compounds were visualized by UV irradiation (longwave at
365 nm or shortwave at 254 nm). All column chromatography was
performed with silica gel 60 (230 – 400.13 mesh, 0.040 – 0.063
mm). The purity of all final compounds was verified by 1H and 13C
NMR analysis, HRMS and melting point. NMR spectra were
obtained at 300 MHz for 1H and 75 MHz for 13C with Bruker® 300
MHz NMR spectrometer. Proton and carbon magnetic resonance
spectra (1H NMR and 13C NMR) were recorded using
tetramethylsilane (TMS) in the solvent of CDCl3 as the internal
standard (1H NMR: CDCl3 at 7.28 ppm; 13C NMR: CDCl3 at 77.04
ppm) or were recorded using tetramethylsilane (TMS) in the solvent
of DMSO-d6 as the internal standard (1H NMR: DMSO at 2.50 ppm;
13C NMR: DMSO at 40.0 ppm). Coupling constants J are reported in
hertz. All the NMR spectra were processed in MestReNova.
Electrospray ionization mass spectrometry experiments (HRMS)
were obtained on a hybrid tandem quadrupole/time-offlight (Q-
TOF) instrument, equipped with a pneumatically assisted
electrospray (Z-spray) ion source (Micromass, Manshester, U.K.)
operated in positive mode. Melting points (m.p. [°C]) of samples
were measured using open capillary tubes.
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ARTICLE
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DOI: 10.1039/D1OB02352G
To an oven-dried Schlenk tube containing the appropriate N-Boc-2-
Alkynyl-5-substituted-3-methylimidazole (1a-r, 4a-l) and (200 mg, 1
Organic & Biomolecular Chemistry Accepted Manuscript
equiv.) in dichloroethane DCE (5 mL) was added silver carbonate
Ag2CO3 (0.1 equiv.) and Trifluoroacetic acid TFA (2 equiv.). The
reaction mixture was stirred at 60 °C for 6 hours under argon
atmosphere. The progress of the reaction was monitored by TLC.
After cooling to room temperature, the mixture was concentrated
under vacuum. Then the residue was dissolved in ethyl acetate and
washed with water (2 × 30 mL). The combined organic layers were
dried with MgSO4 and concentrated under reduced pressure. The
crude material was purified by column chromatography to give pure
desired imidazo[1,2-c][1,3]oxazin-5-one 2a-l and 5a-l.
2-Bromo-3-methyl-7-phenyl-5H-imidazo[1,2-c][1,3]oxazin-5-one
(2a). Compound 2a was prepared according to General procedure
for oxacyclization from the reaction of 1a (200 mg, 0.5 mmol),
Ag2CO3 (15.3 mg, 0.05 mmol) and TFA (127 mg, 1.1 mmol). The
crude reaction mixture was purified by column chromatography
(silica gel, petroleum ether/ethyl acetate = 9:1) to provide the
product (135 mg, 80% yield) as a white solid. Melting point: 206–
208 °C. 1H NMR (300 MHz, CDCl3) δ 7.84–7.80 (m, 2H), 7.52–7.50
(m, 3H), 6.99 (s, 1H), 2.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 154.9,
143.8, 143.1, 131.2, 129.6, 129.2 (2C), 125.2 (2C), 124.0, 121.5,
94.2, 11.2. HRMS (ESI) m/z [M+H+] calcd for C13H10BrN2O2:
304.9926; Found: 304.9921.
2-Bromo-7-(4-methoxyphenyl)-3-methyl-5H-imidazo[1,2-
c][1,3]oxazin-5-one (2b). Compound 2b was prepared according to
general procedure for oxacyclization from the reaction of 1b (200
mg, 0.5 mmol), Ag2CO3 (14.1 mg, 0.05 mmol) and TFA (117 mg, 1.0
mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 8:2) to
provide the product (142 mg, 83% yield) as a white solid. Melting
point: 213–215 °C. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J = 9.0 Hz,
2H), 7.00 (d, J = 9.0 Hz, 2H), 6.85 (s, 1H), 3.89 (s, 3H), 2.64 (s, 3H).
13C NMR (75 MHz, CDCl ): δ 162.0, 155.2, 144.2, 143.2, 127.0 (2C),
3
123.6, 121.9, 121.1, 114.6 (2C), 92.3, 55.5, 11.2. HRMS (ESI) m/z
[M+H+] calcd for C14H12BrN2O3: 335.0031; Found: 335.0028.
2-Bromo-7-(4-chlorophenyl)-3-methyl-5H-imidazo[1,2-
c][1,3]oxazin-5-one (2c). Compound 2c was prepared according to
general procedure for oxacyclization from the reaction of 1c (200
mg, 0.51 mmol), Ag2CO3 (14.0 mg, 0.051 mmol) and TFA (116 mg,
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (139 mg, 81% yield) as a white solid. Melting
point: 214–216 °C. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J = 8.7 Hz,
2H), 7.48 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 2.66 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 153.8, 143.6, 142.9, 137.4, 129.5 (2C), 128.0, 126.5
(2C), 124.3, 121.7, 94.5, 11.2. HRMS (ESI) m/z [M+H+] calcd for
C13H9BrClN2O2: 338.9536; Found: 338.9532.
2-Bromo-7-(3-chlorophenyl)-3-methyl-5H-imidazo[1,2-
c][1,3]oxazin-5-one (2d). Compound 2d was prepared according to
general procedure for oxacyclization from the reaction of 1d (200
mg, 0.51 mmol), Ag2CO3 (14.0 mg, 0.051 mmol) and TFA (116 mg,
J. Name., 2013, 00, 1-3 | 7
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ARTICLE
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (147 mg, 86% yield) as a white solid. Melting
point: 212–214 °C. 1H NMR (300 MHz, CDCl3) δ 7.80 (t, J = 1.8 Hz,
1H), 7.69 (dt, J = 6.9, 1.8 Hz, 1H), 7.50–7.42 (m, 2H), 7.00 (s, 1H),
2.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 153.3, 143.4, 142.8, 135.5,
131.2, 131.1, 130.4, 125.3, 124.4, 123.3, 121.9, 95.1, 11.2. HRMS
(ESI) m/z [M+H+] calcd for C13H9BrClN2O2: 338.9536; Found:
338.9531.
