Metal-Free Synthesis of Dibenzoxazepinones via a One-Pot SNAr and Smiles Rearrangement Process: Orthogonality with Copper-Catalyzed Cyclizations

Article abstract of DOI:10.1055/s-0034-1378839

Reported is the transition-metal-free synthesis of substituted dibenzoxazepinones using a convergent domino S_NAr-Smiles rearrangement-S_NAr process. Substrate-scope investigations demonstrated the critical importance of ring electroni

Full text of DOI:10.1055/s-0034-1378839

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1455–1460
letter
1455
T. E. Hurst et al.
Letter
Synlett
Metal-Free Synthesis of Dibenzoxazepinones via a One-Pot SNAr
and Smiles Rearrangement Process: Orthogonality with Copper-
Catalyzed Cyclizations
Timothy E. Hursta
O
O
Matthew O. Kitchinga
Lívia C. R. M. da Frotaa,b
Keller G. Guimarãesa,c
Michael E. Dalziela
NEt
X
R2
NHEt
K2CO3
R1
R1
+
NMP, heat
F
O
HO
transition-metal-free
domino SNAr–Smiles–SNAr
R2
Victor Snieckus*a
12–87% yield
19 examples
a Department of Chemistry, Queen’s University, Kingston, ON, K7L
3N6, Canada
Victor.Snieckus@chem.queensu.ca
b Instituto de Pesquisa de Produtos Naturais, Universidade Federal
Do Rio de Janeiro, Centro de Ciências da Saúde, Bloco H-Ilha do
Fundão, 21941-902, Rio de Janeiro, RJ, Brazil
c Departmento de Química, Universidade Federal de Minas Gerais,
Av. Antônio Carlos, 6627 – 31270-901, Belo Horizonte, MG, Brazil
To Peter, with fond and vivid remembrance of the birth of Synlett and in praise of how far you have taken it.
Received: 11.04.2015
Accepted after revision: 03.06.2015
Published online: 18.06.2015
Recently, we reported a copper-catalyzed synthesis of
dibenzoxazepinones from 2-iodobenzamides which in-
volves an unexpected Smiles rearrangement.10 During our
attempts to elucidate the mechanism of this reaction, we
observed that N-ethyl 4-methyl-2-fluorobenzamide was
converted into the desired dibenzoxazepinone solely under
SNAr conditions in moderate yield. Intrigued by this result,
we sought to optimize and explore the scope of this com-
plementary process, and we now report the highly selective
metal-free synthesis of dibenzoxazepinones 3 from the re-
action of 2-fluorobenzamides 1 with 2-halophenols 2
(Scheme 1).
DOI: 10.1055/s-0034-1378839; Art ID: st-2015-b0267-l
Abstract Reported is the transition-metal-free synthesis of substitut-
ed dibenzoxazepinones using a convergent domino SNAr–Smiles rear-
rangement–SNAr process. Substrate-scope investigations demonstrated
the critical importance of ring electronic effects on the efficiency of the
process. In addition, the orthogonality of this approach with transition-
metal-catalyzed procedures was established.
Key words dibenzoxazepinones, domino reaction, Smiles rearrange-
ment, nucleophilic aromatic substitution, heterocycles
Br
R3
Dibenzo[b,f][1,4]oxazepin-11(10H)-ones are attractive
targets in synthesis due to their extensive and varied bio-
logical activity.1 Thus, unsurprisingly, dibenzoxazepinones
have received considerable attention from the synthetic
community and have traditionally been synthesized via
stepwise classical SNAr and amide-formation methods.2
More recently, dibenzoxazepinones have been prepared by
the intramolecular palladium-catalyzed carbonylative cou-
pling of 2-(2-halophenoxy)anilines3 and by palladium-cata-
lyzed amination of 2-(2-halophenoxy)benzoate esters.4 All
of these methods suffer from the same drawback; the reli-
ance on multistep syntheses which require isolation of in-
termediates at each step. Domino reactions provide an ele-
gant solution to such practical concerns, enabling succes-
sive transformations to occur in a single reaction vessel.5
A resurgence in the investigation of domino SNAr–
Smiles rearrangement processes, first disclosed by
Sapegin,6 has been spearheaded by Ma and co-workers as
demonstrated in their one-pot approaches to dibenzoxaze-
pinones7 and related tricyclic systems.8 Similar approaches
to other fused heterocycles have also been reported.9
O
O
F
HO
NR2
NHR2
2
R1
R1
catalyst, base
DMF or NMP, heat
O
R3
1
3
SNAr
SNAr
O
O
OH
O
NHR2
Br
R1
NR2
R1
Br
Smiles
R3
R3
4
5
Scheme 1 One-pot domino approach to dibenzoxazepinones 3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1455–1460

