Copper-catalysed cross-coupling affected by the Smiles rearrangement: A new chapter on diversifying the synthesis of chiral fluorinated 1,4-benzoxazine derivatives

Article abstract of DOI:10.1039/c5ra18897k

Synthesis of different chiral fluorinated Boc-[1,4]benzoxazins from their open chain precursors were investigated. The NMR spectra and crystallographic data showed the presence of the Smiles Rearrangement (SR) followed by copper catalysed coupling. The in

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Copper-Catalysed Cross-Coupling Affected by the Smiles
Rearrangement: A New Chapter on Diversifying the Synthesis of
Chiral Fluorinated 1,4-Benzoxazine Derivatives
Received 00th January 20xx,
Saba Alapour,a Deresh Ramjugernathb and Neil A. Koorbanallya*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Synthesis of different chiral fluorinated Boc-[1,4]benzoxazin from reaction11 and the copper-catalysed intramolecular direct ring
a
their open chain precursors were investigated. The NMR spectra closure,12 biocatalytic method13 and several other older
and crystallographic data showed the presence of the Smiles methods.14-18
Rearrangement (SR) followed by copper catalysed coupling. The
Rearrangement reactions are generally undesired, but in many
instances can be favourable since they are able to facilitate the
synthesis of synthetically complicated chemicals.19 Additionally,
these reactions provide an opportunity to synthesise organic
molecules that were not possible previously.
influence of the Boc protecting group, solvent, base, catalyst and
the conformational changes of adducts was explored in detail by
careful reaction optimization. No product was obtained in the
absence of Boc, indicating its crucial role. Finally, a new
mechanism for the SR copper catalysed ring closure was proposed.
The Smiles Rearrangement (SR) has been used in the synthesis of
different benzoxazinones.20-23 To the best of our knowledge there
have been no reports of this rearrangement in the synthesis of
benzoxazines. In spite of the wealth of literature pertaining to SR,
there is still a gap in the literature with regard to studies on the
conformational effect on the copper catalysed ring closure via SR. It
is well accepted that conformations of precursors can play a crucial
role in chemical reactions and biological activity.24-30 As such, there
is a need to explore this aspect further.
Benzoxazines exist in many drugs and herbicides, and are widely
used as building blocks of bioactive molecules. They exhibit
interesting biological and pharmaceutical properties such as
progesterone receptor (PR) modulation, antianxiety, anti-HIV,
agonist and antagonist activities.1-4 Particularly, chiral
dihydrobenzo[1,4]oxazines attracted much attention due to their
interesting biological activities.5, 6 Chiral dihydrobenzo[1,4]oxazines
are also employed as catalysts for the asymmetric transfer
hydrogenation of α,β-unsaturated aldehydes.7
The initial aim of our work was to synthesise Levofloxacin’s
precursor (6fi) via a copper catalysed ring closure, but surprisingly
the interruption by the SR was detected in all derivatives. Further
investigation led us to provide a new insight to this rearrangement.
The effects of conformational change as well as the presence of
fluorine in novel derivatives of benzoxazines were investigated by
NMR and X-ray crystallography. These studies helped us to propose
Fluorine atoms contained in the core structure of a drug results in
enhancement of several biological properties such as solubility,
lipophilicity, metabolic stability and binding selectivity.8
Levofloxacin, Ciprofloxacin, Norfloxacin and Efavirenz are examples
of pharmaceutical drugs containing a fluorine atom together with
dihydrobenzo[1,4]oxazines in the same molecule.8-10
Consequently, a wide range of synthetic procedures have been a new mechanism for the one pot SR-ring closure reaction of
developed for the synthesis of these fluorinated chiral benzoxazine type compounds. Herein we report an operationally
benzoxazines. These procedures include direct cyclization using a simple and economic technique for the synthesis of
metal catalyst such as Pd in the Buchwald-Hartwig coupling enantiomerically pure fluorinated [1,4]-benzoxazines assisted by
the SR and involving a copper mediated intramolecular ring closure,
which can be considered as a novel procedure in comparison to the
existing literature.
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Scheme 1. Synthesis of Boc-[1,4]benzoxazin 6
indicated that Cu(OAc)2.H2O was the best catalyst amongst other
copper sources. Control experiments in the absence of ligand
revealed that Cu(OAc)2.H2O alone was capable of this catalytic
performance and application of an external ligand poisoned the
reactions. In addition, no product was formed in the absence of
copper, indicating its importance in the mechanism of the reaction.