2-Bromo-7-(2-chlorophenyl)-3-methyl-5H-imidazo[1,2-
c][1,3]oxazin-5-one (2e). Compound 2e was prepared according to
general procedure for oxacyclization from the reaction of 1e (200
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mg, 0.51 mmol), Ag2CO3 (14.0 mg, 0.051 mmol) and TFA (116 mg,
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (113 mg, 66% yield) as a white solid. Melting
point: 149–151 °C. 1H NMR (300 MHz, CDCl3): δ 7.74–7.70 (m, 1H),
7.55–7.51 (m, 1H), 7.47–7.39 (m, 2H), 7.15 (s, 1H), 2.68 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 152.4, 143.2, 143.2, 132.5, 131.7, 131.1,
130.2, 129.2, 127.3, 124.3, 121.7, 100.4, 11.2. HRMS (ESI) m/z
[M+H+] calcd for C13H9BrClN2O2: 338.9536; Found: 338.9531.
2-Bromo-7-(2-fluorophenyl)-3-methyl-5H-imidazo[1,2-
c][1,3]oxazin-5-one (2f). Compound 2f was prepared according to
general procedure for oxacyclization from the reaction of 1f (200
mg, 0.53 mmol), Ag2CO3 (14.6 mg, 0.053 mmol) and TFA (121 mg,
1.06 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (131 mg, 77% yield) as a white solid. Melting
point: 201–203 °C. 1H NMR (300 MHz, CDCl3): δ 7.94 (td, J = 7.8, 1.8
Hz, 1H), 7.51–7.44 (m, 1H), 7.34 (d, J = 0.9 Hz, 1H), 7.31 (d, J = 0.9
Hz, 1H), 7.28 (s, 1H), 2.67 (s, 3H). 19F NMR (282 MHz, CDCl3): δ -
110.68. 13C NMR (75 MHz, CDCl3): δ 160.1 (d, J = 252.7 Hz), 149.3 (d,
J = 4.5 Hz), 143.6, 142.9, 132.3 (d, J = 9.0 Hz), 127.9 (d, J = 0.8 Hz),
124.8 (d, J = 3.0 Hz), 124.3, 121.9, 118.0 (d, J = 9.8 Hz), 116.8 (d, J =
22.5 Hz), 99.4 (d, J = 17.3 Hz), 11.2. HRMS (ESI) m/z [M+H+] calcd for
C13H9BrFN2O2: 322.9831; Found: 322.9825.
2-Bromo-7-(2,4-difluorophenyl)-3-methyl-5H-imidazo[1,2-
c][1,3]oxazin-5-one (2g). Compound 2g was prepared according to
General procedure for oxacyclization from the reaction of 1g (200
mg, 0.5 mmol), Ag2CO3 (13.9 mg, 0.05 mmol) and TFA (115 mg, 1.01
mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (148 mg, 86% yield) as a white solid. Melting
point: 217–219 °C. 1H NMR (300 MHz, CDCl3) δ 7.98–7.90 (m, 1H),
7.09–6.95 (m, 2H), 7.21 (s, 1H), 2.66 (s, 3H). 19F NMR (282 MHz,
CDCl3): δ -104.22 (d, J = 11.3 Hz), -106.18 (d, J = 11.3 Hz). 13C NMR
(75 MHz, CDCl3) δ 164.1 (dd, J = 256.0, 12.3 Hz), 160.5 (dd, J = 257.5,
11.9 Hz), 148.6, 143.5, 142.8, 129.3 (dd, J = 10.0, 2.8 Hz), 124.3,
122.0, 114.5, 112.4 (dd, J = 21.6, 3.6 Hz), 106.4 (t, J = 26.0 Hz), 99.4
(dd, J = 16.8, 1.7 Hz), 11.2. HRMS (ESI) m/z [M+H+] calcd for
C13H8BrF2N2O2: 340.9737; Found: 340.9733.
2-Bromo-3-methyl-7-(pyridin-2-yl)-5H-imidazo[1,2-c][1,3]oxazin-5-
one (2h). Compound 2h was prepared according to General
procedure for oxacyclization from the reaction of 1h (200 mg, 0.55
8 | J. Name., 2012, 00, 1-3
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Journal Name
mmol), Ag2CO3 (15.3 mg, 0.055 mmol) and TFA (126 mg, 1.12
View Article Online
mmol). The crude reaction mixture was DOI:purified by column
10.1039/D1OB02352G
chromatography (silica gel, petroleum ether/ethyl acetate = 5:5) to
provide the product (117 mg, 69% yield) as a white solid. Melting
Organic & Biomolecular Chemistry Accepted Manuscript
point: 193–195 °C. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 4.2 Hz,
1H), 7.94 (d, J = 7.8 Hz, 1H), 7.86 (td, J = 7.8, 1.2 Hz, 1H), 7.67 (s,
1H), 7.39 (ddd, J = 7.5, 4.5, 1.2 Hz, 1H), 2.68 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 153.5, 150.2, 147.5, 143.7, 143.0, 137.2, 125.1, 124.6,
122.2, 119.9, 96.4, 11.3. HRMS (ESI) m/z [M+H+] calcd for
C12H9BrN3O2: 305.9878; Found: 305.9872.
2-Bromo-3-methyl-7-(pyridin-3-yl)-5H-imidazo[1,2-c][1,3]oxazin-5-
one (2i). Compound 2i was prepared according to General
procedure for oxacyclization from the reaction of 1i (200 mg, 0.55
mmol), Ag2CO3 (15.3 mg, 0.055 mmol) and TFA (126 mg, 1.12
mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 5:5) to
provide the product (118 mg, 70% yield) as a white solid. Melting
point: 245–247 °C. 1H NMR (300 MHz, CDCl3) δ 9.07 (d, J = 1.8 Hz,
1H), 8.74 (dd, J = 4.8, 1.5 Hz, 1H), 8.11 (dt, J = 8.1, 1.8 Hz, 1H), 7.47
(dd, J = 8.1, 4.8 Hz, 1H), 7.07 (s, 1H), 2.68 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 152.3, 151.7, 146.5, 143.2, 142.8, 132.4, 125.9, 124.6,
123.8, 122.0, 95.5, 11.2. HRMS (ESI) m/z [M+H+] calcd for
C12H9BrN3O2: 305.9878; Found: 305.9875.
