Convenient Assembly of Privileged (Hetero)Arene-Fused Benzo[1.4]oxazepines by Two Tandem SNAr Events. Part 2 – The Use of o-[N-(Hetero)aryl]aminomethyl Phenols

Article abstract of DOI:10.1002/ejoc.201900264

As was anticipated based on mechanistic reasoning, bis-nucleophilic o-(arylamino)methyl phenols underwent a facile, base-promoted cyclocondensation with reactivity matched bis-electrophilic (hetero)aromatic substrates to give a rare type of substituted di

Full text of DOI:10.1002/ejoc.201900264

A Journal of
Accepted Article
Title: Convenient Assembly of Privileged (Hetero)Arene-Fused
Benzo[1.4]oxazepines via Two Tandem SNAr Events. Part 2 –
The Use of o-(N-(Hetero)aryl)aminomethyl phenols
Authors: Andrey Firsov, Alexander Sapegin, and Mikhail Krasavin
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
Convenient
Assembly
of
Privileged
(Hetero)Arene-Fused
Benzo[1.4]oxazepines via Two Tandem SNAr Events. Part 2 – The Use of o-(N-
(Hetero)aryl)aminomethyl phenols
Andrey Firsov,[a] Alexander Sapegin[a] and Mikhail Krasavin*[a]
[a] A. Firsov, Dr. A. Sapegin, Prof. Dr. M. Krasavin
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
E-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
Supporting information and ORCID(s) from the author(s) for this article are available on the
WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
Abstract: As was anticipated based on mechanistic reasoning, bis-nucleophilic o-
(arylamino)methyl phenols underwent a facile, base-promoted cyclocondensation with reactivity
matched bis-electrophilic (hetero)aromatic substrates to give a rare type of substituted diarene-
fused [1.4]oxazepines. The finding further supports the idea of the importance of the Smiles
rearrangement in the interim of two SNAr events ultimately leading to the formation of the
central cycle in the newly formed tricylic scaffold.
Introduction
In the recent years, we have been developing a facile approach to constructing (hetero)arene-
fused benzo[1.4]oxazepines 3 which involves a base-promoted cyclocondensation of reactivity
matched bis-nucleophiles 1 and (hetero)aromatic bis-electrophiles 2 vicinally substituted with
two leaving groups (LGs). The reaction is thought to proceed via two consecutive SNAr steps
intermitted by a Smiles rearrangement step. The latter have been shown to be essential for the
completion of the ring-forming process: substrate pairs that are not capable of effectively
undergoing said ON (hetero)aryl group migration do not yield the anticipated [1.4]oxazepine
product and the process stalls after the first SNAr step.[1] The approach is rather universal for
phenols substituted at the ortho-position with a nucleophilic ‘Y-Z-H’ motif which can be
activated by deprotonation in the course of the reaction. So far, we have shown it to be
applicable to the one-step synthesis of carba- and aza-versions of dibenzo[b,f][1,4]oxazepin-
11(10H)-ones
(3a),[2]
dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines
(3b),[3]
2,3-
dihydrodibenzo[b,f]imidazo[1,2-d][1,4]oxazepines (3c),[4] dibenzo[b,f][1,4,5]oxathiazepine 5,5-
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
dioxides (3d),[5] 10-alkoxydibenzo[b,f][1,4]oxazepin-11(10H)-ones (3e),[6] and 10-carbonyl
dibenzo[b,f][1,4]oxazepines (3f)[1] (Scheme 1).
Scheme 1. General synthetic approach to tricycles 3.
The latter case (1f3f) provided a particularly useful insight into the mechanistic requirements
for the formation of the [1.4]oxazepine ring.[1] Unlike in other bis-nucleophiles 1a-e, the
phenolic hydroxyl group in 1f is not stabilized by conjugation with an electron-withdrawing
group. This raises the energy of phenoxide 7 and thus makes it energetically unfeasible for
certain substrate pairs (those which do not sufficiently stabilize the postulated Meisenheimer
intermediate 6) to undergo the Smiles rearrangement after the initial SNAr step. This led to the
formation and isolation of diaryl ether 5 as the sole principal product of the reaction with such
substrate pairs. Considering that we were able to restore the desired course of the ring-forming
process toward 8 by introducing electron-withdrawing R group in substrates 1f (thereby
stabilizing 7 and rendering the Smiles rearrangement a thermodynamically feasible process), we
pondered other means to drive it forward. It occurred to us that by increasing nucleophilicity of
the nitrogen-atom in intermediate 4, the Smiles rearrangement would become more kinetically
favored. While some degree of delocalization of the negative charge in 4 is probably needed to
enable formation of the latter, replacing the carbonyl substituent in 1f with a (hetero)aromatic
substituent (9) may serve the purpose and favor the Smiles rearrangement for those substrates 2
which previously did not yield [1.4]oxazepines 8 (Fig. 1). Herein, we present the outcome of
testing this hypothesis.[7]
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
Fig. 1. Involvement of the previously explored (1f) and the newly investigated (9) bis-
nucleophiles in cyclocondensation with reactivity-matched partners 2.