Various bases were also tested and amongst these, Cs2CO3 showed
the best results. This was in agreement with other reports.6, 31, 35, 37
Table 1. Synthesis of different Boc-benzoxazine via SR copper
catalyzed ring closure. (Temperature: 90 °C).
X1
Boc
N
R2
Boc
NH
Cu(OAc)2. H2O, Cs2CO3
and NMP
O
Commercially available alaninol 1 was protected with Boc via
standard procedures11 to give 2, which was transformed to a cyclic
sulfamidate 3 over two steps with 90% overall yield.11 The reaction
of 3 and phenol 4 afforded the product 5 by nucleophilic cleavage in
98% yield.11 The reaction of 5 with a catalytic amount of copper (II)
acetate (20 mol %,) at 90 °C in (undried) NMP in the presence of
Cs2CO3 (3 eq.) provided Boc-[1,4]benzoxazin 6 by replacing the
leaving group X1 (either Br, I or F depending on the substrate)
(Scheme 1, Table 1).
O
X2
X2
R2
No
.
Adduct (5)
(Yielda %)
Boc-[1,4]benzoxazine
(yielda %)b,c
1
2
3
5a (99%)
5b (99%)
5c (99%)
6a (84%)
6a (82%)
6b (NR)
On inspection of the 13C and 19F NMR data of the product 6f from
the precursor 5h (available in the supplementary data), it was
apparent that the expected 6fi (Scheme 2) did not form since there
was a missing C-F resonance in the 13C NMR spectrum and only a
single fluorine resonance was observed in the 19F NMR spectrum.
The optimized reaction conditions were applied to 5d and the same
observation was found in the spectra of 6c. Instead of 6ci (scheme
2), the rearranged compound (6c) was found to be the actual
structure. This rearrangement, where the stronger F base acts as a
leaving group, can be categorized as a SR that typically occurs in the
presence of base in polar solvents.6, 31, 32 Some reports have shown
that Cu was essential for the SR ring closure to occur.6, 33-36
4
5d (99%)
6c (96%)
6d (87%)
5
6
7
5e (98%)
5f (98%)
5g (99%)
Scheme 2. Synthesis of Boc-[1,4]benzoxazin 6 interrupted by SR
6d (82%)
6e (NR)
8
5h (99%)
6f (98%)
6g (NR)
9
5i (99%)
a Isolated yield (%). b Temperature: 90 °C. c The reaction time for all reactions is
24 hours.
The reactions were repeated with the optimised conditions at room
temperature instead of 90 °C. Surprisingly, the coupling reaction on
5d and 5h proceeded to 6c and 6f with 90 % yield at room
temperature, while 5a and 5b proceeded to 6a, and 5e and 5f to 6d
Considerable optimization (available in supplementary data)
showed that undried NMP (N-methyl-2-pyrrolidone) provided the
best yield amongst other polar aprotic solvents. These results also
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at 90 °C only and no product was observed at room temperature prompted us to study the conformation of adducts in the reaction
(Table 1). With the precursors 5c, 5g and 5i, the products 6b, 6e in order to gain an insight into how the products were formed.