2-Bromo-3-methyl-7-(thiophen-3-yl)-5H-imidazo[1,2-c][1,3]oxazin-
5-one (2j). Compound 2i was prepared according to General
procedure for oxacyclization from the reaction of 1j (200 mg, 0.55
mmol), Ag2CO3 (15.1 mg, 0.055 mmol) and TFA (125 mg, 1.09
mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (147 mg, 87% yield) as a white solid. Melting
point: 243–245 °C. 1H NMR (300 MHz, CDCl3) δ 7.91 (dd, J = 3.0, 1.2
Hz, 1H), 7.46 (dd, J = 5.1, 3.0 Hz, 1H), 7.39 (dd, J= 5.1, 1.2 Hz, 1H),
6.81 (s, 1H), 2.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 151.6, 143.8,
143.0, 131.8, 127.8, 125.6, 124.2, 124.1, 121.3, 93.6, 11.2. HRMS
(ESI) m/z [M+H+] calcd for C11H8BrN2O2S: 310.9490 ; Found:
310.9484.
2-Bromo-7-cyclohexyl-3-methyl-5H-imidazo[1,2-c][1,3]oxazin-5-
one (2k). Compound 2k was prepared according to general
procedure for oxacyclization from the reaction of 1k (200 mg, 0.55
mmol), Ag2CO3 (15.1 mg, 0.055 mmol) and TFA (125 mg, 1.09
mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (85 mg, 50% yield) as a white solid. Melting
point: 152–154 °C. 1H NMR (300 MHz, CDCl3) δ 6.31 (s, 1H), 2.60 (s,
3H), 2.48–2.38 (m, 1H), 2.03–2.00 (m, 2H), 1.88–1.86 (m, 2H), 1.78–
1.74 (m, 1H), 1.47–1.23 (m, 5H). 13C NMR (75 MHz, CDCl3) δ 164.1,
143.8, 123.8, 123.4, 120.6, 94.5, 41.1, 30.1 (2C), 25.6 (2C), 11.1.
HRMS (ESI) m/z [M+H+] calcd for C13H16BrN2O2: 311.0395; Found:
311.0388.
2-Bromo-3-methyl-7-phenethyl-5H-imidazo[1,2-c][1,3]oxazin-5-
one (2l). Compound 2l was prepared according to general
procedure for oxacyclization from the reaction of 1l (200 mg, 0.52
mmol), Ag2CO3 (14.2 mg, 0.052 mmol) and TFA (117 mg, 1.03
mmol). The crude reaction mixture was purified by column
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chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (137 mg, 80% yield) as a yellow solid. Melting
point: 155–157 °C. 1H NMR (300 MHz, CDCl3) δ 7.34–7.19 (m, 5H),
6.29 (s, 1H), 3.02 (t, J = 7.2 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.61 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 158.6, 143.6, 143.3, 139.2, 128.8
(2C), 128.2 (2C), 126.7, 123.6, 120.9, 97.1, 34.4, 32.6, 11.1. HRMS
(ESI) m/z [M+H+] calcd for C15H14BrN2O2: 333.0239; Found:
333.0235.
3-Methyl-7-phenyl-2-(phenylethynyl)-5H-imidazo[1,2-
c][1,3]oxazin-5-one (5a). Compound 5a was prepared according to
general procedure for oxacyclization from the reaction of 4a (200
mg, 0.52 mmol), Ag2CO3 (14.2 mg, 0.052 mmol) and TFA (117 mg,
Published on 21 January 2022. Downloaded by UNIVERSITE DE TOURS on 1/30/2022 8:54:27 PM.
1.03 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (145 mg, 85% yield) as a yellow solid. Melting
point: 224–226 °C. 1H NMR (300 MHz, CDCl3) δ 7.86–7.83 (m, 2H),
7.61–7.58 (m, 2H), 7.56–7.49 (m, 3H), 7.43–7.35 (m, 3H), 7.04 (s,
1H), 2.82 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 154.9, 143.9, 143.7,
131.7 (2C), 131.0, 129.8, 129.1 (2C), 128.7, 128.4 (2C), 127.0, 125.5,
125.2 (2C), 122.5, 94.6, 94.0, 81.0, 11.6. HRMS (ESI) m/z [M+H+]
calcd for C21H15N2O2: 32.1134; Found: 327.1130.
7-(4-Methoxyphenyl)-2-[(4-methoxyphenyl)ethynyl]-3-methyl-5H-
imidazo[1,2-c][1,3]oxazin-5-one (5b). Compound 5b was prepared
according to general procedure for oxacyclization from the reaction
of 4b (200 mg, 0.45 mmol), Ag2CO3 (12.5 mg, 0.045 mmol) and TFA
(103 mg, 0.90 mmol). The crude reaction mixture was purified by
column chromatography (silica gel, petroleum ether/ethyl acetate =
8:2) to provide the product (117 mg, 67% yield) as a yellow solid.
Melting point: 227–229 °C. 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J =
9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H), 6.91 (d, J
= 9.0 Hz, 2H), 6.87 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.79 (s, 3H). 13C
NMR (75 MHz, DMSO-d6) δ 161.7, 160.2, 154.4, 144.9, 133.4 (2C),
129.9, 127.8, 127.3 (2C), 125.7, 122.7, 115.0 (2C), 115.0 (2C), 114.2,
96.9, 93.4, 81.2, 55.9, 55.8, 11.8. HRMS (ESI) m/z [M+H+] calcd for
C23H19N2O4: 387.1345; Found: 387.1343.
