Oxidative synthesis of benzo[1,4]oxazines from α-branched primary amines and ortho-benzoquinones

Article abstract of DOI:10.1016/j.tet.2019.130726

The efficient oxidative construction of benzo[1,4]oxazines from simple α-branched amines and ortho-benzoquinones is reported. The procedure pivots on a triethylamine and iodine mediated oxidative ring closure from the ketimine intermediate formed upon their condensation. This reaction was shown to tolerate a variety of α-branched benzylamines and downstream derivatization to substituted benzomorpholine structures was also demonstrated.

Full text of DOI:10.1016/j.tet.2019.130726

Journal Pre-proof
Oxidative synthesis of Benzo[1,4]oxazines from α-branched primary amines and
ortho-benzoquinones
Dhananjayan Vasu, Jamie A. Leitch, Darren J. Dixon
PII:
S0040-4020(19)31109-3
https://doi.org/10.1016/j.tet.2019.130726
TET 130726
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 September 2019
Revised Date: 14 October 2019
Accepted Date: 19 October 2019
Please cite this article as: Vasu D, Leitch JA, Dixon DJ, Oxidative synthesis of Benzo[1,4]oxazines from
α-branched primary amines and ortho-benzoquinones, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.130726.
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Tetrahedron
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Oxidative Synthesis of Benzo[1,4]oxazines from α-Branched Primary Amines and ortho-
Benzoquinones
Dhananjayan Vasu,†,¥ Jamie A. Leitch,† and Darren J. Dixon†*
†
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
*E-mail: darren.dixon@chem.ox.ac.uk
¥
Present Address: Department of Chemistry, Northwestern University, Sheridan Road, Illinois, 60208 USA
Dedicated to Professor Stephen G. Davies for his valued mentorship and inspiring contributions to organic synthesis
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The efficient oxidative construction of benzo[1,4]oxazines from simple α-branched amines
and ortho-benzoquinones is reported. The procedure pivots on a triethylamine and iodine
mediated oxidative ring closure from the ketimine intermediate formed upon their
condensation. This reaction was shown to tolerate a variety of α-branched benzylamines and
downstream derivatization to substituted benzomorpholine structures was also demonstrated.
Available online
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Very recently, our group disclosed the application of the ketimine
intermediates for carbon-carbon bond formation in a three-step,
one-pot protocol for the α-functionalization of primary amines.
The ketimine intermediates would engage with nucleophiles
(Scheme 1, I) such as organometallic reagents and cyanide, and
also in photoredox reverse polarity catalysis, enabling union with
electrophiles via an intermediary nucleophilic α-amino radical.14
In a continuation of our work, and aligned to Lumb’s elegant
report on the manipulation of similar quinone intermediates into
a diverse portfolio of heterocycles, we were intrigued to explore
the performance of the ketimines intermediates in subsequent
ring forming reactions, and herein we wish to report our findings.
The use of ortho-benzoquinone reagents for the efficient
oxidation of amines leads back to pioneering work from McCoy
and Day,1 and Corey.2 These studies revealed that treatment of a
primary amine with ortho-benzoquinones afforded the
corresponding aldehyde/ketone via a mechanism that involved an
initial condensation to afford the Schiff base, a subsequent [1,5]-
H-shift, and a final hydrolysis of the resulting imine. These
investigations also confirmed that the imine intermediates
(Scheme 1, I) are in equilibrium with their corresponding ring-
closed hemiaminal forms (Scheme 1, II). More recent
investigations from the groups of Klinman and Mure,3 and Sayre4
amongst others5 have established that this type of mechanism is
also at play in copper amine oxidases,6 facilitating the
biocatalytic conversion of primary amines to aldehydes utilizing
a quinone co-factor.
2. Results and Discussion
During some preliminary studies leading up to our amine-to-
amine C-H functionalization protocol,14 we noted that in
instances where the nucleophilic addition step was somewhat
inefficient (for various reasons), low yields of benzo[1,4]oxazine
products were obtained from the reaction mixture. This product –
presumably arising from base-mediated iodine oxidation of the
ketimine intermediate – constitutes a formal α-oxidation / β-C–H
functionalization of the amine substrate rather than just α-
These biocatalytic studies have launched recent interest in
synthetic bio-inspired amine manipulation using ortho-quinones,7
with notable contributions from Stahl,8 Kobayashi,9 Largeron and
Fleury10 (for amine oxidation), Qu,11 Clift12 (for amine
functionalization), and Lumb13 (for heterocycle synthesis).
oxidation
/
functionalization as was expected. As
Scheme 1: Previous work on the functionalization of primary
amines with ortho-benzoquinones and the current application to
oxidative benzo[1,4]oxazine synthesis.
benzo[1,4]oxazines have been shown to possess interesting
biologically activity for potential use in cancer therapeutics,15 we
recognized that establishing a mild and simple protocol to access
them could be of interest to future discovery and development
programmes.
