Facile entry into structurally diverse, privileged, (hetero)arene-fused N-alkoxy 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2016.11.064

Rare and highly medicinally relevant N-alkoxy-substituted benzo[1,4]oxazepines have been synthesized conveniently via the base-promoted S_NAr/Smiles rearrangement/S_NAr tandem cyclization of N-alkoxysalicylamides with a range of bis-electrophilic substrates; subsequent de-alkylation gives rise to the respective N-hydroxy versions. The compounds reported herein significantly add to the contemporary arsenal of small molecule tools for drug discovery.

Full text of DOI:10.1016/j.tetlet.2016.11.064

Accepted Manuscript
Facile entry into structurally diverse, privileged, (hetero)arene-fused N-alkoxy
3
,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones
Alexander Sapegin, Elena Reutskaya, Alexey Smirnov, Mikhail Korsakov,
Mikhail Krasavin
PII:
S0040-4039(16)31532-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.064
TETL 48350
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 October 2016
12 November 2016
15 November 2016
Please cite this article as: Sapegin, A., Reutskaya, E., Smirnov, A., Korsakov, M., Krasavin, M., Facile entry into
structurally diverse, privileged, (hetero)arene-fused N-alkoxy 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.064
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Facile entry into structurally diverse, privileged, (hetero)arene-fused N-alkoxy
,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones
3
Alexander Sapegin, Elena Reutskaya, Alexey Smirnov, Mikhail Korsakov, and Mikhail
*
Krasavin

Facile entry into structurally diverse, privileged, (hetero)arene-fused N-alkoxy
,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones
3
a
b
b
b
Alexander Sapegin, Elena Reutskaya, Alexey Smirnov, Mikhail Korsakov, and Mikhail
*
, a
Krasavin
a
Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof,
1
98504 Russian Federation
b
The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl,
1
50000, Russian Federation
*
Corresponding Author; phone: + 7 931 3617872, fax: +7 812 428 6939.
E-mail: m.krasavin@spbu.ru
URL: http://krasavin-group.org
Abstract: Rare and highly medicinally relevant N-alkoxy-substituted benzo[1,4]oxazepines have
been synthesized conveniently via the base-promoted S
N
Ar/Smiles rearrangement/S Ar tandem
N
cyclization of N-alkoxysalicylamides with a range of bis-electrophilic substrates; subsequent de-
alkylation gives rise to the respective N-hydroxy versions. The compounds reported herein
significantly add to the contemporary arsenal of small molecule tools for drug discovery.
Keywords: tandem cyclization, nucleophilic aromatic substitution, Smiles rearrangement,
tricyclic scaffolds, benzo[1,4]oxazepines, privileged structures, Lossen rearrangement.
1
Tricyclic (hetero)arene-fused benzo[1,4]oxazepines belong to a broad family of privileged
tricyclic systems (Fig. 1) that has delivered numerous biologically active compounds and drugs
2
in diverse disease areas. For example, in 2016 alone, tricyclic benzo[1,4]oxazepine scaffolds
3
have been explored in the context of modulating the nuclear farnesoid X receptor (FXR), serine
4
hydroxymethyltransferase 2 (SHMT2) inhibition, and blocking serotonin receptor 5HT2B
5
activity (Fig. 2).