7-(4-Chlorophenyl)-2-[(4-chlorophenyl)ethynyl]-3-methyl-5H-
imidazo[1,2-c][1,3]oxazin-5-one (5c). Compound 5c was prepared
according to general procedure for oxacyclization from the reaction
of 4c (200 mg, 0.44 mmol), Ag2CO3 (12.3 mg, 0.044 mmol) and TFA
(101 mg, 0.89 mmol). The crude reaction mixture was purified by
column chromatography (silica gel, petroleum ether/ethyl acetate =
9:1) to provide the product (117 mg, 67% yield) as a white solid.
Melting point: 271–273 °C. 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J =
8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.36 (d, J
= 8.7 Hz, 2H), 6.98 (s, 1H), 2.81 (s, 3H). 13C NMR (75 MHz, THF-d8) δ
151.5, 142.3, 141.4, 134.3, 132.4, 130.9 (2C), 128.8, 127.4, 127.2
(2C), 126.8 (2C), 124.6 (2C), 124.5, 119.7, 93.2, 89.7, 81.1, 8.7.
HRMS (ESI) m/z [M+H+] calcd for C21H13Cl2N2O2: 395.0354; Found:
395.0350.
7-(3-Chlorophenyl)-2-[(3-chlorophenyl)ethynyl]-3-methyl-5H-
imidazo[1,2-c][1,3]oxazin-5-one (5d). Compound 5d was prepared
according to general procedure for oxacyclization from the reaction
of 4d (200 mg, 0.44 mmol), Ag2CO3 (12.3 mg, 0.044 mmol) and TFA
(101 mg, 0.89 mmol). The crude reaction mixture was purified by
column chromatography (silica gel, petroleum ether/ethyl acetate =
9:1) to provide the product (154 mg, 88% yield) as a white solid.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Melting point: 223–225 °C. 1H NMR (300 MHz, CDCl3):View δ 7.83 (t, J =
Article Online
2.1 Hz, 1H), 7.72 (dt, J = 6.9, 2.1 Hz, 1H), DOI:
7.5710.1039/D1OB02352G
(t, J = 1.8 Hz, 1H),
7.52–7.42 (m, 3H), 7.38–7.29 (m, 2H), 7.02 (s, 1H), 2.82 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 153.5, 143.5, 143.3, 135.4, 134.3, 131.4
Organic & Biomolecular Chemistry Accepted Manuscript
(2C), 131.0 (2C), 130.4, 129.8, 129.7, 129.1, 126.8, 125.3, 124.1,
123.3, 95.4, 92.6, 82.1, 11.6. HRMS (ESI) m/z [M+H+] calcd for
C21H13Cl2N2O2: 395.0354; Found: 395.0351.
7-(2-Chlorophenyl)-2-[(2-chlorophenyl)ethynyl]-3-methyl-5H-
imidazo[1,2-c][1,3]oxazin-5-one (5e). Compound 5e was prepared
according to general procedure for oxacyclization from the reaction
of 4e (200 mg, 0.44 mmol), Ag2CO3 (12.3 mg, 0.044 mmol) and TFA
(101 mg, 0.89 mmol). The crude reaction mixture was purified by
column chromatography (silica gel, petroleum ether/ethyl acetate =
9:1) to provide the product (159 mg, 91% yield) as a yellow solid.
Melting point: 164–166 °C. 1H NMR (300 MHz, CDCl3): δ 7.78–7.71
(m, 1H), 7.65–7.61 (m, 1H), 7.57–7.53 (m, 1H), 7.49–7.40 (m, 3H),
7.35–7.25 (m, 2H), 7.17 (s, 1H), 2.87 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 152.5, 143.6, 143.4, 135.8, 133.2, 132.6, 131.6, 131.3,
131.1, 130.2, 129.7, 129.3 (2C), 127.2, 126.9, 126.6, 122.5, 100.8,
90.7, 86.2, 11.6. HRMS (ESI) m/z [M+H+] calcd for C21H13Cl2N2O2:
395.0354; Found: 395.0349.
7-Cyclohexyl-2-cyclohexylethynyl-3-methylimidazo[1,2-
c][1,3]oxazin-5-one (5f). Compound 5f was prepared according to
general procedure for oxacyclization from the reaction of 4f (200
mg, 0.51 mmol), Ag2CO3 (14.0 mg, 0.051 mmol) and TFA (116 mg,
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (147 mg, 86% yield) as a yellow solid. Melting
point: 122–124 °C. 1H NMR (300 MHz, CDCl3) δ 6.34 (s, 1H), 2.68–
2.62 (m, 4H), 2.48–2.41 (m, 1H), 2.07–2.00 (m, 2H), 1.97–1.82 (m,
4H), 1.82–1.70 (m, 3H), 1.65–1.50 (m, 3H), 1.48–1.24 (m, 8H). 13C
NMR (75 MHz, CDCl3): δ 163.6, 144.5, 143.4, 128.4, 126.6, 99.0,
94.7, 72.3, 41.0 (2C), 32.5 (2C), 30.1 (2C), 29.7, 25.9, 25.7 (3C), 24.8,
11.3. HRMS (ESI) m/z [M+H+] calcd for C21H27N2O2: 339.2073;
Found: 339.2069.
7-Butyl-2-(hex-1-yn-1-yl)-3-methyl-5H-imidazo[1,2-c][1,3]oxazin-5-
one (5g). Compound 5g was prepared according to general
procedure for oxacyclization from the reaction of 4g (200 mg, 0.58
mmol), Ag2CO3 (16.1 mg, 0.058 mmol) and TFA (133 mg, 1.2 mmol).
The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (155 mg, 93% yield) as a yellow solid. Melting
point: 72–74 °C. 1H NMR (300 MHz, CDCl3) δ 6.38 (s, 1H), 2.66 (s,
3H), 2.54 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.64 (quint, J =
7.8 Hz, 4H), 1.53–1.38 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 159.6, 144.4, 143.2, 128.5,
126.5, 96.6, 95.2, 72.3, 32.3, 30.6, 28.4, 22.0 (2C), 19.2, 13.6 (2C),
11.3. HRMS (ESI) m/z [M+H+] calcd for C17H23N2O2: 287.1760;
Found: 287.1755.
