A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride

Article abstract of DOI:10.1016/j.tetlet.2019.151163

A facile and efficient method has been developed for the synthesis of (Z)-6-allyl-1-phenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]diazonin-7-one and (Z)-1,6-diphenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]diazonin-7-one from anthranilamide via N-arylation/N-allylation and from isatoic anhydride via ring opening/N-arylation/N-allylation followed by ring closing metathesis using Grubbs-II catalyst as a key step. Grubbs-II catalyst was found to be superior over Grubbs-I catalyst in terms of reaction time and yield of the product, and the routes developed were suitable to synthesize benzo fused nine membered nitrogen heterocycles. The requirement of diallylated substrates with protected amine and amide nitrogen is suitable for RCM has been established for the synthesis of diazoninone derivatives.

Full text of DOI:10.1016/j.tetlet.2019.151163

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-
one derivatives via arylation-allylation-RCM pathway of anthranilamide
and isatoic anhydride
Motakatla Novanna a, Sathananthan Kannadasan a, Ponnusamy Shanmugam b,
⇑
a Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
b Organic and Bioorganic Chemistry Division, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute (CLRI), Adyar, Chennai 600020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient method has been developed for the synthesis of (Z)-6-allyl-1-phenyl-1,2,5,6-
tetrahydro-7H-benzo[b][1,5]diazonin-7-one and (Z)-1,6-diphenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]-
diazonin-7-one from anthranilamide via N-arylation/N-allylation and from isatoic anhydride via ring
opening/N-arylation/N-allylation followed by ring closing metathesis using Grubbs-II catalyst as a key
step. Grubbs-II catalyst was found to be superior over Grubbs-I catalyst in terms of reaction time and
yield of the product, and the routes developed were suitable to synthesize benzo fused nine membered
nitrogen heterocycles. The requirement of diallylated substrates with protected amine and amide nitro-
gen is suitable for RCM has been established for the synthesis of diazoninone derivatives.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 8 August 2019
Revised 11 September 2019
Accepted 16 September 2019
Available online xxxx
Keywords:
Aryl amino amides
Isatoic anhydride
Allylation
Arylation
RCM
Benzo[b][1,5]diazonin-7-one
Introduction
peptide mimics with a ring size from five to large complex macro-
cycles [13]. furthermore, synthesis of unsaturated / fused bicyclic
Among medium size ring heterocycles, nine membered azoni-
nones and diazoninones are important due to their existence in
the biologically active natural products (Fig. 1) [1], as drug candi-
dates [2], as materials [3] and as catalyst [4]. Several synthetic
strategies have been developed for the synthesis of azoninones /
diazoninones. The methods include gold catalyzed intramolecular
Ugi hydroarylation [1h], copper catalyzed intramolecular N-
arylation of phosphoramidates and carbamates [5], C-N coupling
of b-lactam and arylhalides followed by trans amidation [6], alky-
lation followed by ring closing metathesis (RCM) [7], Beckmann
rearrangement of cyclooctenone oxime [8], Ugi multicomponent
reaction (MCR) followed by RCM [9], cross coupling of allyl/
homoallyl amino acids followed by RCM [10], aza-Claisen rear-
rangement of 2-vinylpyrrolidines [11], photochemical reaction of
chromium carbene complex and 3°-allyl amines followed by aza-
Cope rearrangement [12]. The RCM have been demonstrated as
one of the powerful tool as an efficient synthetic protocol to syn-
thesize functionalized carbo- and heterocycles. Most of these com-
pounds have been found to be part of natural products or acts as
lactams have been achieved via RCM [14]. Both anthranilamide
[15] and isatoic anhydride [16] have been utilized synthons for
the synthesis of biologically important nitrogen and oxygen hete-
rocyclic compounds.
Despite several methods were reported [5–12] for the construc-
tion of azoninones/diazoninones, it suffers by by-product forma-
tion, lower yields, longer reaction time and harsh reaction
conditions and hence better synthetic methods are still in demand.
Therefore, to overcome the difficulties, we have developed two dif-
ferent pathways for the construction of benzo-fused diazoninones
starting from readily available anthranilamide 1 and isatoic anhy-
dride 10 via a sequence of reactions viz. arylation/allylation-RCM
reaction. The reaction sequence has advantages such as shorter
reaction time and excellent yields. The details of the synthesis,
optimization, scope and limitation of the methodology is outlined
in this manuscript.
Our initial effort to achieve the synthesis of benzo[b][1,5]dia-
zonin-7-one A, a retrosynthetic analysis is proposed in Scheme 1.
Thus, the benzo fused diazoninone derivative A could be obtained
from anthranilamide diallyl derivative B via a RCM. The diallyl
derivative B could be prepared by direct N, N-diallyaltion of
anthranilamide C with ally bromide under basic conditions.
⇑
Corresponding author.
E-mail addresses: kannadasan.s@vit.ac.in (S. Kannadasan), shanmu196@rediff-
mail.com (P. Shanmugam).
https://doi.org/10.1016/j.tetlet.2019.151163
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Novanna, S. Kannadasan and P. Shanmugam, A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one
derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151163

