Metal-free formal synthesis of phenoxazine

Article abstract of DOI:10.3762/bjoc.14.126

A transition metal-free formal synthesis of phenoxazine is presented. The key step of the sequence is a high-yielding O-arylation of a phenol with an unsymmetrical diaryliodonium salt to provide an ortho-disubstituted diaryl ether. This species was cyclized to acetylphenoxazine in moderate yield. The overall yield in the three-step sequence is 72% based on recovered diaryl ether. An interesting, unusually stable iodine(III) intermediate in the O-arylation was observed by NMR and could be converted to the product upon longer reaction time.

Full text of DOI:10.3762/bjoc.14.126

Metal-free formal synthesis of phenoxazine
Gabriella Kervefors, Antonia Becker, Chandan Dey and Berit Olofsson*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1491–1497.
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, SE-106-91 Stockholm, Sweden
doi:10.3762/bjoc.14.126
Received: 30 March 2018
Accepted: 06 June 2018
Published: 20 June 2018
Email:
Berit Olofsson* - berit.olofsson@su.se
*
Corresponding author
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
Keywords:
arylation; cyclization; diaryl ether; diaryliodonium salt; phenol
Guest Editor: T. Wirth
©
2018 Kervefors et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A transition metal-free formal synthesis of phenoxazine is presented. The key step of the sequence is a high-yielding O-arylation of
a phenol with an unsymmetrical diaryliodonium salt to provide an ortho-disubstituted diaryl ether. This species was cyclized to
acetylphenoxazine in moderate yield. The overall yield in the three-step sequence is 72% based on recovered diaryl ether. An inter-
esting, unusually stable iodine(III) intermediate in the O-arylation was observed by NMR and could be converted to the product
upon longer reaction time.
Introduction
Phenoxazine (1) is a tricyclic compound consisting of an rated with electron-withdrawing substituents, which proceed
oxazine ring fused between two benzene rings. A range of com- through a Smiles rearrangement (Scheme 1a) [15-17]. More
pounds with interesting biological or photophysical properties recently, Bolm and co-workers reported a metal-free cycliza-
contain the phenoxazine core, where the amine moiety is either tion of iodo-substituted diaryl ethers with a broad scope
functionalized or oxidized to the corresponding imine [1-4]. (Scheme 1b) [18]. Transition metal-catalyzed cross couplings
Phenoxazine derivatives can display antitumor activity [5-8], have also been employed to form the required C–O and C–N
are present in a variety of dyes [9], and can be applied in bonds, e.g., by Cu-catalyzed cyclization of 2-(2-bromo-
chemosensors and dye-sensitized solar cells (Figure 1) [10-12]. phenoxy)anilines [17,19,20]. A Pd-catalyzed double N-aryl-
N-Arylphenoxazines were recently employed as photoredox ation using di(2-bromoaryl) ethers and primary amines was
catalysts in metal-free polymerizations [13].
recently developed (Scheme 1c) [21]. Furthermore, N-functio-
nalization of the phenoxazine core can be performed under
The first synthesis of phenoxazine dates back more than metal-free conditions [22].
00 years [14], and a range of synthetic routes to this target has
1
since been developed [1]. Transition metal-free routes include Our research group has reported highly efficient O-arylations of
the synthesis from 2-aminophenols and 3,4-dihaloarenes deco- phenols using diaryliodonium salts [23-25], which are reactive
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Beilstein J. Org. Chem. 2018, 14, 1491–1497.
Figure 1: Compounds containing a phenoxazine moiety.
Scheme 1: Reported syntheses of phenoxazine derivatives.
electrophilic arylation reagents [26-28]. As diaryliodonium salts According to the retrosynthesis depicted in Scheme 2, target 1
can be easily synthesized in a one-pot manner [28], we envi- would be formed from acetyl derivative 2, which can be derived
sioned that phenoxazines could be obtained in a straightfor- from the functionalized diaryl ether 3 using Bolm’s N-arylation
ward and efficient manner from commercially available starting (see Scheme 1c) [18]. The synthesis of diaryl ether 3 is the key
materials.
step of the sequence, proceeding via arylation of phenols with
Scheme 2: Retrosynthesis of phenoxazine.
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Beilstein J. Org. Chem. 2018, 14, 1491–1497.
diaryliodonium salts using our reported methodology [23-25]. tandem arylation and cyclization to reach N-acetylphenoxazine
In reactions with unsymmetrical iodonium salts, this type of (2) in one pot. The arylations were analyzed by crude 1H NMR
O-arylation is known to have an ortho-effect, i.e., chemoselec- yields using an internal standard and revealed that a minor
tive transfer of the ortho-substituted aryl moiety [29,30]. The amount of a byproduct was formed along with the expected
use of unsymmetrical iodonium salts facilitates the synthesis of diaryl ether 3 (Table 1, entry 1). This was initially believed to
the reagents and avoids waste of an expensive iodoarene, and be 2-iodophenyl 4-anisyl ether, i.e., the diaryl ether that would
we hence envisioned chemoselective transfer of the desired aryl form upon transfer of the anisyl moiety to the nucleophile. The
moiety from an unsymmetrical salt with a suitable “dummy” reaction was thus further investigated to find conditions that
aryl group.
would allow high yield of 3 with complete chemoselectivity.