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T. E. Hurst et al.
Letter
Synlett
Optimization of the reaction was carried out using the
readily accessible N-ethyl 2-fluorobenzamide 1a and com-
mercially available 2-bromo-4-chlorophenol 2 under mi-
crowave conditions. By employing NMP as the reaction sol-
vent, direct comparisons to our previously reported cop-
per-catalyzed process are facilitated.10 A brief examination
of different bases and reagent stoichiometry provided the
optimal conditions (Table 1, entry 4). Examination of the 2-
halophenol component revealed that 2-chloro and 2-fluo-
rophenols were equally competent in the reaction (Table 1,
entries 8 and 9). However, 2-bromophenols were chosen for
the bulk of this study due to their greater commercial avail-
ability and lower cost.
Fortunately, all these dibenzoxazepinones can be easily
prepared in 78%, 86%, and 85% yields (for 3b, 3c, and 3d, re-
spectively) using our copper-catalyzed approach.10
In contrast, benzamides bearing electron-withdrawing
groups proved excellent substrates (Table 2, entries 7–9).
Not only were the desired products 3e–g obtained in high
yields, but lower temperatures were acceptable to effect the
transformations. To establish the lack of any specific micro-
wave effect,13 a reaction using 4-cyano-2-fluorobenzamide
was also performed under conventional heating conditions
to give an identical yield of 3e to that obtained under mi-
crowave irradiation. Since using microwave reactors remain
a safe and convenient way to perform high temperature re-
actions, we adopted this technology for our study.14
Due to its high efficiency in the reaction, and the preva-
lence of the CF3 group in biologically relevant compounds,15
trifluoromethylbenzamide 1e was chosen as the model
substrate for investigation of the scope of the phenolic cou-
pling partner (Table 3).
Table 1 Optimization Studies in the Synthesis of Dibenzoxazepinones
3a
X
Cl
O
O
HO
As observed previously,10 the electronic character of the
substituent on the phenol component is an important fac-
tor in determining whether high yields of products are ob-
tained. Particularly good substrates are heavily halogenated
phenols and electronically deficient heterocycles (Table 3,
entries 4, 5, 8), which are known to be effective participants
in Smiles rearrangement processes.6–10,16 Substituents
which modulate either the nucleophilicity of the phenol
(Table 3, entry 6) or lessen the stability of the putative
Meisenheimer intermediate17 (Table 3, entries 1, 2, 7) de-
crease the efficiency of the reaction.
NEt
NHEt
2
base, NMP
temp, time
F
O
Cl
1a
3a
Entry 2 (equiv) Base (equiv)
X
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
1.2
2
K2CO3 (2.4)
K2CO3 (3)
Br
220
220
220
220
220
220
220
220
200
2
1
2
2
2
2
2
2
2
47
47
54
62
50
–
Br
Br
Br
Br
Br
Br
Cl
F
2
K2CO3 (3)
2
K2CO3 (2.1)
Cs2CO3 (2.1)
K3PO4 (2.1)
DIPEA (2.1)
K2CO3 (2.1)
K2CO3 (2.1)
Cognizant of the potential convolution of metal-cata-
lyzed coupling and SNAr methods,18 we were keen to exam-
ine the orthogonality of our current method with our pre-
viously disclosed copper-catalyzed process.10 To test this
2
2
2
0
2
61
57
hypothesis,
2-bromo-4-trifluoromethyl-6-fluoroben-
zamide (4) was prepared (Scheme 2) via the effective DoM
strategy.19 Thus, taking advantage of the synergistic direct-
ing ability of the two halogens, addition of 3-bromo-5-fluo-
ro-trifluoromethylbenzene to LDA under inverse metala-
tion conditions, followed by inverse quench onto dry ice
gave the desired acid, which was readily converted into am-
ide 4 under standard conditions (see Supporting Informa-
tion).
Gratifyingly, treatment of 4 under the optimal SNAr con-
ditions delivered 1-bromo-dibenzoxazepinone 5 as the ma-
jor product albeit in 26% yield, whilst the application of our
copper-catalyzed method10 led chemoselectively to the 1-
fluoro derivative 7 as the sole product. Further derivatiza-
tion of 5 and 7 was accomplished by either Suzuki–Miyaura
cross-coupling (for 5) or SNAr reactions (for 7) to afford 1-
substituted dibenzoxazepinones 6 and 8a–c, respectively. It
is challenging to prepare these compounds directly, as ster-
ically congested amides perform poorly in the Smiles rear-
rangement.10
2
Armed with the optimal conditions, our attention
turned to examining the scope of the benzamide compo-
nent (Table 2). As expected from a reaction operating under
a SNAr manifold, altering the electronic properties of the
benzamide has a profound effect on the reaction efficien-
cy.11 For example, in comparison to our prototype substrate
3a (Table 2, entry 1), introduction of the weakly electron-
donating methyl group (3b, Table 2, entry 2) led to a notice-
able decrease in yield. This could be effectively countered
by employing the more reactive 2-fluoro-4-chlorophenol
(Table 2, entry 3), which increased the yield to 67%, restor-
ing the efficacy of the process.12 Inclusion of the strongly
electron-donating methoxy group (Table 2, entry 4) exacer-
bated this problem, affording dibenzoxazepinone 3c in sig-
nificantly reduced yield, which could not be improved with
recourse to the alternate phenolic nucleophile (Table 2, en-
try 5). Additionally, 2-fluoro-5-bromobenzamide led to
product in a disappointing yield of 26% (Table 2, entry 6).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1455–1460