Figure 1. Privileged tricycles for drug design.
Figure 2. Examples of bioactive tricyclic benzo[1,4]oxazepines from the recent literature.
Recently, we have been engaged in developing a unified synthetic methodology toward tricyclic
benzo[1,4]oxazepines that represents a facile, modular approach with an opportunity for flexible
variation of the fused (hetero)aromatic ring portion of the scaffold. The strategy involves
condensation, in the presence of potassium carbonate, of suitably functionalized phenols 1 with
partners 2 containing two leaving groups (1,2-dihalo- or 1-halo-2-nitro (hetero)aromatics). The
cyclization is the net result of tandem S
N
Ar – Smiles rearrangement – S Ar steps (Scheme 1). It
N
is the interplay of these events that is thought to enable the non-catalyzed ring-forming process
which, in many cases, would be difficult to envision taking place without a metal-based catalyst.
Depending on the nature of the Y-Z-H moiety in 1 and the structure of the bis-electrophilic
partner 2, numerous novel or known medicinally important ring systems can be accessed in an
6
expedited fashion. To-date, we have reported benzo[1,4]oxazepines containing lactam (3) or
7
8-10
sultam (4) central (seven-membered) rings, as well as pyrazole- (5)
and imidazoline-fused
6) scaffolds. N-Alkoxy (as well as N-hydroxy) benzo[1,4]oxazepin-5-ones 7 are surprisingly
scarce in the medicinal chemistry literature In fact, only one example of such compounds
namely, 10-methoxy(hydroxy)dibenzo[b,f][1,4]oxazepin-11(10H)-one) has been described in
1
1
(
(
1
2
the context of HIV-1 reverse transcriptase inhibition. In this study, we investigated the
applicability of the above unified synthetic strategy toward the synthesis of N-alkoxy(hydroxy)
tricyclic benzo[1,4]oxazepin-5-ones 7 (Scheme 1).
Scheme 1. Synthetic strategy toward tricyclic benzo[1,4]oxazepines as previously described by
us (3-6) and pursued in this work (7).

We reasoned that the target N-hydroxy and N-alkoxy tricyclic benzo[1,4]oxazepines are
interrelated and one could either target the N-hydroxy version 9 first (using commercially
available N,2-dihydroxybenzamide, 8) and then introduce the O-alkyl group or prepare various
N-alkoxy versions directly and eventually rely on the vast commercially available arsenal of O-
alkyl hydroxylamines and N-alkoxy-2-hydroxybenzamides 10 amenable therefrom (Fig. 3).
Figure 3. Possible approaches to N-alkoxy tricyclic benzo[1,4]oxazepines 7.
However, when hydroxamic acid 8 was treated with bis-electrophilic substrates 2a-b in the
presence of K
2
CO
3
in DMF, it underwent clean conversion to benzo[d]oxazol-2(3H)-one 11
while 2a-b were transformed into their hydroxy-substituted versions 12a-b. Such an outcome, in
1
3-14
our view, can be rationalized by the initial O-arylation of the hydroxamic acid moiety
1
3
followed by Lossen-type rearrangement (Scheme 2).
Scheme 2. Attempted reaction of hydroxamic acid 8 with bis-electrophilic substrates 2a-b.

To explore the alternative approach, we prepared N-alkoxy-2-hydroxybenzamides 10a-b using a
standard amide coupling approach and introduced them into reaction with a series of bis-
electrophilic (hetero)aromatic substrates 2a-i in the presence of K
2
CO in DMF. To our delight,
3
the reaction (Scheme 3) proceeded to completion within 2-6 h at 30-70 ºC, yielding the target N-
methoxy (7a-h) and N-benzyloxy (7i-j) 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones in fair to
1
5
excellent yields (Table 1). The same approach will likely apply to the preparation of other O-
substituted analogs of 7a-j via the use of numerous other hydroxamic acid esters akin to 10a-b.
Scheme 3. Reaction of (hetero)aromatic substrates 2a-i with N-alkoxy-2-hydroxybenzamides
1
0a-b.
Table 1. N-methoxy (7a-h) and N-benzyloxy (7i-j) 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-
ones prepared in this work.
o
Entry
1
10
2
7
Time (h) T ( C) Yield (%)
10a
6
5
3
60
60
40
81
74
63
2
c
b
d
7
a
2
3
10a
10a
2
2
7
b
7
c
4
10a
3
50
76
2
e
7
d