Two different approaches to reach 3 are illustrated, either em- The amount of byproduct remained approximately constant
ploying 2-iodophenol (4) and 2-acetamido-substituted salt 5 when solvents and bases were screened (Table 1, entries 1–4,
(
(
route A) or N-functionalized phenol 6 with 2-iodophenyl salt 7 see also Supporting Information File 1), whereas certain
route B). In route A, the chemoselective transfer of the changes in stoichiometry influenced the yield (Table 1, entries
2
-amido aryl group over the other aryl group would require a 5–7). Diaryl ether 3 was efficiently formed using the conditions
quite electron-rich dummy group or the use of a symmetric in entry 7, and could be easily isolated by flash chromatogra-
iodonium salt (R = 2-NHAc). In route B, the challenge would phy in 91% yield. A shortening of the reaction time to 1 h
instead be the synthesis of iodonium salt 7, as the iodo substitu- profoundly increased the amount of byproduct to 52% (Table 1,
ent might be prone to oxidation. Furthermore, selective O-aryl- entry 8). Surprisingly, the desired product 3 could be isolated in
ation in the presence of an amide moiety could be challenging, 58% yield from this experiment after prolonged storage of the
as N-arylation of amides with diaryliodonium salts proceeds at neat crude product at rt, along with 52% of 4-iodoanisol (see
room temperature [31,32].
Supporting Information File 1).
Results and Discussion
This observation is in line with a ligand-coupling (LC) mecha-
We initially focused on route A and decided to explore an nism [30,35,36] where the observed byproduct could be the
anisyl moiety as dummy group in iodonium salt 5. The elec- T-shaped intermediate 9 or the corresponding 4-coordinated
tronic difference between the aryl groups in the formed salt species with two phenoxide units [37]. This type of intermedi-
should be sufficient to allow chemoselective transfer of the ate is expected in LC reactions but can rarely be detected. The
desired aryl moiety, and the ortho-effect exerted by the 2-amido groups of Quideau and Muñiz have reported such compounds
substituent was expected to improve the chemoselectivity using an ortho-nitro substituted phenol and tetrafluorophthal-
further. Salt 5a was synthesized in good yield using our re- imide as nucleophiles, respectively [38,39]. Those compounds
ported arylboronic acid methodology [33] (Scheme 3). Attempts were isolable at room temperature and could be converted to the
to form the corresponding tosylate salt, either from iodoarene 8 arylated products upon heating. The reactivity of 9 is unusual,
with anisole and mCPBA/TsOH [34] or via anion exchange of as it proved stable to neutral work-up with brine, formed prod-
5
a were in vain.
uct 3 upon longer reaction time or rt storage in CDCl3 or neat,
but decomposed to starting materials upon work-up with sat.
The O-arylation of 2-iodophenol (4) with salt 5a was investigat- ammonium chloride solution (Table 1, entry 11).
ed using our previously reported methodology [24,25]. As ex-
pected, the reaction proceeded well, both in THF and toluene, Due to the successful outcome of route A, pathway B was only
of which the latter was most appealing as it might allow a briefly explored. Several dummy groups were considered for
Scheme 3: Synthesis of iodonium salt 5a.
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Beilstein J. Org. Chem. 2018, 14, 1491–1497.
Table 1: Optimization of the O-arylation of route A.a
entry
1
phenol 4
salt 5a
(equiv)
base
(equiv)
T (°C)
time (h)
yield 3 (%)b
yield byproduct (%)c
(equiv)
1
1
1
1
1.1
1.1
1.1
1.1
t-BuOK (1.1)
t-BuOK (1.1)
NaH (1.1)
rt
rt
rt
rt
18
18
18
18
80
67
14
65
3
2
2
2
2d
3
4
K2CO3 (1.1)
5
6
7
1
1
1.5
1.5
1
t-BuOK (1.1)
t-BuOK (1.5)
t-BuOK (1.5)
rt
rt
rt
18
18
18
77
74
4
14
5
1.5
89 (91)
8
9
1.5
1
1
1
1
1
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
rt
40
80
rt
1
1
1
1
9 (58)
49
52
38
10
1.5
1.5
79
4
11e
7
trace
aPhenol 4 (0.2 mmol) and base were stirred in anhydrous toluene (1 mL) for 30 min at rt before addition of 5a. The reaction was stirred at the tabu-
lated temperature and time and quenched with brine (see Supporting Information File 1 for details). b1H NMR yield using dibromomethane as internal
standard (isolated yield in parenthesis). c1H NMR yield based on the assumption of one OMe group in byproduct, see Supporting Information File 1.
d0.5 mL DME as co-solvent. eQuenched with sat. ammonium chloride solution instead of brine.