Pleasingly when conducting the transformation using 1-
phenylethan-1-amine (1a) and 3,5-di-tert-butyl-o-benzoquinone
(2a) without the organometallic addition step, efficient
heterocycle formation (3a) resulted (81%, Scheme 2A, entry 1).
In attempts to increase yield and probe the reaction mechanism
different oxidation conditions were studied (entries 2-6). When
we exchanged the oxidation system for H5IO6, no formation of 3a
was observed (entry 2), and acetophenone – arising from
hydrolysis of the ketimine intermediate – was isolated in almost
quantitiatve yield from the reaction mixture.
1

Scheme 2: (A) Optimization of the synthesis of
benzo[1,4]oxazine from primary amines. (B) Plausible reaction
mechanism.
Furthermore, PhI(OAc)2 also gave no formation of the 3a (entry
3).16 Preliminary investigations suggested a solvent switch to
acetonitrile would still permit ketimine formation and would
create a more streamlined process. Using this solvent and with
iodine as the oxidant and switching to triethylamine as the base
we were delighted to find that the benzo[1,4]oxazine 3a was
formed in 89% yield (entry 4). Further experiments demonstrated
that using NIS as the oxidant with no added base was ineffective,
however, on addition of base, reactivity was restored (entries 5-
6).
As there is a need for an electrophilic iodine oxidant plus a base
for efficient formation of benzo[1,4]oxazine 3a, a plausible
mechanistic pathway arises (Scheme 2B). We suggest that –
aligned to previous reports – condensation of our primary amine
with the ortho-benzoquinone delivers the ketimine/hemiaminal
equilibrating pair [I]. Added Brønsted base then promotes
ketimine / enamine tautomerization and in the presence of iodine,
the enamine nucleophile reacts to afford the α-imino-alkyl iodide
[III]. Subsequent base-promoted intramolecular ring closure from
the pendant phenol delivers the benzo[1,4]-oxazine.
With optimal conditions in hand we proceeded to explore the
scope of this transformation (Scheme 3). Gratifyingly
substitution across the aromatic ring of the phenylethanamine
was tolerated as ortho-, meta-, and para-methoxyarenes delivered
the heterocyclic product in excellent yields (3b-d). Following
this, substrates possessing alkyl substituents and naphthyl
derivatives were submitted to the reaction conditions and
pleasingly formed products in excellent efficiency (3e-h).
Halogen (3i-k), nitro (3m), ester (3n) and even phenolic (3o)
substituents were also compatible with the transformation and the
respective products were obtained in good to excellent yields.
Furthermore heteroaromatic ethyl amine substrates were studied;
2-, 3-, and 4-pyridyl systems performed effectively, as did one
containing a thiophene structure (3s); in all cases the desired
benzo[1,4]-oxazine product was obtained with excellent
efficiency.
Scheme 3: Scope of the oxidative synthesis of benzo[1,4]oxazines
R'
I2 (2 eq)
NEt3 (3 eq)
HO
N
NH2
O
O
MeCN
O
R'
R'
R
0 °C - rt
rt, 2-8 h
R
N
10-60 mins
R
1a-t
2a-c
3a-v
tBu
tBu
tBu
tBu
tBu
tBu
O
N
O
N
O
N
O
O
N
O
N
tBu
tBu
tBu
N
tBu
tBu
tBu
R
Me
tBu
3a
3b
R= 4-MeO, : 96%
3e
3f
3g
3h
: 86%
: 89%
: 83%
: 79%
: 81%
3c
R= 3-MeO, : 82%
R= 2-MeO, 3d: 75%
tBu
tBu
tBu
tBu
tBu
tBu
O
N
O
O
O
O
N
O
F
tBu
N
tBu
HO
N
tBu
N
tBu
tBu
N
tBu
N
O2N
MeO2C
R
3i
R= F, : 85%
3j
R= Cl, : 87%
3l
3m
3n
3o
3p
: 61%
: 84%
: 75%
: 79%
: 65%
F
R= Br, 3k: 89%
tBu
tBu
iPr
tBu
tBu
O
O
O
O
N
O
N
O
N
tBu
N
tBu
N
iPr
tBu
tBu
N
S
O
N
3q
3r
3s
: 93%
3t
3u
: 72%
: 67%
: 78%
: 85%
2

with the solvent resonance as internal standard: CDCl3, δ = 77.16
ppm; CD3OD, δ = 49.00 ppm. High-resolution mass spectra
(HRMS) were recorded on Bruker Daltonics MicroTOF mass
spectrometer equipped with an ESI source. Infrared spectra (IR)
were recorded on a Bruker Tensor 27 FT-IR spectrometer from a
thin film on a diamond ATR module and reported a selected
maximum absorbances.
On varying the quinone coupling partner, we were pleased to see
that iso-propyl variant (3u) proceeded well under the reaction
conditions. Unfortunately neither substrates bearing further
functionalization on the β-position of the primary amine nor
unsubstituted ortho-benzoquinones were tolerated in this
methodology.