2
M. Novanna et al. / Tetrahedron Letters xxx (xxxx) xxx
benzodiazoninones. Thus, we revised the retrosynthetic pathway
as shown in Scheme 3.
Accordingly, the benzodiazoninone derivative
A could be
obtained from N-phenyl, N, N-diallyl derivative D via RCM. The
N-phenyl, N, N-diallyl derivative D can be achieved by allylation
of N-arylated anthranilamide E. While intermediate E could be
obtained from Cha-Evans-Lam coupling reaction of anthanilamide
C
with aryl boronic acid under copper catalyst conditions
(Scheme 3).
According to Scheme 3, the Cham-Evans-Lam coupling reaction
of anthranilamide 1 in MeOH upon treatment with phenyl boronic
acid, CuCl/TEA at room temperature afforded N-arylated com-
pound 7 in 87% yield. Further, reaction of N-arylated compound 7
in DMSO with allyl bromide and KOH at 70 °C for 12 h provided
N-arylated-N, N-diallylated product 8a and N-arylated-triallylated
product 8b in 25% and 70% yield, respectively (Scheme 4). RCM
reaction of compound 8a in toluene with 5 mol% Grubbs I catalyst
for 24 h failed to provide benzodiazoninone and the unreacted
starting material was recovered quantitatively. Repeating the
above reaction with Grubbs II also failed to provide the desired
product. The free -NH group of compound 8a might coordinate
with catalyst, thus interrupts the catalytic cycle leading to failed
RCM reaction [17]. However, RCM reaction of the triallylated pro-
duct 8b in toluene with 5 mol% Grubbs I catalyst afforded the
desired benzodiazoninone derivative 9a in 70% yield within five
minutes. The structure of product 9a was confirmed by analysis
of spectroscopic data (See SI).
Fig. 1. Natural products with heterononine cores.
Scheme 1. Retrosynthesis analysis for 5,6-dihydro-benzo[b][1,5]diazonin-7(2H)-
one A.
Thus, anthaliniamide 1 in DMSO upon treatment with excess of
allyl bromide 2 and KOH/alumina at 70 °C for 24 h provided three
products namely, amine N-allylated product 3, amide N-allylated
product 4 and N, N-diallylated product 5 in 20%, 60% and 10%
yields, respectively (Scheme 2). Although the most suitable RCM
substrate 5 was obtained only in 10%, the same was obtained in
90% from the second allylation of mono allylated compound 4 by
the treatment of allyl bromide, and sodium carbonate at 70 °C for
12 h. To our dismay, the key RCM reaction of diallylated compound
5 in CH2Cl2 with 5 mol% Grubbs I/II catalysts failed to provide the
benzodiazinone derivative and the unreacted starting material
was recovered quantitatively.
In the quest to optimise the condition and to improve the yield
of 9a, parameters such as solvent, catalyst, catalyst loading, tem-
perature and reaction time were considered. Thus, RCM reaction
of compound 8b was carried out using Grubbs II catalyst and
observed a slight improvement in the yield of 9a up to 80% (Table 1,
entry 2). Hence, Grubbs II catalyst was used for all the subsequent
optimization reactions. The reactions with prolonged reaction time
and increased catalyst loading did not altered the yield of 9a
(Table 1, entries 3–5). Among the reactions in different solvents
such as DCM, benzene, toluene, THF, toluene was found to be suit-
able solvent with improved yield (90%) of compound 9a (Table 1,
The failure of RCM reaction of N,N-diallylated compound 5
prompted us to find the reason for it. Literature revealed that the
synthesis of medium size ring products mainly depend on the con-
formational and stereochemical feature of the double bonds in the
starting material when the RCM reactions is concerned [6,17].
Thus, we assumed of introducing a substitution at amine nitrogen
prior to allylation would provide a diallylated product with a sub-
stitution would be a conformationally favoured and suitable sub-
strate for RCM to provide target nine membered
Scheme 3. Revised retrosynthesis from anthranilamide.
Scheme 2. Synthesis and attempted RCM of N-allyl-2-(allylamino)benzamide 5.
Please cite this article as: M. Novanna, S. Kannadasan and P. Shanmugam, A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one
derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151163

