Combining C-H functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo[1,3]oxazepines

Article abstract of DOI:10.1016/j.tet.2018.05.066

C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo [1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo [1,3]oxazepines.

Full text of DOI:10.1016/j.tet.2018.05.066

Accepted Manuscript
Combining C-H functionalisation and flow photochemical heterocyclic metamorphosis
(FP-HM) for the synthesis of benzo[1,3]oxazepines
Jasraj S. Babra, Andrew T. Russell, Christopher D. Smith, Yuxiong Zhang
PII:
S0040-4020(18)30614-8
10.1016/j.tet.2018.05.066
TET 29573
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 February 2018
Revised Date: 18 May 2018
Accepted Date: 22 May 2018
Please cite this article as: Babra JS, Russell AT, Smith CD, Zhang Y, Combining C-H functionalisation
and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo[1,3]oxazepines,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.066.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Combining C-H Functionalisation and Flow
Photochemical Heterocyclic Metamorphosis
(FP-HM) for the Synthesis of
Leave this area blank for abstract info.
Benzo[1,3]oxazepines
Jasraj S. Babra,a Andrew T. Russell,a Christopher. D. Smith,a* and Yuxiong Zhanga
a Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
Combining C-H Functionalisation and Flow Photochemical Heterocyclic
Metamorphosis (FP-HM) for the Synthesis of Benzo[1,3]oxazepines
Jasraj S. Babra,a Andrew T. Russell,a Christopher D. Smith,a* and Yuxiong Zhanga
* Corresponding Author: c.d.smith@reading.ac.uk (C. D. Smith)
a Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
Keywords: Flow; Photochemistry; Heterocyclic metamorphosis; Quinoline N-oxide;
Benzo[1,3]oxazepine.
Published in celebration of the Sir Derek Barton Centennial.
Abstract
C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-
HM) have been combined to synthesize a library of benzo[1,3]oxazepines, a rarely described
heterocyclic family. This combined protocol allows a range of arylated products to be made
from simple starting materials, and the cheap flow photochemical system has proven
effective for rapid synthesis of gram-quantities of benzo[1,3]oxazepines.
Introduction
Within medicinal chemistry, the rapid generation of a library of products to investigate
structure-activity relationships is vital for the synthesis of biologically-active molecules and
investigation of a biological hypothesis.1 Significant additional diversity may be obtained by
the late-stage functionalisation of advanced intermediates or complex natural products by
exploiting existing functionality, whilst avoiding linear sequences and duplicated synthetic
efforts.2 Two examples extensively used within medicinal chemistry include fluorination,3 to
adjust a drug’s metabolic profile and properties, and C-H functionalisation,4 to introduce
further complexity or add functionality. There are, however, draw-backs to this approach
such as a lack of generality, functionalisation of only one site or even the formation
intractable mixtures. An alternative less widely-investigated approach is exploitation of
existing functionality by metamorphosing one heterocycle into another. Late-stage
heterocyclic metamorphosis5 allows for significant transformation of a molecule’s physical
properties, for example by altering the basicity, the dipole moment, and any hydrogen-bond
affinity, as well as the geometrical configuration.6 The new molecular scaffold generated,
and the subsequent library of derivatives, can be screened for biological activity alongside
the original heterocycle, allowing for rapid data generation. One important consideration of
late-stage functionalisation is that the method should be mild and chemo-selective and we
believe that the Flow Photochemical Heterocyclic Metamorphosis (FP-HM) protocol detailed
herein fulfils these requirements.
We have directed our heterocyclic metamorphosis efforts towards transformations of the
quinoline ring system, due to its importance in medicinal chemistry and as a privileged
scaffold in the treatment of malaria (Scheme 1) and in anti-cancer drugs (Topotecan).7
Kaneko,8 Buchardt9 and Albini10 have observed that quinoline N-oxides (3) can be
1