We then looked to demonstrate that the benzo[1,4]oxazine
products could be transformed into substituted benzomorpholine
structures. In order to explore this we subjected
benzo[1,4]oxazine 3a to nucleophilic allylation and cyanation
conditions. Satisfyingly, these efforts delivered α-allyl (4a) and
α-cyano (4b) benzomorpholine derivatives in excellent yields
(Scheme 4).
General procedure for the synthesis of benzo[1,4]oxazines:
To a stirred solution of ortho-benzoquinone (0.825 mmol, 1.0
equiv) in acetonitrile (4.0 mL), was added dropwise a solution of
primary amine (0.825 mmol, 1.0 equiv) in acetonitrile (4.25 mL)
over 5 min under an argon atmosphere. The deep green coloured
solution was stirred at room temperature for 2-8 h. After
completion of the reaction, as indicated by TLC, the reaction
mixture was cooled to 0 ˚C. To this, triethylamine (0.34 mL, 2.48
mmol, 3 equiv) and iodine granules (0.419 g, 1.65 mmol, 2 eq),
were added. The resulting mixture was stirred vigorously for 10-
60 minutes under argon atmosphere. Upon completion, the
reaction mixture was diluted with water and extracted with
EtOAc (3 x 5 mL). The combined organic layer was washed with
aqueous saturated sodium thiosulfate (1 x 10 mL) and brine (2 x
10 mL), respectively, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude residue was purified by silica
gel column chromatography eluting with pentane:EtOAc (95:5-
80:20 v:v) to afford the desired benzo[1,4]oxazine product.
Scheme 4: Synthesis of benzomorpholines from the
benzo[1,4]oxazine product 3a.
Data for the benzo[1,4]oxazine products:
Conclusion
In conclusion we have disclosed a new one-pot synthesis of
substituted benzo[1,4]-oxazines from α-branched amines and
ortho-quinones. This transformation proceeds via the well-
precedented quinone oxidative rearrangement upon initial
condensation, followed by an electrophilic iodine/base mediated
ring closure to create the oxazine heterocycle. The transformation
was applicable to a wide range of α-branched benzylamine
derivatives and their respective benzo[1,4]-oxazines products
were afforded in excellent yields.
6,8-di-tert-butyl-3-phenyl-2H-benzo[b][1,4]oxazine (3a).
Yellow amorphous solid (236 mg, 0.734 mmol, 89%). FT-IR
1
(thin film) νmax (cm-1): 3961, 2905, 1601, 1479, 14478. H NMR
(400 MHz, CDCl3): δ 7.98 – 7.89 (m, 2H), 7.50 – 7.46 (m, 3H),
7.38 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 4.99 (s, 2H),
1.42 (s, 9H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 158.5,
144.3, 142.7, 136.9, 135.9, 134.4, 131.0, 128.9, 126.6, 123.2,
122.8, 62.1, 34.8, 34.7, 31.7, 29.9. HRMS (ESI) Calcd for
C22H28NO [(M+H)+]: 322.2165, found: 322.2167.
Acknowledgement. D.V. acknowledge funding from the
European Union’s Horizon 2020 research and innovation
framework programme under the Marie Skłodowska-Curie grant
agreement No 703789. J.A.L. thanks the Leverhulme Trust
(RPG-2017-069) for a research fellowship.
6,8-di-tert-butyl-3-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazine
(3b).
Off-white solid (223 mg, 0.634 mmol, 96%). FT-IR (thin film)
1
νmax (cm-1): 2968, 1734, 1606, 1560, 1515, 1502, 1462, 1422. H
NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.9 Hz, 2H), 7.34 (d, J =
2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H),
4.94 (s, 2H), 3.87 (s, 3H), 1.41 (s, 9H), 1.35 (s, 9H). 13C NMR
(101 MHz, CDCl3): δ 162.0, 158.0, 144.2, 142.7, 136.8, 134.6,
128.6, 128.3, 122.7, 122.5, 114.3, 61.9, 55.6, 34.8, 34.6, 31.7,
29.9. HRMS (ESI) Calcd for C23H30NO2 [(M+H)+]: 352.2271,
found: 352.2271.
Conflict of interest: The authors declare no conflict of interest
3. Experimental
General information:
All reagents were purchased from commercial sources and used
without further purification. Unless otherwise noted, all the
reactions were performed under argon atmosphere. All reactions
were monitored by thin-layer chromatography (TLC) using
Merck Kieselgel 60 F254 fluorescent treated silica. Visualization
was accomplished under UV light (λmax= 254 nm) and by staining
with potassium permanganate staining dip. Chromatographic
purification was performed on VWR 60 silica gel 40-63 ꢀm
6,8-di-tert-butyl-3-(3-methoxyphenyl)-2H-benzo[b][1,4]oxazine
(3c).