M. Novanna et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 4. Synthesis of 6-allyl-1-phenyl-5,6-dihydro-1H-benzo[b][1,5]diazonin-7(2H)-one 9a.
Table 1
entries 6–10). The reactions with elevated temperatures in toluene
did not improved the yield. A slight decrement in the yield was
observed in a reaction after 60 min at 120 °C (Table 1, entries
11–12). Thus, condition shown in entry 8, Table 1 was found to
be optimum condition.
A plausible mechanism for the formation of product 9a is
shown in Scheme 5. Accordingly, initial reaction of terminal allyl
and methylene group of Grubbs II catalyst lead to the formation
of metallacyclobutane intermediate I, which upon cycloreversion
leads to metal-carbene intermediate II with the elimination of
ethene. Subsequently the metal-carbene intermediate II forms a
second metallacyclobutane intermediate III with the second termi-
nal allyl group. The final cyclo reversion of intermediate III leads to
the formation of desired product 9a.
The failed RCM reaction of substrates 5 and 8a and successful
substrate 8b suggested that the only tetrasubstituted anthranil-
amide substrates are suitable for RCM reaction to afford benzodia-
zoninone. Hence, we again revised the retrosynthetic approach for
the general synthesis of N, N-diphenyl benzodiazoninone starting
from isatoic anhydride (Scheme 6). As shown in Scheme 6, the ben-
zodiazoninone derivative A could be derived from N, N-diphenyl, N,
N-diallyl derivative F via RCM. The N, N-diphenyl, N, N-diallyl
derivative F in turn can be achieved by allylation of N, N-arylated
anthranilamide G. While intermediate G could be obtained from
Cha-Evans-Lam coupling reaction of N-arylated anthranilamide H
with aryl boronic acid/copper catalyst conditions. Compound H
could obtained from isatoic anhydride I by a known procedure
[18].
Optimization of synthesis of compound 9a.
Entry Solvent
Catalyst (mol%) Temp (°C) Time (min.) % Yield 9aa
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCM
Grubbs I (5)
Grubbs II (5)
Grubbs II (5)
Grubbs II (5)
Grubbs II (10)
Grubbs II (5)
Grubbs II (5)
RT
RT
RT
RT
RT
RT
RT
RT
RT
50
100
120
5
5
30
60
5
70
80
80
80
80
85
87
90b
80
90
90
87
5
5
C6H6
Toluene Grubbs II (5)
THF Grubbs II (5)
5
5
9
10
11
12
Toluene Grubbs II (5)
Toluene Grubbs II (5)
Toluene Grubbs II (5)
5
5
60
a
Isolated yield.
Optimised condition.
b
The amide N-arylated product 12 was obtained from a known
reaction of isatoic anhydride 10 with aniline 11a in water at room
temperature [18]. Subsequent Cham-Evans-Lam coupling [19]
reaction of compound 12a with phenyl boronic acid 6a, CuCl/TEA
at room temperature afforded N, N-diarylated compound 13a in
85% yield. Subsequent reaction of compound 13a with allyl bro-
mide/KOH at 70 °C for 12 h provided N, N-diallylated product 14a
in 89% yield (Scheme 7). Similarly, compounds 14b and 14c were
prepared from compounds 13b and 13c in 92% and 90% yields,
respectively.
Scheme 5. Plausible mechanism for the formation of compound 9a.
Scheme 6. Revised retrosynthesis from isatoic anhydride.
Please cite this article as: M. Novanna, S. Kannadasan and P. Shanmugam, A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one
derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151163

4
M. Novanna et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 7. Synthesis of N1, N2-diaryl N1, N2-diallyl aminoamides14a-c from isatoic anhydride 10.
As described for compound 9a, the final RCM reaction of the
diaryl-diallylated product 14a in toluene with 5 mol% Grubbs II
catalyst afforded the desired benzodiazoninone derivative 9b in
92% yield within five minutes (Scheme 8). The other substrates
14b and 14c under similar conditions afforded benzodiazoninone
derivatives 9c and 9d in excellent yields.
All the new compounds were characterised by spectroscopic
data such as 1H NMR, 13C NMR, DEPT-135 and HRMS. The final
structure proof of a representative compound 9c was obtained
from single-crystal XRD method (Fig. 2).
In conclusion, we have demonstrated a facile and efficient
method for the synthesis of (Z)-6-allyl-1-phenyl-1,2,5,6-tetrahy-
dro-7H-benzo[b][1,5]diazonin-7-one and (Z)-1,6-diphenyl-1,2,5,6-
tetrahydro-7H-benzo[b][1,5]diazonin-7-one from anthranilamide
via N-arylation/N-allylation and from isatoic anhydride via ring
opening/N-arylation/N-allylation followed by ring closing
metathesis using Grubbs-II catalyst as a key step. Further work in
exploring the synthesis of medium size ring compounds utilising
the synthetic strategy described in this manuscript is in progress.
Fig. 2. ORTEP diagram of compound 9c (CCDC 1920126) [20].
Funding information
M. N. thanks UGC (New Delhi) for the award of RGNF. P. S.
thanks financial supports from the DST (New Delhi) vide Grant
No. SB/EMEQ-044/2014.
Acknowledgments
P. S. thanks the Director, CSIR-CLRI and S. K. thanks the Chancel-
lor, VIT-Vellore for providing infrastructure facilities. The authors
thanks SAIF-IITM for single crystal XRD analysis and CSIR-NIIST,
Thiruvananthapuram for HRMS analysis.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151163.
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Please cite this article as: M. Novanna, S. Kannadasan and P. Shanmugam, A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one
derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151163