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
transformed into benzo[1,3]oxazepines (4), in variable yields when irradiated at >300 nm in
non-hydrogen-bonding solvents. Benzo[1,3]oxazepines are an unusual heterocyclic system
that have not been extensively reported11 and although formally anti-aromatic, the 2-aryl
derivatives are easily isolated and purified. Importantly, the seven-membered [1,3]-
oxazepine ring leads to a slight geometrical distortion with respect to the quinoline ring
system, and thus offers an interesting counterpoint to the parent quinoline for biological
testing.
Biologically important quinolines
NMe2
Me
N
HO
O
Et2N
OH
NH
N
N
O
N
O
Me
Cl
N
Et
OH
O
Chloroquine
anti-malarial
Quinine
anti-malarial
Topotecan
Anti-cancer
This work
R
R
R
(i) Oxidation
(ii) C-H
O
N
H
N
Ar
N
functionalisation
Ar
O
3
hν (>300 nm)
PhMe, 10 min
1
4
quinoline
quinoline
N-oxide
benzo[1,3]oxazepine
Flow Photochemical
Heterocyclic
Metamorphosis (FP-HM)
Scheme 1. Biologically important quinolines and the general scheme of this communication.
Results and Discussion
Commercially available quinoline (1a) was oxidised with sodium perborate in glacial AcOH
(Scheme 2) to form the N-oxide derivative 2a.12 At this point we wished to develop a route
to diversify this simple quinoline N-oxide by arylating the 2-position using C-H
functionalisation. Whilst a range of methods for this transformation are known,13 we
decided to use a slight variation of the Minisci-like radical arylation, reported by Horan, to
form 3a.13b Horan’s method uses diazonium salts derived in situ from anilines, and offers
many benefits in terms of cost of materials, ready availability of aniline substrates,
operational simplicity and facile purification. With a reliable route to the desired 2-aryl-
quinoline N-oxide (3a) in hand, we investigated the photochemical rearrangement of the
quinoline N-oxide to the corresponding benzo[1,3]oxazepine 4a.
1 eq. p-EtO2CC6H4NH2
1.2 eq. t-BuONO
MeCN, 40 °C
2 eq. NaBO3·4H2O
AcOH, 40 °C
N
H
N
O
H
2a
1a
56%
hν (>300 nm)
PhMe
O
N
N
O
CO2Et
3a
39%
4a
Batch 73%
CO2Et
Scheme 2. Initial investigation towards benzo[1,3]oxazepine 4a.
The UV-Vis spectrum of N-oxide 3a shows a significant band λmax (PhMe) = 346 nm, ε = 14.3
M-1cm-1 (Figure 1, red), which maps onto the broad band with λmax = 335 nm of the
commercially available 25 W Exo Terra UVB200 bulb (Figure 1, dotted blue). The use of such
a 25 W bulb has many safety, cost and practical advantages over the powerful medium
pressure mercury lamps that have been used in other systems10a,d and permits facile scaling
of the reactions when larger quantities of material are required due to its price and ready
2