Yellow oil (190 mg, 0.541 mmol, 82%). FT-IR (thin film) νmax
1
(cm-1): 2981, 2889, 1582, 1462. H NMR (400 MHz, CDCl3):
1
7.57 (dd, J = 2.6, 1.5 Hz, 1H), 7.43 (dt, J = 7.7, 1.4 Hz, 1H), 7.41
– 7.34 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 7.04 (ddd, J = 8.0, 2.7,
1.2 Hz, 1H), 4.96 (s, 2H), 3.90 (s, 3H), 1.42 (s, 9H), 1.36 (s, 9H).
13C NMR (101 MHz, CDCl3): δ 160.1, 158.3, 144.3, 142.8,
137.3, 136.9, 134.4, 129.8, 123.3, 122.8, 119.1, 117.5, 111.2,
62.1, 55.6, 34.8, 34.6, 31.7, 29.9. HRMS (ESI) Calcd for
C23H30NO2 [(M+H)+]: 352.2271, found: 352.2266.
using HPLC grade solvents that were used as supplied. H and
13C NMR spectra were recorded on a Bruker spectrometer
operating at 400 or 500 MHz in deuterated solvents at 25 ºC.
Proton chemical shifts (δ) are given in parts per million (ppm)
relative to tetramethylsilane (TMS) with the solvent resonance as
internal standard: CDCl3, δ = 7.26 ppm; CD3OD, δ = 3.31 ppm.
Carbon chemical shifts are reported in ppm (δ) relative to TMS
3

6,8-di-tert-butyl-3-(4-fluorophenyl)-2H-benzo[b][1,4]oxazine
6,8-di-tert-butyl-3-(2-methoxyphenyl)-2H-benzo[b][1,4]oxazine
(3i).
(3d).
Yellow solid (207 mg, 0.610 mmol, 85%). FT-IR (thin film) νmax
1
Pale yellow soild (175 mg, 0.498 mmol, 75%). FT-IR (thin film)
(cm-1): 2981, 2889, 1601, 1510, 1475. H NMR (400 MHz,
1
νmax (cm-1): 2959, 1601, 1488, 1463, 1437, 1411. H NMR (400
CDCl3): δ 7.97 – 7.92 (m, 2H), 7.36 (d, J = 2.4 Hz, 1H), 7.22 (d,
J = 2.4 Hz, 1H), 7.19 – 7.13 (m, 2H), 4.95 (s, 2H), 1.42 (s, 9H),
1.35 (s, 9H). 19F NMR (377 MHz, CDCl3): δ -109.0. 13C NMR
(101 MHz, CDCl3): δ 164.6 (d, JC-F = 252.7 Hz), 157.3, 144.4,
142.6, 136.9, 134.3, 132.2 (d, JC-F = 3.3 Hz), 128.7 (d, JC-F = 8.7
Hz), 123.3, 122.8, 116.0 (d, JC-F = 22.1 Hz), 61.9, 34.8, 34.6,
31.7, 29.9. HRMS (ESI) Calcd for C22H27FNO [(M+H)+]:
340.2071, found: 340.2057.
MHz, CDCl3): δ 7.86 (dd, J = 7.6, 1.8 Hz, 1H), 7.44 – 7.39 (m,
1H), 7.37 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.06 (td, J
= 7.5, 1.0 Hz, 1H), 6.95 (dd, J = 8.3, 1.0 Hz, 1H), 4.84 (s, 2H),
3.88 (s, 3H), 1.40 (s, 9H), 1.33 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 160.7, 158.5, 144.1, 143.4, 136.9, 134.8, 131.8, 129.6,
126.9, 122.8, 122.5, 121.4, 111.1, 64.5, 55.6, 34.8, 34.7, 31.7,
29.9. HRMS (ESI) Calcd for C23H30NO2 [(M+H)+]: 352.2271,
found: 352.2272.
6,8-di-tert-butyl-3-(4-chlorophenyl)-2H-benzo[b][1,4]oxazine
6,8-di-tert-butyl-3-(p-tolyl)-2H-benzo[b][1,4]oxazine (3e).
(3j)
Yellow oil (206 mg, 0.614 mmol, 83%). FT-IR (thin film) νmax
(cm-1): 2980, 2969, 1601, 1641, 1478, 1461. 1H NMR (400 MHz,
CDCl3): 7.84 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.28
(d, J = 8.2 Hz, 2H), 7.20 (d, J = 2.4 Hz, 1H), 4.96 (s, 2H), 2.42
(s, 3H), 1.42 (s, 9H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3):
δ 158.5, 144.2, 142.8, 141.4, 136.8, 134.5, 133.2, 129.6, 126.6,
122.9, 122.7, 62.0, 34.8, 34.6, 31.7, 29.9, 21.7. HRMS (ESI)
Calcd for C23H30NO [(M+H)+]: 336.2322, found: 336.2317.