Results and Discussion
For our initial experiments, we selected bis-electrophilic 2,3-dichloro-5-nitropyridine (2a) as it
previously failed to deliver [1.4]benzoxazepine cyclocondensation products 8 with bis-
nucleophiles 1f. Instead, only respective diaryl ethers 5a-b were obtained in modest yield
attesting to the failure of the respective initial adduct 4 to go through the Smiles rearrangement
barrier.[1] When we attempted involving 2a in Cs2CO3-promoted reaction with 9a (prepared, as
all other phenol bis-nucleophiles employed in this work, via reductive amination of salicylic
aldehyde with respective aromatic amine[8]), the full consumption of the starting materials was
achieved in 24 h at 110 ºC and, to our delight, the anticipated product 10a was obtained in 47%
yield. In addition to [1.4]oxazepine 10a, however, a substantial amount (32%) of non-cyclized
product 11a lacking the o-hydroxybenzyl moiety was isolated from the reaction mixture
(Scheme 2).
O
Y
O
NH
Cl
Cl
NO2
Cs2CO3
N
Y
O
N
(A)
H
+
OH
DMF, r.t.-45 oC
24 h
N
Cl
NO2
1f
2a
5a, Y = OMe, 34%
5b, Y = pyrrolidin-1-yl, 66%
N
N
N
N
2a, Cs2CO3
N
HN
(B)
H
+
N
N
DMF, 110 oC
24 h
OH
Cl
O
9a
NO2
NO2
10a, 47%
11a, 32%
Scheme 2. (A) The earlier observed reactions of 2a with bis-nucleophiles 1f[1] and (B) the
recently obtained result from its reaction with 9a.
Both products 10a and 11a presumably resulted from reactions involving the Smiles
rearrangement. 10a is the direct manifestation of the reactivity depicted in Fig. 1. 11a cannot
form in a direct SNAr-type reaction with 9a acting as an N-nucleophile (as we demonstrated in
the control experiments discussed below). A feasible mechanism justifying the formation of 11a
is shown in Fig. 2. It involves the same steps as the formation of 10a except for the last step
where, instead of the second, ring-closing SNAr event, the loss of o-hydroxybenzyl group (likely
in the form of o-quinone methide) likely occurred.
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
Fig. 2. Mechanistic rationale for the formation of products 10a and 11a.
Having established 9a as a competent bis-nucleophile for condensation with bis-electrophilic
(hetero)aromatic substrates 2a capably of going through the Smiles rearrangement en route to
[1.4]oxazepine 10a (while also observing an unexpected complication in the formation of 11a),
we proceeded to screen a set of o-(arylamino)methyl phenols (9a-d) in reactions with bis-
electrophilic (hetero)aromatic partners 2a-h (Table 1). All reactions were run under essentially
the same conditions; slight variations in temperature and reaction time were dictated by the need
to drive reactions to completion (as monitored by analytical HPLC analysis of the reaction
mixtures).
Table 1. Reactions of o-(arylamino)methyl phenols 9a-d with bis-electrophilic (hetero)aromatic
substrates 2a-h.
T
Time Yield
Entry
9
2
Product 10(11)
(ºC)
(h)
(%)
N
N
N
O
47
(10a);
32
10a
NO2
1
110
24
(11a)
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
2
110
110
24
24
67
51
3
4
5
6
6
110
110
110
110
36
36
36
36
48
51
62
59
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
7
80
80
12
12
72
74
8
9
80
12
76
10
11
80
12
24
68
59
100
12
100
24
54
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
13
100
100
100
24
24
24
51
58
41
14
15
16
100
24
55
As it is evident from the data presented in Table 1, the unwanted o-quinone methide elimination
leading to the formation (sometimes exclusive) of non-cyclized products 11 was substrate-
specific and was observed only in reactions involving 2a as the bis-electrophilic partner. In all
other cases, the desired tricylic N-(hetero)aryl [1.4]diazepinones 10a-o were obtained in fair to
good yields. The regiochemical identity of these compounds, corresponding to the intermittent
Smiles rearrangement, was unequivocally established, when possible, by the through-space
interactions between neighboring protons in the NOESY spectra as shown in Fig. 3 for a set of
representative compounds.