2-(4-Methoxyphenylethynyl)-3-methyl-7-phenylimidazo[1,2-
c][1,3]oxazin-5-one (5h). Compound 5h was prepared according to
general procedure for oxacyclization from the reaction of 4h (200
mg, 0.48 mmol), Ag2CO3 (13.4 mg, 0.048 mmol) and TFA (111 mg,
1.0 mmol). The crude reaction mixture was purified by column
J. Name., 2013, 00, 1-3 | 9
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Biomolecular Chemistry
ARTICLE
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (119 mg, 69% yield) as a white solid. Melting
point: 207–209 °C. 1H NMR (300 MHz, CDCl3): δ 7.83 (dd, J = 7.2, 2.4
Hz, 2H), 7.54–7.50 (m, 5H), 7.00 (s, 1H), 6.90 (d, J = 9.0 Hz, 2H), 3.86
(s, 3H), 2.81 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 160.0, 154.8, 143.7,
143.7, 133.2 (2C), 130.9, 129.8, 129.6, 129.1 (2C), 127.3, 125.2 (2C),
114.6, 114.1 (2C), 94.6, 94.0, 79.8, 55.3, 11.5. HRMS (ESI) m/z
[M+H+] calcd for C22H17N2O3: 357.1239; Found: 357.1233.
2-(4-t-butylphenylethynyl)-3-methyl-7-phenylimidazo[1,2-
c][1,3]oxazin-5-one (5i). Compound 5i was prepared according to
general procedure for oxacyclization from the reaction of 4i (200
mg, 0.46 mmol), Ag2CO3 (12.6 mg, 0.046 mmol) and TFA (104 mg,
Published on 21 January 2022. Downloaded by UNIVERSITE DE TOURS on 1/30/2022 8:54:27 PM.
0.9 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (106 mg, 61% yield) as a white solid. Melting
point: 209–211 °C. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, J = 6.0, 2.1
Hz, 2H), 7.55-7.50 (m, 5H), 7.40 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 2.81
(s, 3H) 1.35 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 154.8, 152.1, 143.8,
143.7, 131.4 (2C), 131.0, 129.9, 129.8, 129.1 (2C), 127.2, 125.4 (2C),
125.2 (2C), 119.5, 94.6, 94.2, 80.4, 34.8, 31.2 (3C), 11.5. HRMS (ESI)
m/z [M+H+] calcd for C25H23N2O2: 383.1760; Found: 383.1754.
2-(4-Chlorophenylethynyl)-3-methyl-7-phenylimidazo[1,2-
c][1,3]oxazin-5-one (5j). Compound 5j was prepared according to
general procedure for oxacyclization from the reaction of 4j (200
mg, 0.48 mmol), Ag2CO3 (13.2 mg, 0.048 mmol) and TFA (110 mg,
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (121 mg, 70% yield) as a white solid. Melting
point: 236–238 °C. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, J = 6.0, 2.4
Hz, 2H), 7.53-7.50 (m, 5H), 7.36 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 2.81
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 155.1, 144.0, 143.7, 134.8,
132.9 (2C), 131.1, 130.4, 129.7, 129.3 (2C), 129.1, 128.8 (2C), 126.7,
125.6, 125.3 (2C), 121.0, 94.6, 92.8, 82.8, 11.6. HRMS (ESI) m/z
[M+H+] calcd for C21H14ClN2O2: 361.0744; Found: 361.0740.
2-(3-Chlorophenylethynyl)-3-methyl-7-phenylimidazo[1,2-
c][1,3]oxazin-5-one (5k). Compound 5k was prepared according to
general procedure for oxacyclization from the reaction of 4k (200
mg, 0.48 mmol), Ag2CO3 (13.2 mg, 0.048 mmol) and TFA (110 mg,
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (131 mg, 76% yield) as a white solid. Melting
point: 216–218 °C. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, J = 6.3, 2.4
Hz, 2H), 7.57-7.45 (m, 5H), 7.38-7.29 (m, 2H), 7.01 (s, 1H), 2.82 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 155.0, 144.0, 143.6, 134.3, 131.4,
131.1, 130.7, 129.8, 129.7, 129.6, 129.1 (2C), 129.0, 126.6, 125.2
(2C), 124.2, 94.5, 92.4, 82.3, 11.6. HRMS (ESI) m/z [M+H+] calcd for
C21H14ClN2O2: 361.0744; Found: 361.0738.
3-Methyl-7-phenyl-2-(thiophen-3-ylethynyl)imidazo[1,2-
c][1,3]oxazin-5-one (5l). Compound 5l was prepared according to
general procedure for oxacyclization from the reaction of 4l (200
mg, 0.51 mmol), Ag2CO3 (14.2 mg, 0.051 mmol) and TFA (117 mg,
1.0 mmol). The crude reaction mixture was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to
provide the product (120 mg, 70% yield) as a white solid. Melting
10 | J. Name., 2012, 00, 1-3
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Page 10 of 13
Journal Name
point: 212–214 °C. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, J = 6.3, 2.7
View Article Online
Hz, 2H), 7.61 (dd, J = 3.0, 1.2 Hz, 1H), 7.54-7.50
DOI:(m, 3H), 7.33 (dd, J =
10.1039/D1OB02352G
5.1, 1.2 Hz, 2H), 7.25 (dd, J = 5.1, 3.0 Hz, 1H), 7.00 (s, 1H), 2.81 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 154.9, 143.8, 143.7, 131.0, 130.0,
Organic & Biomolecular Chemistry Accepted Manuscript
129.8, 129.7, 129.4, 129.1 (2C), 127.0, 125.5, 125.2 (2C), 121.6,
94.6, 89.1, 80.6, 11.5. HRMS (ESI) m/z [M+H+] calcd for
C19H13N2O2S: 333.0698; Found: 333.0692.
General procedure for Suzuki-Miyaura cross-coupling reaction of
2a with boronic acid.