Yellow oil (199 mg, 0.559 mmol, 87%). FT-IR (thin film) νmax
(cm-1): 2981, 2889, 1594, 1475. 1H NMR (400 MHz, CDCl3): δ
7.90 – 7.85 (m, 2H), 7.48 – 7.42 (m, 2H), 7.35 (d, J = 2.4 Hz,
1H), 7.22 (d, J = 2.4 Hz, 1H), 4.95 (s, 2H), 1.41 (s, 9H), 1.35 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 157.1, 144.5, 142.6, 137.1,
137.0, 134.3 (2xC), 129.2, 127.9, 123.5, 122.8, 61.8, 34.8, 34.7,
31.7, 29.9. HRMS (ESI) Calcd for C22H2735ClNO [(M+H)+]:
356.1776, found: 356.1777.
6,8-di-tert-butyl-3-(4-(tert-butyl)phenyl)-2H-
3-(4-bromophenyl)-6,8-di-tert-butyl-2H-benzo[b][1,4]oxazine
benzo[b][1,4]oxazine (3f).
(3k)
Pale yellow solid (168 mg, 0.445 mmol, 79%). FT-IR (thin film)
νmax (cm-1): 2926, 2905, 2970, 1607, 1557, 1478, 1410. 1H NMR
(400 MHz, CDCl3): δ 7.88 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6
Hz, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 4.97
(s, 2H), 1.42 (s, 9H), 1.37 (s, 9H), 1.36 (s, 9H). 13C NMR (101
MHz, CDCl3): δ 158.5, 154.5, 144.2, 142.8, 136.8, 134.6, 133.2,
126.4, 125.8, 122.9, 122.7, 62.0, 35.1, 34.8, 34.6, 31.7, 31.3,
29.9. HRMS (ESI) Calcd for C26H36NO [(M+H)+]: 378.2791,
found: 378.2792.
Yellow oil (178 mg, 0.445 mmol, 89%). FT-IR (thin film) νmax
1
(cm-1): 2981, 2889, 1734, 1589, 1477. H NMR (400 MHz,
CDCl3): 7.84 – 7.77 (m, 2H), 7.64 – 7.57 (m, 2H), 7.35 (d, J =
2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 4.94 (s, 2H), 1.40 (s, 9H),
1.34 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 157.2, 144.5,
142.6, 137.0, 134.7, 134.3, 132.1, 128.1, 125.6, 123.5, 122.8,
61.7, 34.8, 34.6, 31.7, 29.9. HRMS (ESI) Calcd for
C22H2779BrNO [(M+H)+]: 400.1271, found: 400.1269.
6,8-di-tert-butyl-3-(3,5-difluorophenyl)-2H-
6,8-di-tert-butyl-3-(naphthalen-1-yl)-2H-benzo[b][1,4]oxazine
benzo[b][1,4]oxazine (3l)
(3g).
Pale yellow solid (190 mg, 0.532 mmol, 84%). FT-IR (thin film)
1
Yellow oil (176 mg, 0.474 mmol, 81%). FT-IR (thin film) νmax
(cm-1): 2962, 2904, 1591, 1509, 1479, 1462, 1410. 1H NMR (400
MHz, CDCl3): δ 8.50 – 8.39 (m, 1H), 7.98 – 7.87 (m, 2H), 7.66
(dd, J = 7.1, 1.3 Hz, 1H), 7.61 – 7.52 (m, 3H), 7.45 (d, J = 2.4
Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 4.95 (s, 2H), 1.45 (s, 9H), 1.37
(s, 9H). 13C NMR (101 MHz, CDCl3): δ 161.5, 144.5, 142.8,
137.2, 135.0, 134.5, 134.2, 130.7, 130.6, 128.8, 127.3, 126.5,
126.3, 125.7, 125.2, 123.5, 122.9, 64.9, 34.9, 34.7, 31.7, 30.0.
HRMS (ESI) Calcd for C26H30NO [(M+H)+]: 372.2322, found:
372.2328.
νmax (cm-1): 2981, 2889, 1622, 1592, 1461. H NMR (400 MHz,
CDCl3): δ 7.51 – 7.42 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.24 (d,
J = 2.4 Hz, 1H), 6.92 (tt, J = 8.6, 2.3 Hz, 1H), 4.91 (s, 2H), 1.40
(s, 9H), 1.35 (s, 9H). 19F NMR (377 MHz, CDCl3): δ -108.7. 13
C
NMR (101 MHz, CDCl3): δ 163.4 (dd, JC-F = 250.1, 12.3 Hz),
155.7 (t, JC-F = 3.2 Hz), 144.7, 142.7, 139.1 (t, JC-F = 9.3
Hz),137.1, 134.0, 124.1, 123.1, 109.5 (dd, JC-F = 19.1, 7.4 Hz),
106.2 (t, JC-F = 25.6 Hz), 61.8, 34.8, 34.7, 31.6, 29.9. HRMS
(ESI) Calcd for C22H26F2NO [(M+H)+]: 358.1977, found:
358.1975.