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
availability. When a toluene solution of 3a (1 mg/mL; 3.5 mM) in a Pyrex™ test tube (20 mL)
was irradiated for 18 hrs with the 25 W Exo Terra UVB200 bulb full conversion to
benzo[1,3]oxazepine 4a was observed, along with some photochemical decomposition.
Following flash column chromatography, 1,3-oxazepine 4a was isolated in 73% yield.
Figure 1. UV-Vis of compound 3a overlaid with the output of the Exo Terra UVB200 bulb
(toluene, unscaled).
On the basis of this promising result, we attempted the transformation in our
photochemical flow reactor, similar to those previously described.14 Accordingly, N-oxide 3a
was dissolved in toluene (5 mM), and pumped using a Vapourtec E-Series peristaltic pump
through a 10 mL reactor (PFA tubing: 1/16” OD, 0.5 mm ID) that was wrapped around a 25
W Exo Terra UVB200 lamp, and the solution irradiated. No degassing of the solution was
performed. By 1H-NMR we observed complete conversion into the desired
benzo[1,3]oxazepine 4a (Scheme 3) in only 6 min and compound 4a was isolated in near
quantitative yield. Following further experimentation, we extended the residence time in
the reactor to 10 minutes to account for any operational or substrate variabilities. This
significant improvement on the previous literature protocols in terms of yield, time and the
continuous nature of the process makes scale-up facile. To prove the effectiveness of the
procedure, we synthesized 1.9 g of 4a within a 17 h period, providing the product in 98%
yield and excellent purity. For comparison, in 18 h the batch-mode could only process
milligram quantities of material in small 20 mL Pyrex test tubes due to the poor irradiation
profile of classical laboratory glassware, additionally, the purity profile of the crude 1H-NMR
was significantly inferior.
O
N
N
O
CO2Et
hν (>300 nm)
PhMe, 10 min
0.005 M
3a
4a
50 mg
2 g
CO2Et
97%
98%
Flow
Scheme 3. FP-HM performed on a gram-scale.
With conditions for conversion of the parent quinolone to the N-oxide, C-H functionalisation
and heterocycle metamorphosis in hand, our attention turned to investigating the scope of
the reaction. Commercially available quinolines 1a and 1b were converted to the
corresponding N-oxides (2a and 2b). C-H functionalisation was successful and provided
3

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
access to the requisite 2-arylquinoline N-oxides (3a-k), albeit in moderate yield. The main
difficulties were found with sterically hindered anilines, for example in the case of 3f where
only trace quantities were isolated, and 3k where the yield was 16% (Table 1). Pleasingly,
when substrates 3a-k were subjected to the flow photochemical heterocyclic
metamorphosis (FP-HM) conditions the reaction was successful (Table 1, 4a-k). In all cases
the product was either prepared in analytically pure form, or, use of a short plug of silica
was sufficient to remove base-line impurities. Esters, nitriles and halides all successfully
underwent FP-HM in excellent yields (>90%). The only exceptions were the ortho-Me N-
oxide (4k), which was isolated in 75% yield, and the para-nitro-substituted example (4d,
66% yield), which presented a slight difficulty because it was poorly soluble in toluene and
was dissolved in a 1:1 solution of MeCN:PhMe. In this case, full conversion of this substrate
was not achieved within the usual 10 minutes residence time and 15 min was chosen as a
compromise; longer reaction times led to substantial photodegradation.
R
R
R
1 eq. ArNH2, 1.2 t-BuONO
O
MeCN, 18 h, r.t. to 40 °C
N
O
H
N
O
Ar
N
C-H Functionalisation
Ar
hν (>300 nm)
PhMe, 10 min
FPHM
2a-b
3a-k
4a-k
Table 1: Substrate scope of C-H Functionalisation and FP-HM.
Starting N-
C-H coupling
partner – ArNH2
C-H
Entry
FP-HMb
Oxide
Functionalisationa
1
4-EtO2CC6H4NH2
97% (50 mg scale)
98% (2 g scale)
4a
2a
2a
2a
39%, 3a
2
3
4-FC6H4NH2
4-ClC6H4NH2
31%, 3b
45%, 3c
92%, 4b
95%, 4c
4
5
2a
2a
4-O2NC6H4NH2
63%, 3d
35%, 3e
66%, 4dc
95%, 4e
PhNH2
4