The Suzuki-Miyaura cross coupling reaction was conducted
according to a modified literature procedure.79 An flame-dried 15
mL sealed-tube flask equipped with a magnetic stir bar, was
charged with 2a (200 mg, 0.66 mmol, 1.0 equiv), boronic acid (0.85
mmol, 1.3 equiv), anhydrous potassium phosphate tribasic (279 mg,
1.32 mmol, 2.0 equiv), tris(dba)dipalladium (15.1 mg, 2.5 mol%) and
XPhos (31.4 mg, 10 mol%). The vial was sealed with a septum, then
evacuated and backfilled several time with Argon. A solution of
toluene (5.0 mL) and deionized water (0.5 mL) was then added and
the reaction mixture was stirred at 110 °C for 1 hour under argon
atmosphere. Once cooled to room temperature, the mixture was
concentrated under reduced pressure. The solid formed was
suspended in ethyl acetate (150 mL) and washed with saturated
NH4Cl solution (15 mL) and water (15 mL). The combined organic
layers were dried with MgSO4, filtered, and concentrated in vacuo.
The crude material was purified by column chromatography on
silica gel to give desired pure products 6.
2-(4-Methoxyphenyl)-3-methyl-7-phenylimidazo[1,2-c][1,3]oxazin-
5-one (6a). Compound 6a was prepared according to general
procedure for Suzuki-Miyaura cross-coupling reaction from 2a (200
mg, 0.66 mmol, 1.0 equiv), 4-methoxyphenylboronic acid (130 mg,
0.85 mmol, 1.3 equiv), anhydrous potassium phosphate tribasic
(279 mg, 1.32 mmol, 2.0 equiv), tris(dba)dipalladium (15.1 mg, 2.5
mol%) and XPhos (31.4 mg, 10 mol%). The crude reaction mixture
was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 9:1) to provide the product (203 mg, 93%
yield) as a white solid. Melting point: 207–209 °C. 1H NMR (300
MHz, CDCl3): δ 7.84 (d, J = 4.8 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.51
(d, J = 4.8 Hz, 2H), 7.10 (s, 1H), 7.02 (d, J = 8.1 Hz, 2H), 3.88 (s, 3H),
2.86 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 159.4, 153.9, 144.5, 143.6,
142.3, 130.7, 130.0, 129.3 (2C), 129.0 (2C), 125.6, 125.0 (2C), 121.1,
114.0 (2C), 94.8, 55.3, 11.7. HRMS (ESI) m/z [M+H+] calcd for
C20H17N2O3: 333.1239; Found: 333.1233.
2-(3-Methoxyphenyl)-3-methyl-7-phenylimidazo[1,2-c][1,3]oxazin-
5-one (6b). Compound 6b was prepared according to general
procedure for Suzuki-Miyaura cross-coupling reaction from 2a (200
mg, 0.66 mmol, 1.0 equiv), 3-methoxyphenylboronic acid (130 mg,
0.85 mmol, 1.3 equiv), anhydrous potassium phosphate tribasic
(279 mg, 1.32 mmol, 2.0 equiv), tris(dba)dipalladium (15.1 mg, 2.5
mol%) and XPhos (31.4 mg, 10 mol%). The crude reaction mixture
was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 9:1) to provide the product (194 mg, 89%
yield) as a white solid. Melting point: 175–177 °C. 1H NMR (300
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
MHz, CDCl3): δ 7.84 (dd, J = 5.1, 1.8 Hz, 2H), 7.54-7.49 (m, 3H), 7.40
(t, J = 8.1 Hz, 1H), 7.30-7.27 (m, 2H), 7.10 (s, 1H), 6.95 (ddd, J = 8.4,
3.6, 1.2 Hz, 1H), 3.90 (s,3H), 2.88 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 159.8, 154.1, 144.4, 143.67, 142.4, 134.4, 130.7, 130.0, 129.6,
129.1 (2C), 125.1 (2C), 122.3, 120.5, 113.9, 113.5, 94.8, 55.3, 11.7.
HRMS (ESI) m/z [M+H+] calcd for C20H17N2O3: 333.1239; Found:
333.1233.
2-(2-Methoxyphenyl)-3-methyl-7-phenylimidazo[1,2-c][1,3]oxazin-
5-one (6c). Compound 6c was prepared according to general
procedure for Suzuki-Miyaura cross-coupling reaction from 2a (200
mg, 0.66 mmol, 1.0 equiv), 2-methoxyphenylboronic acid (130 mg,
0.85 mmol, 1.3 equiv), anhydrous potassium phosphate tribasic
Published on 21 January 2022. Downloaded by UNIVERSITE DE TOURS on 1/30/2022 8:54:27 PM.
(279 mg, 1.32 mmol, 2.0 equiv), tris(dba)dipalladium (15.1 mg, 2.5
mol%) and XPhos (31.4 mg, 10 mol%). The crude reaction mixture
was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 9:1) to provide the product (175 mg, 80%
yield) as a white solid. Melting point: 174–176 °C. 1H NMR (300
MHz, CDCl3): δ 7.84 (dd, J = 6.9, 1.8 Hz, 2H), 7.53-7.39 (m, 5H), 7.11-
7.01 (m, 3H), 3.88 (s, 3H), 2.63 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
157.0, 153.7, 144.5, 143.6, 140.0, 131.6, 130.6, 130.2, 129.9, 129.1
(2C), 125.1 (2C), 124.0, 122.0, 120.7, 111.1, 95.1, 55.5, 11.8. HRMS
(ESI) m/z [M+H+] calcd for C20H17N2O3: 333.1239; Found: 333.1234.
3-Methyl-7-phenyl-2-styrylimidazo[1,2-c][1,3]oxazin-5-one (6d).