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
Fig. 3. Through-space interactions observed in the NOESY spectra of compouns 10c, 10j and
10k.
The results presented in Table 1 also allow concluding that a number of substrates (2a-e), some
of which were previously deemed unreactive towards weaker bis-nucleophiles 1f (presumably,
due to inability of the initial SNAr products to cross the Smiles rearrangement barrier) were now
found capable of delivering the target [1.4]oxazepines 10 via tandem SNAr-Smiles
rearrangement-SNAr process.
In order to additionally confirm that compounds 11 cannot form via a direct SNAr process
involving bis-nucleophilic phenols as N-nucleophiles, we prepared and tested methoxy derivative
9e in the reaction with 2f. While this attempt delivered no product, the respective N-methyl
derivative 12 gave phenoxy pyrazine product 13, thereby confirming that the phenoxide anion is
the one capable of bringing about SNAr steps leading to the formation of products 10(11)
(Scheme 3).
Scheme 3. Results of control experiments with O- and N-substituted compounds 9e and 12.
It should be noted that compounds 10a-o reported in this work are representatives of an
exceedingly rare type of substituted diarene-fused [1.4]oxazepines substituted with a (hetero)aryl
group at the ring nitrogen atom. Although they clearly belong to the general cluster of privileged
tricyclic scaffolds,[1] these compounds have not been subject of extensive biological annotation
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
(perhaps due to the lack of streamlined methods to construct them), except for some examples of
histone deacetylase inhibitors[9] and compounds endowed with hyperthermal activity.[10]
Conclusions
In summary, by using mechanistic reasoning we designed a series of structurally simple bis-
nucleophilic phenols having greater nucleophilicity compared to previously studied versions of
these substrates. These gave rise to a rare type of substituted tricyclic [1.4]oxazepines in base-
promoted cyclocondensation reaction with reactivity-matched bis-electrophilic aromatic
partners. The scope of the reaction is markedly broader with respect to the latter. The study
further supports the hypothesis about the Smiles rearrangement occurring in these reactions in
the interim of two SNAr events as a pre-requisite to a successful formation of [1.4]oxazepine
ring.
Experimental Section
General procedure for preparation of compounds 10a-o and 11a-c. A mixture of
aminophenol 9a-c (0.5 mmol), bis-electrophilic (hetero)aromatic substrates (0.5 mmol) and
freshly calcinated Cs2CO3 (490 mg, 1.5 mmol) in anhydrous DMF (2 mL) was stirred, at a given
temperature for 12 h. DMF was removed in vacuo and the residue was treated with water (10
mL), which caused a viscous oil to separate. It was extracted with CH2Cl2 (5 mL), the organic
layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel using an appropriate gradient of
ethyl acetate in hexanes as eluent.
Acknowledgement
This research was supported by the Russian Science Foundation (grant no. 17-73-20185). We
thank the Research Centre for Magnetic Resonance, the Center for Chemical Analysis and
Materials Research, and the Centre for X-ray Diffraction Methods of Saint Petersburg State
University Research Park for obtaining the analytical data.
Keywords: nucleophilic aromatic substitution; Smiles rearrangement; [1.4]oxazepines;
privileged structures; reactivity-matched synthons
[1] A. Sapegin, M. Krasavin, Eur. J. Org. Chem. 2019, the preceding publication in this issue.
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10.1002/ejoc.201900264
European Journal of Organic Chemistry
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Graphical Abstract:
TOC text:
Simple bis-nucleohilic o-[(hetero)arylamino]methyl phenols are more reactive than the earlier
studied acyl versions in the formation of [1.4]oxazepine cycle via double nucleophilic
substitution. The resulting structurally new N-(hetero)aryl [1.4]oxazepines formed in good yield.
This finding supports the idea of the importance of the Smiles rearrangements in between of the
two SNAr events.
Key topic:
Heterocycle synthesis
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