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Table 2 Synthesis of Compounds 3a–g. Variation of Benzamide Substituents
Br
Cl
O
O
NEt
NHEt
HO
R1
R1
2a
F
O
K2CO3, NMP
1a–g
3a–g
temp, time
Cl
Entry
Amide 1
Product 3
Temp (°C)
220
Time (h)
Yield (%)
O
O
F
NEt
NHEt
1
2
62
O
1a
Cl
3a
O
O
O
F
NEt
NHEt
2
3
4
5
6
220
220
220
220
220
2
2
2
2
2
40
Me
Me
1b
Cl
3b
3b
1b
67a
14
O
O
F
NEt
NHEt
MeO
O
MeO
1c
Cl
3c
3c
1c
Br
1d
19a
26
O
O
Br
NEt
NHEt
NHEt
NHEt
NHEt
O
F
Cl
3d
O
O
NEt
NEt
NEt
7
8
9
150
150
150
2
2
2
82 (84)b
NC
O
NC
1e
F
Cl
3e
O
O
F3C
F3C
78
O
F
1f
Cl
3f
O
O
O2N
O2N
70
O
F
1g
Cl
3g
a 2-Fluoro-4-chlorophenol was used instead of 2-bromo-4-chlorophenol.
b Yield in parentheses refers to a reaction carried out under conventional heating.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1455–1460