Compound 6d was prepared according to general procedure for
Suzuki-Miyaura cross-coupling reaction from 2a (200 mg, 0.66
mmol, 1.0 equiv), trans-2-Phenylvinylboronic acid (126 mg, 0.85
mmol, 1.3 equiv), anhydrous potassium phosphate tribasic (279 mg,
1.32 mmol, 2.0 equiv), tris(dba)dipalladium (15.1 mg, 2.5 mol%) and
XPhos (31.4 mg, 10 mol%). The crude reaction mixture was purified
by column chromatography (silica gel, petroleum ether/ethyl
acetate = 9:1) to provide the product (203 mg, 94% yield) as a white
solid. Melting point: 263–265 °C. 1H NMR (300 MHz, CDCl3): δ 7.83
(dd, J = 5.4, 2.1 Hz, 2H), 7.59-7.47 (m, 5H), 7.39 (t, J = 7.5 Hz, 2H),
7.31 (d, J = 7.2 Hz, 1H), 7.07-7.01 (m, 2H), 2.78 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 153.9, 144.8, 140.0, 137.4, 131.2, 131.0, 130.6, 129.8
(2C), 129.6 (2C), 129.1, 128.1, 127.1 (2C), 125.4 (2C), 123.7, 118.4,
95.3, 10.7. HRMS (ESI) m/z [M+H+] calcd for C21H17N2O2: 329.1290;
Found: 329.1284.
General procedure for Sonogashira cross-coupling reaction of 2a.
In a flame-dried 15mL schlenk tube equipped with a stirring bar and
septum, 2a (200 mg, 0.66 mmol, 1.0 equiv), Pd2(dba)3 (30.1 mg,
0.033 mmol, 0.05 equiv), XPhos (31.4 mg, 0.066 mmol, 0.1 equiv)
and CuI (12.5 mg, 0.066 mmol, 0.1 equiv) were suspended in 8 mL
of degassed triethylamine. Solution of terminal alkyne (0.85 mmol,
1.3 equiv) in 2 mL of Et3N was added dropwise via syringe to the
first solution and the resulting mixture was bubbled and sparged
with argon for 5 min. The reaction was stirred at 80 °C for 1h. The
progress of the reaction was monitored by TLC. After cooling to
room temperature, the resultant suspension was concentrated
under vacuum affording the crude residue. Purification by column
chromatography on silica gel afforded pure desired compounds 5a,
5h and 7a-b.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
2-(4-Fluorophenylethynyl)-3-methyl-7-phenylimidazo[1,2- View Article Online
c][1,3]oxazin-5-one (7a). Compound 7a wasDOI: prepared according to
10.1039/D1OB02352G
general procedure for Sonogashira cross-coupling reaction from 2a
(200 mg, 0.66 mmol, 1.0 equiv), Pd2(dba)3 (30.1 mg, 0.033 mmol,
Organic & Biomolecular Chemistry Accepted Manuscript
0.05 equiv), XPhos (31.4 mg, 0.066 mmol, 0.1 equiv), CuI (12.5 mg,
0.066 mmol, 0.1 equiv) and 1-ethynyl-4-fluorobenzene (103 mg,
0.85 mmol, 1.3 equiv). The crude reaction mixture was purified by
column chromatography (silica gel, petroleum ether/ethyl acetate =
9:1) to provide the product (183 mg, 81% yield) as a white solid.
Melting point: 225–227 °C. 1H NMR (300 MHz, CDCl3): δ 7.83 (dd, J =
6.0, 2.4 Hz, 2H), 7.60-7.50 (m, 5H), 7.08 (t, J = 8.7 Hz, 2H), 7.0 (s,
1H), 2.81 (s, 3H). 19F NMR (282 MHz, CDCl3): δ -110.01. 13C NMR (75
MHz, CDCl3): δ 162.8 (d, J = 249.75 Hz), 154.9, 143.9, 143.6, 133.6
(2C), 131.0, 130.2, 129.7, 129.1 (2C), 126.8, 125.2 (2C), 118.6, 115.8
(2C) (d, J = 21.75 Hz), 94.5, 92.8, 80.8, 11.6. HRMS (ESI) m/z [M+H+]
calcd for C21H14FN2O2: 345.1039; Found: 345.1034.
2-Hexynyl-3-methyl-7-phenylimidazo[1,2-c][1,3]oxazin-5-one (7b).
Compound 7b was prepared according to general procedure for
Sonogashira cross-coupling reaction from 2a (200 mg, 0.66 mmol,
1.0 equiv), Pd2(dba)3 (30.1 mg, 0.033 mmol, 0.05 equiv), XPhos
(31.4 mg, 0.066 mmol, 0.1 equiv), CuI (12.5 mg, 0.066 mmol, 0.1
equiv) and 1-hexyne (70 mg, 0.85 mmol, 1.3 equiv). The crude
reaction mixture was purified by column chromatography (silica gel,
petroleum ether/ethyl acetate = 9:1) to provide the product (141
mg, 70% yield) as a white solid. Melting point: 126–128 °C. 1H NMR
(300 MHz, CDCl3): δ 7.82 (dd, J = 6.0, 2.4 Hz, 2H), 7.52-7.49 (m, 3H),
6.97 (s, 1H), 2.72 (s, 3H), 2.49 (t, J = 6.9 Hz, 2H), 1.67-1.48 (m, 4H),
0.97 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 154.6, 143.7,
143.4, 130.9, 129.9, 129.1 (2C), 127.9 (2C), 125.1 (2C), 95.4, 94.6,
72.3, 30.6, 22.0, 19.2, 13.6, 11.3. HRMS (ESI) m/z [M+H+] calcd for
C19H19N2O2: 307.1447; Found: 307.1439.
General procedure for Heck cross-coupling reaction of 2a.
To a flame-dried pressure tube equipped with a magnetic stir bar
was added sequentially compound 2a (200 mg, 0.66 mmol, 1.0
equiv), alkene (1.64 mmol, 2.5 equiv), anhydrous potassium
phosphate tribasic (279 mg, 1.32 mmol, 2.0 equiv),
tris(dba)dipalldium (60.2 mg, 0.066 mmol, 0.1 equiv) and XPhos
(31.4 mg, 0.066 mmol, 0.1 equiv). The tube was then sealed with a
screw cap with a septum and Toluene (5 mL) was then added by
syringe and stirred. The sealed-tube was then purged of air by
evacuating under vacuum and refilling with Argon three times. The
reaction mixture was then warmed to 130 °C for 16 hours and then
allowed to cool. The progress of the reaction was monitored by TLC.