and 6g could not be formed even at 90 °C. This observation
Scheme 3. Plausible catalytic cycle for formation of Boc-[1,4]benzoxazin through the SR copper catalyzed ring closure reaction
F
F
F
F
F
F
F
F
F
F
Ionic
Cu
O
N
O
Br
Cs2CO3
O
O
N
O
O
O
O
O
Br
Br
Br
Boc
Br
HN
Me
N
O
Me
Meisenheimer complex
5h(c)
NH
O
H
H
H
H
H
Me
H
H
O
O
H
H
5h(a)
F
F
F
5h(b)
Br
F
F
F
Br
Cu II (OAc)2
Cu I (OAc)
O
O
Boc
N
O
O
N
OCu
Cs2CO3
N
N
N
O
O
O
Br
Br
F
Br
O
F
OCs
OCu
H
OH
H
H
H
F
Me
H
Me
H
Me
6f
H
H
H
5h(f)
5h(e)
5h(d)
The presence of an iodine or bromine atom in the ortho position to in increasing the acidity of the amide proton and makes its
the oxygenated side without further substitution (5a, 5b, 5e and 5f) deprotonation via Cs2CO3 easier.35, 40
provided almost the same yield for the cyclized products 6a and 6d
It is also well accepted that the localized negative charge on the
(~85 %) (Table 1). The highest yield was obtained for 6e (98%) with
nitrogen in our study increases its nucleophilic strength.39 Polar
the 5h precursor. The other precursor with an ortho positioned F
aprotic solvents such as DMF and NMP are frequently used in the
SR, which is in a good agreement with our optimized data.34, 35 It is
atom, 5d also had a similar yield of 96%. Therefore, it can be
concluded that electron-withdrawing effect of fluorine in the ortho-
also suggested that these types of solvents stabilize the
position of the aromatic ring stabilizes the formed intermediate
Meisenheimer complex and help improve the results.35
(Meisenheimer complex 5h(c) in Scheme 3) and therefore, the
highest yields were obtained for 6c and 6f.38 Zhao et al. in 2012
This copper catalysed coupling reaction is known to occur through
the presence of Cu(I). This is supported by literature, which reports
that Cu(II) and Cu(0) as a source of Cu will be transformed to
Cu(I).41, 42 There are also reports that Cu(II) performed better than
Cu(I) based on the selected conditions of the reaction.36, 43
also showed that strong electron-withdrawing groups on the
aromatic rings increase the yields of SR.31
It is likely that the SR copper catalysed ring closure reaction in this
study may follow the proposed mechanism in scheme 3. In this
proposed mechanism, the proton of the amide was removed from
5h(a) in the presence of Cs2CO3 as a base (Scheme 3). This is
followed by a nucleophilic substitution of the nitrogen onto the
aromatic ring producing 5h(d). In the final step, the resulting
nucleophilic oxygen in the side chain substitutes the ortho
positioned F atom to yield the product 6f.
In addition, when there is competition between Br and F, the
expected leaving group is assumed to be Br, the better of the two
leaving groups. This did not occur in our experiments. The
presence of steric hindrance between the Boc protecting group
(5h(f) scheme3) and Br with a large atomic radius (in comparison to
F) causes the oxygen to substitute the F instead of Br on the
aromatic ring.
The existence of different parameters seems to have a direct
impact on the initiation of this reaction. The presence of the Boc
Based on the proposed mechanism in Scheme 3, this conformer
(5h) facilitated the SR by shortening the distance between the
nucleophile and the electrophile (ipso carbon) (Figure 1) for the
39
protecting group seems to play a crucial role in the SR. To prove
this hypothesis, we applied the optimised reaction conditions on
deprotected 5h and observed that no cyclisation took place.
Furthermore, it is suggested that the presence of a carbonyl group
in the neighbouring NH (amide group) increases its nucleophilic
effect in the SR.39 It is highly likely that this is the reason why there
are no reports on the presence of SR for 1,4-benzoxazine, while this
rearrangement was frequently reported for benzoxazinones.
occurrence of nucleophilic substitution.
These desirable
conformations of 5d and 5h assist these reactions, so much so that
these reactions could proceed at room temperature with high yield.
As can be seen from Figure 1, 5h (and probably 5d) possess a folded
structure. Based on a review published by O’Hagan44, it can be
proposed that the fluorine atoms in the aromatic ring of adduct 5g
(and 5d) is situated in an ideal position for a dipole-dipole
interaction, which results in the conformer shown in Figures 1 and
Cu(OAc)2 and Cs2CO3 are two other important reagents needed for
this rearrangement to occur. The presence of ionic Cu plays a role
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2. Since fluorine atoms are well-known π donors, this interaction
can be due to hyper-conjugation of the highly polarized C-F bonds,
which is stabilized by the π system of the aromatic ring and provide
the gauche conformer in 5g (and 5d) (Figure 2(a)).45-47
Acknowledgment
This research was supported by grants from the National
Research Foundation (NRF), South Africa and was supported
by the South African Research Chairs Initiative of the
Department of Science and Technology. We thank Dr Bernard
Owaga and Mr Sizwe Zamisa for assistance with X-Ray
crystallography.
Figure 1. Crystal structure of 5e, 5f and 5h and the distances
between the ipso carbon and nitrogen
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