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Table 3 Synthesis of Compounds 3h–n: Variation of Phenol Substituents
Br
R
O
O
HO
F3C
F3C
NEt
NHEt
2b–i
K2CO3, NMP
temp, time
F
O
R
1e
3h–n
Entry
2-Halophenol
Product
Temp (°C)
Time (h)
Yield (%)
O
X
F3C
NEt
1
2
180
150
2
3
24
37
HO
O
2b X = Br
3h
3h
2c X = F
O
F3C
NEt
Br
Me
3
180
4
21
O
HO
2d
Me
3i
O
F3C
NEt
Br
X
4
5
6
150
150
150
2
2
2
87
64
37
O
HO
2e X = Br
X
3j X = Br
3k X = F
2f X = F
O
F3C
NEt
Br
CN
O
HO
2g
CN
3l
O
F3C
NEt
Br
7
180
4
45
O
HO
2h
3m
O
Br
N
F3C
NEt
8
150
2
84
HO
2i
O
N
3n
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4-MeOC6H4B(OH)2
(1.2 equiv)
Pd(PPh3)4 (5 mol%)
O
O
Br
Ar
2a (2 equiv)
K2CO3 (2.1 equiv)
NEt
NEt
2 M Na2CO3–DME (1:1)
90 °C, 12 h
NMP, 150 °C, 2 h
SNAr
F3C
F3C
O
O
Br
O
F
cross-coupling
5, 26%
6
Cl
Cl
NHEt
Ar = 4-MeOC6H4, 89%
F3C
O
O
Cu(dbm)2
(5 mol%)
2a (1.2 equiv)
F
Nu
NuH (1.2 equiv)
K2CO3 (2.4 equiv)
4
NEt
NEt
NMP, 120 °C, 18 h
SNAr
K3PO4 (2.4 equiv)
DMF, 120 °C, 6 h
F3C
F3C
O
O
8a–c
cross-coupling
7, 50%
Cl
Cl
NuH = PhSH, 67%
(S)-PhCH(Me)NH2, 54%
2-F-4-ClC6H3OH, 94%
Scheme 2 Chemoselective synthesis and derivatization of 1-bromo- and 1-fluoro-dibenzoxazepinones 5 and 7.
Considered together, these results provide complemen-
tary methods for the synthesis of 1-substituted dibenzox-
azepinones, which are difficult to access by current meth-
ods.10,20
In summary, we have described a general, highly che-
moselective, and metal-free domino approach for the con-
struction of dibenzoxazepinones from 2-fluorobenzamides
and 2-halophenols. Furthermore, we have demonstrated
the orthogonality21 of this methodology with our copper-
catalyzed process and the tandem application of both of
these methods in the synthesis of challenging 1-substituted
dibenzoxazepinones.10,20,22
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Acknowledgment
NSERC Canada is gratefully acknowledged for continuing support via
the Discovery Grant (DG) program. CNPq, CAPES and Fapemig are
thanked for their generous scholarship support of KGG and LF.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378839.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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compound characterization.
General Procedure – Reaction of 2-Fluorobenzamides with
2-Bromophenols
A sealable tube (10 mL) was charged with the 2-fluoroben-
zamide (1.00 mmol), the 2-bromophenol (2.00 mmol), and
K2CO3 (0.290 g, 2.10 mmol). NMP (3 mL) was added, and the
tube was sealed. The heterogeneous reaction mixture was
heated to 150 °C, 180 °C, or 220 °C for 2–4 h under microwave
irradiation (Biotage Initiator Microwave operating at 400 W).
After cooling to r.t., the reaction mixture was partitioned
between 2 M HCl (20 mL) and EtOAc (3 × 20 mL). The combined
organics were washed with 2 M NaOH (2 × 20 mL) and sat. brine
(20 mL), dried over MgSO4, subjected to filtration, and concen-
trated in vacuo. The crude product was purified by flash chro-
matography on silica gel, eluting with EtOAc–hexanes (1:19 to
1:5) to deliver the title compound.
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references therein.
(13) (a) Kappe, C. O.; Pieber, B.; Dallinger, D. Angew. Chem. Int. Ed.
2013, 52, 1088. (b) Dudley, G. B.; Steigman, A. E.; Rosana, M. R.
Angew. Chem. Int. Ed. 2013, 52, 7918. (c) Kappe, C. O. Angew.
Chem. Int. Ed. 2013, 52, 7924.
(14) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(15) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Ma, J.-A.; Cahard,
D. J. Fluorine Chem. 2007, 128, 975. (c) Meanwell, N. A. J. Med.
Chem. 2011, 54, 2529. (d) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature (London, U.K.) 2011, 473, 470.
N-Ethyl 7-Chlorodibenz[b,f][1,4]oxazepin-11(10H)-one (3a)
The reaction of N-ethyl 2-fluorobenzamide (1a, 0.167 g, 1.00
mmol) with 2-bromo-4-chlorophenol (2a, 0.415 g, 2.00 mmol)
at 220 °C for 2 h gave 3a as a colorless solid (0.170 g, 62%); mp
124–126 °C. IR (film): 1645, 1607 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.89 (dd, J = 1.7, 7.8 Hz, 1 H), 7.48 (dt, J = 1.5, 7.8 Hz,
1 H), 7.32 (d, J = 2.3 Hz, 1 H), 7.28 (s, 1 H), 7.26 (d, J = 7.3 Hz, 1
H), 7.22–7.18 (m, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 1.40 (t, J = 7.1 Hz,
3 H). 13C NMR (100 MHz, CDCl3): δ = 165.7 (C), 160.1 (C), 154.9
(C), 133.6 (C), 133.3 (CH), 132.0 (CH), 130.9 (C), 126.6 (C), 125.9
(CH), 124.5 (CH), 123.7 (CH), 121.9 (CH), 119.5 (CH), 44.2 (CH2),
13.6 (Me). LRMS (EI): m/z (%) = 273/275 (58/19) [M+], 238 (100),
210 (24), 195 (26), 139 (15), 105 (10), 84 (13). HRMS (EI): m/z
calcd for C15H12ClNO2+: 273.0557; found: 273.0563.
(16) Reinaud, O.; Capdevielle, P.; Maumy, M. J. Chem. Soc., Perkin
Trans. 1 1991, 2129.
(17) (a) Artamkina, G. A.; Egorov, M. P.; Beletskaya, I. P. Chem. Rev.
1982, 82, 427. (b) Meisenheimer, J. Justus Liebigs Ann. Chem.
1902, 323, 205.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1455–1460