6,8-di-tert-butyl-3-(naphthalen-2-yl)-2H-benzo[b][1,4]oxazine
6,8-di-tert-butyl-3-(4-nitrophenyl)-2H-benzo[b][1,4]oxazine
(3h)
(3m)
Yellow solid (186 mg, 0.501 mmol, 86%). FT-IR (thin film) νmax
(cm-1): 2981, 1699, 14622. 1H NMR (400 MHz, CDCl3): δ 8.29 –
8.20 (m, 2H), 7.96 – 7.84 (m, 3H), 7.59 – 7.50 (m, 2H), 7.42 (d, J
= 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 5.12 (s, 2H), 1.44 (s,
9H), 1.37 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 158.2, 144.4,
142.8, 136.9, 134.7, 134.6, 133.3, 133.1, 129.0, 128.8, 128.0,
127.6, 126.9, 126.8, 123.6, 123.3, 122.9, 62.0, 34.8, 34.7, 31.7,
29.9. HRMS (ESI) Calcd for C26H30NO [(M+H)+]: 372.2322,
found: 372.2322.
Yellow solid (167 mg, 0.456 mmol, 75%). FT-IR (thin film) νmax
1
(cm-1): 2980, 1598, 1523, 1478. H NMR (400 MHz, CDCl3): δ
8.33 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 2.4
Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 5.01 (s, 2H), 1.41 (s, 9H), 1.35
(s, 9H). 13C NMR (101 MHz, CDCl3): δ 155.8, 149.1, 144.8,
142.6, 141.3, 137.2, 134.2, 127.4, 124.5, 124.1, 123.3, 61.8, 34.8,
34.7, 31.6, 29.9. HRMS (ESI) Calcd for C22H27N2O3 [(M+H)+]:
367.2016, found: 367.2016.
4

144.4, 142.9, 141.9, 136.9, 134.4, 130.4, 128.0, 127.9, 123.0,
122.5, 62.1, 34.8, 34.7, 31.7, 29.9. HRMS (ESI) Calcd for
C20H26NOS [(M+H)+]: 328.1730, found: 328.1730.
methyl
yl)benzoate (3n)
4-(6,8-di-tert-butyl-2H-benzo[b][1,4]oxazin-3-
Pale yellow solid (168 mg, 0.443 mmol, 79%). FT-IR (thin film)
1
νmax (cm-1): 2981, 2889, 1726, 1612, 1462. H NMR (400 MHz,
3-(benzo[d][1,3]dioxol-5-yl)-6,8-di-tert-butyl-2H-
CDCl3): δ 8.18 – 8.10 (m, 2H), 8.04 – 7.96 (m, 2H), 7.37 (d, J =
2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 5.00 (s, 2H), 3.95 (s, 3H),
1.41 (s, 9H), 1.35 (s, 9H).13C NMR (101 MHz, CDCl3): δ 166.7,
157.3, 144.5, 142.7, 139.7, 137.0, 134.4, 132.0, 130.1, 126.5,
123.9, 123.1, 61.9, 52.5, 34.8, 34.7, 31.7, 29.9. HRMS (ESI)
Calcd for C24H30NO3 [(M+H)+]: 380.2220, found: 380.2219.
benzo[b][1,4]oxazine (3t)
Yellow solid, (188 mg, 0.514 mmol, 85%). FT-IR (thin film)
νmax (cm-1): 2981, 2889, 1474. H NMR (400 MHz, CDCl3): δ
1
7.59 (d, J = 1.7 Hz, 1H), 7.33 (td, J = 3.7, 1.8 Hz, 2H), 7.19 (d, J
= 2.4 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.03 (s, 2H), 4.91 (s,
2H), 1.41 (s, 9H), 1.35 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
157.6, 150.2, 148.6, 144.3, 142.7, 136.8, 134.4, 130.5, 122.8,
122.6, 121.4, 108.2, 106.7, 101.7, 62.0, 34.8, 34.6, 31.7, 29.9.
HRMS (ESI) Calcd for C23H28NO3 [(M+H)+]: 366.2064, found:
366.2060.
4-(6,8-di-tert-butyl-2H-benzo[b][1,4]oxazin-3-yl)phenol (3o)
Yellow oil, (159 mg, 0.471 mmol, 65%). FT-IR (thin film) νmax
(cm-1):2981, 2889, 1671, 1595, 1514, 1462. 1H NMR (400 MHz,
CDCl3 and CD3OD): δ 7.08 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 2.4
Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 2.4 Hz, 1H), 4.64
(s, 2H), 1.40 (s, 9H), 1.11 (s, 9H). 13C NMR (101 MHz, CDCl3
and CD3OD): δ 166.9, 158.3, 145.6, 142.7, 139.0, 132.1, 130.4,
128.4, 119.5, 117.2, 113.6, 68.2, 35.6, 35.1, 31.6, 30.2. HRMS
(ESI) Calcd for C22H28NO2 [(M+H)+]: 338.2115, found:
338.2116.