The solvent was evaporated and the crude material was then
purified by column chromatography on silica gel with the solvent
system stated to afford corresponding compounds 6d, 8a-c.
3-Methyl-(E)-3-(3-methyl-5-oxo-7-phenyl-5H-imidazo[1,2-
c][1,3]oxazin-2-yl)acrylate (8a). Compound 8a was prepared
according to general procedure for Heck cross-coupling reaction
from 2a (200 mg, 0.66 mmol, 1.0 equiv), Methyl acrylate (152 mg,
1.64 mmol, 2.5 equiv), anhydrous potassium phosphate tribasic
(279 mg, 1.32 mmol, 2.0 equiv), tris(dba)dipalldium (60.2 mg, 0.066
J. Name., 2013, 00, 1-3 | 11
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Biomolecular Chemistry
ARTICLE
mmol, 0.1 equiv) and XPhos (31.4 mg, 0.066 mmol, 0.1 equiv). The
crude reaction mixture was purified by column chromatography
(silica gel, petroleum ether/ethyl acetate = 9:1) to provide the
product (108 mg, 53% yield) as a yellow oil. 1H NMR (300 MHz,
CDCl3): δ 7.85–7.82 (m, 2H), 7.66 (d, J = 15.4 Hz, 1H), 7.53–7.51 (m,
3H), 7.04 (s, 1H), 7.02 (d, J = 12.8 Hz, 0.5H), 6.77 (d, J = 15.4 Hz,
0.5H), 3.84 (s, 1H), 2.79 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 167.5,
155.2, 145.8, 138.3, 132.7, 131.1, 129.7, 129.1 (2C), 127.9, 125.2
(2C), 120.2, 119.5, 94.4, 51.7, 10.6. HRMS (ESI) m/z [M+H+] calcd for
C17H15N2O4: 310.0954; Found: 310.0950.
2-(4-Methoxystyryl)-3-methyl-7-phenylimidazo[1,2-c][1,3]oxazin-
5-one (8b). Compound 8b was prepared according to general
Published on 21 January 2022. Downloaded by UNIVERSITE DE TOURS on 1/30/2022 8:54:27 PM.
procedure for Heck cross-coupling reaction from 2a (200 mg, 0.66
mmol, 1.0 equiv), 4-vinylanisole (221 mg, 1.64 mmol, 2.5 equiv),
anhydrous potassium phosphate tribasic (279 mg, 1.32 mmol, 2.0
equiv), tris(dba)dipalldium (60.2 mg, 0.066 mmol, 0.1 equiv) and
XPhos (31.4 mg, 0.066 mmol, 0.1 equiv). The crude reaction mixture
was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 9:1) to provide the product (179 mg, 76%
yield) as a yellow solid. Melting point: 241–243 °C. 1H NMR (300
MHz, CDCl3): δ 7.83 (dd, J = 5.4, 2.1 Hz, 2H), 7.53-7.50 (m, 5H), 7.44
(d, J = 15.9 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.90 (d, J =
15.9 Hz, 1H), 3.86 (s, 3H), 2.78 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
159.6, 154.5, 144.1, 140.7, 130.8, 130.5, 130.0, 129.8, 129.1 (2C),
127.9 (2C), 125.1 (2C), 122.3, 114.6, 114.2 (2C), 113.6, 94.4, 55.3,
10.5. HRMS (ESI) m/z [M+H+] calcd for C22H19N2O3: 359.1396;
Found: 359.1389.
2-(4-Chlorostyryl)-3-methyl-7-phenylimidazo[1,2-c][1,3]oxazin-5-
one (8c). Compound 8c was prepared according to general
procedure for Heck cross-coupling reaction from 2a (200 mg, 0.66
mmol, 1.0 equiv), 4-Chlorostyrene (228 mg, 1.64 mmol, 2.5 equiv),
anhydrous potassium phosphate tribasic (279 mg, 1.32 mmol, 2.0
equiv), tris(dba)dipalldium (60.2 mg, 0.066 mmol, 0.1 equiv) and
XPhos (31.4 mg, 0.066 mmol, 0.1 equiv). The crude reaction mixture
was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 9:1) to provide the product (131 mg, 55%
yield) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, J = 6.0,
2.1 Hz, 2H), 7.53-7.48 (m, 5H), 7.44 (d, J = 15.9 Hz, 1H), 7.35 (d, J =
8.7 Hz, 2H), 7.06 (s, 1H), 7.01 (d, J = 15.9 Hz, 1H), 2.78 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 154.7, 144.3, 144.1, 140.2, 135.6, 133.5,
130.9, 129.9, 129.5, 129.1, 128.9, 127.8, 125.2, 123.3, 117.3, 94.4,
10.5. HRMS (ESI) m/z [M+H+] calcd for C21H16ClN2O2: 363.0900;
Found: 363.0897.
Conclusions
In conclusion, efficient syntheses of a wide variety of new 2,7-
disubstituted 3-methylimidazo[1,2-c][1,3]oxazin-5-ones have been
developed under mild reaction conditions, using sliver-catalyzed
intramolecular annulation process. This approach accommodates a
variety of aliphatic and (het)aromatic alkynes affording selectively
the 6-endo-dig heterocycles in yields of 50 to 87%, without the
formation of concomitant 5-exo-dig products. Further, the reactivity
of resulting bromine-containing imidazooxazinone was studied
12 | J. Name., 2012, 00, 1-3
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Page 12 of 13
Journal Name
through Suzuki, Sonogashira and Heck cross-coupling reactions,
View Article Online
giving successfully access to the expected 2-substituted
DOI: 10.1039/D1OB02352G
imidazooxazinones in yields of 53 to 94%. In addition, the
mechanism of 6-endo-dig oxacyclization was rationalized through a
Organic & Biomolecular Chemistry Accepted Manuscript
computational study. The synthesis of other polycyclic heterocycles
is underway in our laboratory following this protocol, in order to
demonstrate the versatility and the synthetic potential of this new
catalytic system (Ag2CO3/TFA) to promote annulation.
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
We thank the “Departement d’Analyses Chimiques et
Medicales” (Tours, France) for Chemical Analyses.
Notes and references
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