the iodonium salt 7. A phenyl dummy might give sufficient With high-yielding conditions for the O-arylation step at hand
chemoselectivity due to the ortho-effect, and the synthesis of (Table 1, entry 7), the literature-reported [18] cyclization of 3 to
salt 7a was straightforward using 2-iodophenylboronic acid N-acetylphenoxazine (2) was performed (Scheme 6a). In our
(
Scheme 4a). The use of an anisyl dummy proved more diffi- hands, however, product 2 could only be isolated in 49% yield
cult, and tetrafluoroborate 7b was isolated with impurities using as the cyclization did not reach completion. The ratio of prod-
the arylboronic acid methodology [33] (Scheme 4b). The uct 2 to starting material 3 remained 1:1 also upon modified
mCPBA/TsOH methodology [34] with 1,2-diiodobenzene (10) conditions (see Supporting Information File 1). Still, the reac-
and anisole or trimethoxybenzene (TMP-H) as dummy surpris- tion was clean and the yield based on recovered starting materi-
ingly delivered the corresponding bisiodonium ditosylates [40- al was 96%. The limited conversion into product 2 complicated
4
2] instead of the desired 7 (Scheme 4c, see also Supporting our aim to perform the arylation and cyclization in one pot. The
Information File 1). The stoichiometry of the reaction did not tandem reaction set up depicted in Scheme 6b delivered the
allow complete formation of 11, but the yield based on TMP-H O-arylated 3 in 87% yield, rather than product 2, further illus-
was 89%.
trating the sensitivity of the cyclization step. Attempts to
perform the cyclization with t-BuOK and DMEDA only
The arylation of phenol 6 with unsymmetrical diaryliodonium resulted in byproduct formation.
salt 7a provided the desired diaryl ether 3 in modest yield and
limited chemoselectivity (Scheme 5). Competitive N-arylation The deprotection of 2 is reported to proceed in high yield [18],
of the amide moiety [31,32] was not observed. Preliminary and the synthesis of 2 hence constitutes a metal-free formal syn-
attempts to employ the bisiodonium salt 11 in the arylation of 6 thesis of phenoxazine (1). The complete route is depicted in
were fruitless (see Supporting Information File 1), and we Scheme 7 and delivered N-acetylphenoxazine (2) in 72%
hence concluded that route A was most suitable for further in- overall yield over 3 steps. Combined with the literature yield for
vestigations.
the deprotection, this would provide the target 1 in 65% overall
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Beilstein J. Org. Chem. 2018, 14, 1491–1497.
Scheme 4: Synthesis of iodonium salt 7.
Scheme 5: O-Arylation via route B.
yield based on recovered 3. The required starting materials in
this route can easily be further substituted; hence we expect the
methodology to be applicable also for phenoxazine derivatives.
Conclusion
A transition metal-free formal synthesis of phenoxazine is
presented, relying on the O-arylation of phenol 4 with unsym-
metrical diaryliodonium salt 5a to provide substituted diaryl
ether 3 as the key step. This species underwent an intramolecu-
lar N-arylation to provide the cyclized product 2. The overall
yield in this three-step sequence is 72% based on recovered
diaryl ether. Interestingly, an unusually stable iodine(III) inter-
mediate was formed in the O-arylation. This species survived
neutral work-up and could be converted to product upon longer
reaction time.
Scheme 6: a) Cyclization of diaryl ether 3. b) Attempted one pot-syn-
thesis of 2. aBased on recovered 3.
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Beilstein J. Org. Chem. 2018, 14, 1491–1497.
Scheme 7: Formal synthesis of phenoxazine (1). aBased on recovered 3.
5.
6.
7.
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Supporting Information
Supporting Information File 1
Prinz, H.; Chamasmani, B.; Vogel, K.; Böhm, K. J.; Aicher, B.;
Gerlach, M.; Günther, E. G.; Amon, P.; Ivanov, I.; Müller, K.
J. Med. Chem. 2011, 54, 4247–4263. doi:10.1021/jm200436t
Avendaño, C.; Menéndez, J. C. Medicinal Chemistry of Anticancer
Drugs; Elsevier: Amsterdam, 2008; pp 93–138.
Experimental details for the synthesis of starting materials
and products, analytical data for products 2, 3, 5a, 7a, 9 and
1
1.
[https://www.beilstein-journals.org/bjoc/content/
doi:10.1016/B978-0-444-52824-7.00004-4
supplementary/1860-5397-14-126-S1.pdf]
Gao, S.; Takano, T.; Sada, K.; He, J.; Noda, C.; Hori-Tamura, N.;
Tomoda, A.; Yamamura, H. Br. J. Pharmacol. 2002, 137, 749–755.
doi:10.1038/sj.bjp.0704939
Supporting Information File 2
NMR spectra for products 2, 3, 5a, 7a and 11.
Martinez, V.; Henary, M. Chem. – Eur. J. 2016, 22, 13764–13782.
doi:10.1002/chem.201601570
[https://www.beilstein-journals.org/bjoc/content/
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