6,8-diisopropyl-3-phenyl-2H-benzo[b][1,4]oxazine (3u)
Yellow oil, (99 mg, 0.337 mmol, 72%). FT-IR (thin film) νmax
(cm-1): 2981, 2889, 1462. H NMR (400 MHz, CDCl3): δ 7.98 –
1
7.87 (m, 2H), 7.50 – 7.45 (m, 3H), 7.19 (d, J = 2.2 Hz, 1H), 6.96
(d, J = 2.2 Hz, 1H), 5.02 (s, 2H), 3.29 – 3.22 (m, 1H), 2.92 – 2.85
(m, 1H), 1.26 (dd, J = 6.9, 6.1 Hz, 12H).13C NMR (101 MHz,
CDCl3): δ 158.6, 142.6, 141.6, 135.9, 135.4, 133.8, 131.0, 128.9,
126.6, 124.2, 122.8, 62.9, 33.8, 27.3, 24.3, 22.8. HRMS (ESI)
Calcd for C20H24NO [(M+H)+]: 294.1852, found: 294.1852.
6,8-di-tert-butyl-3-(pyridin-2-yl)-2H-benzo[b][1,4]oxazine (3p)
Yellow solid, (161 mg, 0.499 mmol, 61%). FT-IR (thin film)
1
ν
max (cm-1): 2956, 2868, 1586, 1566, 1479, 1466, 1437, 1409.. H
NMR (400 MHz, CDCl3): δ 8.64 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H),
8.36 (dt, J = 8.0, 1.1 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.38
– 7.32 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H), 5.24 (s, 2H), 1.41 (s,
9H), 1.35 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 159.2, 154.0,
149.0, 144.1, 143.5, 137.2, 136.6, 134.3, 125.0, 123.9, 122.9,
121.3, 61.5, 34.8, 34.6, 31.7, 29.9. HRMS (ESI) Calcd for
C21H27N2O [(M+H)+]: 323.2118, found: 323.2115.
Data for the benzomorpholine products
6,8-di-tert-butyl-3-phenyl-3,4-dihydro-2H-
benzo[b][1,4]oxazine-3-carbonitrile (4a)
To an oven-dried rbf under argon atmosphere, was charged 3a
(75 mg, 0.23 mmol). To the flask was added anhydrous MeOH
(2.4 mL), and the reaction mixture cooled to 0 °C and was added
TMSCN (58 µL, 0.47 mmol) over a 10 minute period. After this
time the reaction mixture was allowed to return to room
temperature and stir for 2 hours. After this time, the reaction
mixture was concentrated in vacuo and purified via silica gel
column chromatography (EtOAc:Pentane, 2:98 v:v) to give a
pale yellow oil, (67 mg, 0.193 mmol, 83%). FT-IR (thin film)
6,8-di-tert-butyl-3-(pyridin-3-yl)-2H-benzo[b][1,4]oxazine (3q)
Brown oil, (175 mg, 0.543 mmol, 67%). FT-IR (thin film) νmax
1
(cm-1): 2980, 2970, 1588, 1476, 1416. H NMR (400 MHz,
CDCl3): δ 9.07 (d, J = 2.3 Hz, 1H), 8.69 (dd, J = 4.9, 1.6 Hz,
1H), 8.31 (dt, J = 8.0, 1.8 Hz, 1H), 7.41 (dd, J = 8.1, 4.7 Hz, 1H),
7.36 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 4.98 (s, 2H),
1.41 (s, 9H), 1.35 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 156.0,
151.6, 147.9, 144.6, 142.6, 137.1, 134.2, 133.9, 131.5, 123.8,
123.7, 122.9, 61.6, 34.8, 34.6, 31.6, 29.9. HRMS (ESI) Calcd for
C21H27N2O [(M+H)+]: 323.2118, found: 323.2117.
νmax (cm-1): 3332, 2962, 2225, 1598, 1451, 1437. H NMR (400
1
MHz, CDCl3) δ 7.81 – 7.64 (m, 2H), 7.56 – 7.42 (m, 3H), 6.89
(d, J = 2.2 Hz, 1H), 6.65 (d, J = 2.2 Hz, 1H), 4.44 (dd, J = 10.8,
2.5 Hz, 1H), 4.30 (s, 1H), 3.97 (d, J = 11.0 Hz, 1H), 1.41 (s, 9H),
1.30 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 144.4, 139.2, 138.2,
135.1, 130.0, 129.8, 129.4, 126.3, 119.3, 116.0, 111.7, 72.4, 56.2,
35.2, 34.6, 31.7, 29.9. HRMS (ESI) Calcd for C23H29N2O
[(M+H)+]: 349.2274, found: 349.2278.
6,8-di-tert-butyl-3-(pyridin-4-yl)-2H-benzo[b][1,4]oxazine (3r)
Yellow powder, (205 mg, 0.636 mmol, 78%). FT-IR (thin film)
1
νmax (cm-1): 2981, 2889, 1462. H NMR (400 MHz, CDCl3): δ
3-allyl-6,8-di-tert-butyl-3-phenyl-3,4-dihydro-2H-
8.79 – 8.70 (m, 2H), 7.81 – 7.71 (m, 2H), 7.37 (d, J = 2.4 Hz,
1H), 7.26 – 7.25 (m, 1H), 4.96 (s, 2H), 1.40 (s, 9H), 1.34 (s, 9H).