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
O
Me
N
6
7
2a
MesNH2
Me
Me
Trace, 3f
38%, 3g
33%, 3h
Not performed, 4f
4-EtO2CC6H4NH2
2b
2b
95%, 4g
8
4-FC6H4NH2
93%, 4h
9
2b
2b
4-NCC6H4NH2
2-MeC6H4NH2
29%, 3j
16%, 3k
98%, 4j
75%, 4k
10
a) C-H Functionalisation performed as per the general procedure A; b) FP-HM performed as per general
procedure B; c) Solvent 1:1 MeCN:PhMe, residence time 15 min.
Conclusions
In conclusion, we have described an efficient method for the synthesis of a small library of
unusual benzo[1,3]oxazepines in a rapid and cheap manner, starting from commercially-
available quinolines. Molecular diversity was achieved through a very mild C-H
functionalisation procedure, providing a route for substrate variability. This communication
has utilised Flow Photochemical Heterocyclic Metamorphosis (FP-HM) to transform the
well-known quinoline scaffold into benzo[1,3]oxazepines, resulting in changes to the
molecule’s basicity, geometry, dipole moment, hydrogen-bonding ability and size.
Heterocyclic metamorphosis represents a different medicinal chemistry paradigm where the
heterocycle is the function of change rather than a final diversification step. Due to the mild
nature of FP-HM (10 min of irradiation) it is expected that valuable quinoline-based natural
products, or late-stage intermediates, could be transformed into the corresponding
benzo[1,3]oxazepines for additional biological testing, or subsequent additional
manipulation. Finally, we have demonstrated the true scalability of FP-HM by the successful
synthesis of 1.9 g of benzo[1,3]oxazepine 4a in 17 hours. The continuous nature of the
process means that further scale-up can be achieved simply by using multiple cheap
photoreactors in series.
5

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
Acknowledgements
The Vapourtec E-Series flow system was purchased using a Royal Society Equipment Grant.
We thank Professor Laurence M. Harwood and his group for their continuous support. We
acknowledge the support and expertise of the Chemical Analysis Facility. Finally, we thank
Dr Phillipa B. Cranwell for helpful discussions.
Experimental
General
1H-NMR spectra were recorded on Bruker DPX-400 (400 MHz) or Bruker Nanobay (400 MHz)
spectrometers using tetramethylsilane (SiMe4, δH = 0.00 ppm); DCCl3 (HCCl3, δH = 7.26 ppm)
or the central resonance of D3COD (D3COD, δH = 2.50 ppm) as internal reference. 13C-NMR
spectra were recorded on Bruker DPX-400 (101 MHz) or Bruker Nanobay (101 MHz)
spectrometers using the central resonance of CDCl3 (CDCl3, δC = 77.16 ppm) or the central
resonance of D3COD (D3COD, δC = 49.00 ppm) as the internal reference. 19F-NMR spectra
were measured relative to CFCl3 δF = 0.00 (external reference). Assignments were made
using a range of NMR experiments (DEPT135, COSY, HMQC and HMBC). All chemical shifts
are quoted in parts per million (ppm) down field from tetramethylsilane, measured from the
centre of the signal except in the case of multiplets of more than one proton, which are
quoted as a range. Splitting patterns are abbreviated as follows: singlet (s), doublet (d),
triplet (t), quartet (q), quintet (quin.), multiplet (m), (ap.) apparent, (br) broad and
combinations thereof. Infrared spectra were recorded on a Perkin-Elmer Spectrum One FT-
IR spectrometer as a thin film. Letters in parentheses refer to relative absorbency of the
main peak: w, weak, < 40%, m, medium, 41-74% of the main peak, s, strong >75%; and br,
broad. Accurate mass data was recorded on a V.G. Micromass 70-70F machine under
chemical ionisation (CI) or under electrospray conditions on a Thermo Scientific LTQ
Orbitrap XL instrument. PE refers to the fraction of light petroleum ether boiling between 40
and 60 °C. All reagents were used as obtained from commercial sources, unless otherwise
stated. Analytical thin layer chromatography (TLC) was performed using pre-coated
Merck aluminum-backed silica gel plates (Silicagel 60 F254). Visualization was by UV light
and/or treatment with acidic potassium permanganate, ninhydrin or acidic ammonium
molybdate(IV). UV-Vis spectrum was collected using a Jenway 6315 Spectrophotometer. The
emission spectrum from the Exo Terra UVB200 bulb was measured using an Ocean Optics
Red Tide USB650 fiber optic spectrometer.
General Procedure A – C-H Functionalisation (3a-k)
The quinoline N-oxide (3 mmol) and aromatic amine (3 mmol) were dissolved in MeCN (10
mL). tert-Butyl nitrite (3.6 mmol) was added in one portion and the reaction was stirred at
ambient temperature for 15 mins, before warming to 40 °C overnight (typically 18 h). The
mixture was dry loaded onto silica gel before purification by flash chromatography (typically
1:1 EtOAc:PE).
6