5
6
10a
10a
5
2
60
30
62
85
2
f
7
e
2
g
7
f
7
8
10a
10a
5
3
70
30
77
69
2
h
7
g
2
i
7
h
9
10b
10b
3
5
50
60
41
37
2
j
7
i
1
0
2
k
7
j
For all tandem S
N
Ar/S Ar cyclizations leading to tricyclic benzo[1,4]oxazepines reported so
N
6
-11
far, the Smiles rearrangement was consistently observed, as confirmed by single-crystal X-ray
analyses and/or conclusive correlations in the NOESY spectra of the respective products, and
1
6
appeared to be a pre-requisite for successful ring formation. In the present study, we also
verified if such a mechanistic picture was maintained for N-methoxysalicylamides 10 by
correlations observed in the NOESY spectrum of compound 7b (Fig. 4).
Figure 4. Through-space correlations observed in the NOESY spectrum of compound 7b.
The rare N-alkoxy-substituted tricyclic benzo[1,4]oxazepines 7a-j are of significant interest as
novel versions of medicinally important, privileged heterocyclic motifs that have high relevance
in diverse biotarget areas (vide supra). They can also be viewed as precursors to the respective
N-hydroxy versions of 7, which are also exceedingly rare, and potentially attainable by O-
dealkylation. To demonstrate such a possibility, O-dealkylation of representative compound (7b)

was performed by treatment with BBr
3 in moderate yield (Scheme 4).
3
to give the respective N-hydroxy-substituted compound
1
Scheme 4. O-Demethylation of compound 7b.
In conclusion, we have developed a convenient and practically simple method to prepare rare,
yet highly medicinally relevant, tricyclic N-alkoxy benzo[1,4]oxazepines with a broad diversity
of fused (hetero)aromatic rings. The compounds can be viewed as precursors to N-hydroxy
analogs which cannot be synthesized directly from the respective hydroxamic acid due to the
prevailing Lossen rearrangement. The compounds significantly expand the arsenal of small
molecule tools for drug discovery and are currently being evaluated as anti-infectives. The
results of these studies will be reported on in due course.
Acknowledgements
We gratefully acknowledge support from the Russian Scientific Fund (Project Grant 14-50-
0
0069). NMR studies were performed at the Research Centre for Magnetic Resonance of Saint
Petersburg State University Research Park.
Supplementary data
The supplementary data containing NMR spectra of the reaction products is available on
http://www.sciencedirect.com.
References and notes
1
2
3
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. Wang, X.; Yang, X.; Pan, S.; Guo, R.; Wu, J.; Zhang, Y.; Cheng, C. Int. Patent Appl. WO
2
016127924A1; Chem. Abstr. 2016, 165, 286979.
. Neamati, N.; Xu, S.; Tamura, S. Int. Patent Appl. WO 2016085990A1; Chem. Abstr. 2016,
65, 62459.
. Zhou, Y.; Ma, J.; Lin, X.; Huang, X.-P.; Wu, K.; Huang, N. J. Med. Chem. 2016, 59, 707-720.
4
5
1
6
. Sapegin, A. V.; Sakharov, V. N.; Kalandadze, L. S.; Smirnov, A. V.; Khristolyubova, T. A.;
Plakhtinskii, V. V.; Ivashchenko, A. V. Mendeleev Commun. 2008, 18, 281.

7
8
9
1
1
1
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2
2
014, 70, 1077-1083.
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1
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1
23, 228002.
General procedure for the preparation of compounds 7a-j: the respective N-
alkoxysalicylamide 10 (2 mmol) and 1,2-dihaloarene (1-halo-2-nitroarene) partner 2 (2 mmol)
were combined in anhydrous DMF (7 mL) with freshly calcinated K CO (829 mg, 6 mmol).
1
5.
2
3
The mixture was stirred at the temperature and time period indicated in Table 2. DMF was
removed in vacuo and the residue treated with water (10 mL), which caused the viscous oil to
separate. This was extracted with CH
anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using an appropriate gradient of CH Cl in hexanes as eluent.
6. In cases when the potential Smiles rearrangement was suppressed by unfavorable
electronic effects in the substrates, the process halts after the first S Ar and the cyclization
does not occur (Sapegin, A.; Krasavin, M. Unpublished results).
2
Cl
2
(5 mL) and the organic layer separated, dried over
2
4
2
2
1
N

Highlights





Rare tricyclic N-alkoxy benzo[1,4]oxazepines synthesized via a novel strategy
Involves a tandem S Ar – Smiles rearrangement - S Ar process
N
N
O-Alkyl hydroxamic acids react with bis-electrophilic (hetero)aromatic compounds
N-Hydroxy compounds can be obtained by O-dealkylation
Free hydroxamic acids do not react in the same way and undergo Lossen rearrangement