13C NMR (101 MHz, CDCl3): δ 156.1, 150.7, 144.7, 142.8,
142.6, 137.2, 134.1, 124.5, 123.3, 120.3, 61.6, 34.8, 34.6, 31.6,
29.9. HRMS (ESI) Calcd for C21H27N2O [(M+H)+]: 323.2118,
found: 323.2117.
benzo[b][1,4]oxazine (4b)
To an oven-dried rbf under argon atmosphere, was charged 3a
(80 mg, 0.25 mmol). To the vessel was charged anhydrous
toluene (2.5 mL). To the reaction mixture was cooled to 0 °C,
and was added TMEDA (35 µL, 0.25 mmol), and allyl
magnesium bromide (1M in Et2O, 0.5 mL, 0.5 mmol). The
reaction mixture was stirred at 0 °C for 30 minutes, before
returning to room temperature and stirring overnight. The
reaction mixture was again cooled to 0 °C, and quenched with
NH4Cl (sat., 1.5 mL) dropwise and the aqueous mixture extracted
with MeCN (3 x 20 mL). The combined organic layers were
washed with aqueous saturated sodium thiosulfate (1 x 10 mL)
and brine (2 x 10 mL), respectively, dried over Na2SO4, filtered,
and concentrated in vacuo. The crude residue was purified via
6,8-di-tert-butyl-3-(thiophen-2-yl)-2H-benzo[b][1,4]oxazine (3s)
Yellow solid, (67 mg, 0.205 mmol, 93%). FT-IR (thin film) νmax
(cm-1): 2980, 2970, 2904, 1665, 1597, 1562, 1477, 1461, 1429,
1
1409. H NMR (400 MHz, CDCl3): δ 7.52 (dd, J = 5.1, 1.1 Hz,
1H), 7.42 (dd, J = 3.8, 1.1 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.19
(d, J = 2.4 Hz, 1H), 7.13 (dd, J = 5.0, 3.7 Hz, 1H), 4.91 (s, 2H),
1.41 (s, 9H), 1.34 (s, 9H).13C NMR (101 MHz, CDCl3): δ 153.5,
5

5. (a) Y. Ohshiro, S. Itoh, Bioorg. Chem. 1991, 19, 169. (b) E. J.
Rodriguez, T. C. Bruice, J. Am. Chem. Soc. 1989, 111, 7947.
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Ed. 2015, 54, 14638. (b) M. Largeron, M.-B. Fleury, Science 2013, 339,
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A. E. Wendlandt, S. S. Stahl, Org. Lett. 2012, 14, 2850
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2016, 4508.
silica gel column chromatography (5% EtOAc in Pentane) to
give a yellow oil, (78 mg, 0.215 mmol, 86%). FT-IR (thin film)
νmax (cm-1): 3305, 2955, 2868, 1638, 1595, 1492, 1436. 1H NMR
(400 MHz, CDCl3): δ 7.53 – 7.47 (m, 2H), 7.41 – 7.34 (m, 2H),
7.30 – 7.24 (m, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.64 (d, J = 2.3 Hz,
1H), 5.57 (dddd, J = 18.1, 10.7, 8.9, 5.7 Hz, 1H), 5.16 – 5.03 (m,
2H), 4.12 (q, J = 10.5 Hz, 3H, NH and OCH2), 2.85 (ddt, J =
13.8, 5.8, 1.3 Hz, 1H), 2.67 (ddt, J = 13.8, 9.0, 0.9 Hz, 1H), 1.36
(s, 9H), 1.32 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 143.5,
142.6, 139.7, 137.3, 132.8, 132.2, 128.6, 127.2, 126.4, 119.6,
113.4, 111.3, 72.7, 55.7, 41.0, 35.0, 34.5, 31.8, 29.9. HRMS
(ESI) Calcd for C25H34NO [(M+H)+]: 364.2635, found: 364.2635.
References
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DEPARTMENT OF CHEMISTRY
Professor Darren J. Dixon
Chemistry Research Laboratory, University of Oxford
Mansfield Road, Oxford OX1 3TA
Tel: +44 (0)1865 275648 Fax: +44 (0)1865 285002
darren.dixon@chem.ox.ac.uk
Dear Professor Nakao
Re: Highlights
Highlights – not sure what this is but on the website it says these are for full research articles. It also
says they are optional. If a highlight is essential I will follow your instructions
Yours sincerely
Darren J. Dixon

DEPARTMENT OF CHEMISTRY
Professor Darren J. Dixon
Chemistry Research Laboratory, University of Oxford
Mansfield Road, Oxford OX1 3TA
Tel: +44 (0)1865 275648 Fax: +44 (0)1865 285002
darren.dixon@chem.ox.ac.uk
Dear Professor Nakao
Conflicts of Interest statement
There are no conflicts of interest.
Yours sincerely
Darren J. Dixon