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
General Procedure B – Flow Photochemical Heterocyclic Metamorphosis (FP-HM) (4a-k)
A solution of substrate in PhMe (typically 50 mg in 30 mL; 5-10 mM) was pumped using a
Vapourtec E-Scholar peristaltic pump system through a 10 mL reactor (PFA tubing: 1/16”
OD, 0.5 mm ID) that was wrapped around a 25 W Exo Terra UVB200 lamp, and the solution
irradiated. In general, the reaction requires a residence time of 6 min (1.67 mL/min);
however, a residence time of 10 mins (1 mL/min) was typically used to account for
experimental variabilities. The output from the reactor was concentrated in vacuo and, if
necessary, was further purified by flash column chromatography (SiO2; 1:2 EtOAc:PE).
Large-Scale Flow Photochemical Heterocyclic Metamorphosis (4a)
2-(4-(Ethoxycarbonyl)phenyl)quinoline 1-oxide (2 g, 6.8 mmol) was dissolved in PhMe (1 L,
6.8 mM) and pumped using a Vapourtec E-Scholar peristaltic pump system through a 10 mL
reactor (PFA tubing: 1/16” OD, 0.5 mm ID) that was wrapped around a 25 W Exo Terra
UVB200 lamp, and the solution irradiated. A residence time of 10 mins was used; the total
reaction time was 17 hours. The output from the reactor was concentrated in vacuo to give
ethyl 4-(benzo[d][1,3]oxazepin-2-yl)benzoate (4a) as a tan solid (1.935 g, 97%).
Batch Photochemical Heterocyclic Metamorphosis (4a)
Approximately 15 mg of N-oxide 3a was dissolved in PhMe (15 mL) and placed in a Pyrex
test-tube. The tube was sealed with a septum and placed next to the Exo Terra UVB200
lamp for 18 h. The reaction was concentrated in vacuo and purified by flash column
chromatography (SiO2; 1:2 EtOAc:PE) to give ethyl 4-(benzo[d][1,3]oxazepin-2-yl)benzoate
(4a) a tan solid (11 mg, 73%).
Quinoline N-oxide15 (2a)
Quinoline (10 g, 77 mmol) was dissolved in AcOH (60 mL), then NaBO3·4H2O (15.7 g, 115.5
mmol) was added portion-wise to the solution over 10 mins. The reaction was heated at 40
˚C overnight. Most of the AcOH was removed in vacuo and then the reaction partitioned
with HCCl3 (100 mL) and H2O (300 mL), and the aqueous phase further extracted into HCCl3
(2×100 mL). The combined organic phases were washed with aq. 2 M NaOH, dried with
MgSO4, filtered, then concentrated in vacuo to produce a dark brown deliquescent solid
(6.23 g, 56%). IR (thin film) ν/cm-1 = 3397brw, 3063w, 2260w, 1656w, 1569w, 1510w,
1447w, 1392m, 1226m. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.76 (d, J = 8.5 Hz, 1H), 8.55 (d, J
= 6.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.83 – 7.70 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.31 (dd, J =
8.5, 6.0 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6): δ/ppm = 140.84 (C), 135.27 (CH), 130.32 (C),
130.32 (CH), 128.76 (CH), 128.66 (CH), 125.11 (CH), 121.94 (CH), 118.87 (CH). HRMS: (ESI+)
[M+H]+ calculated for C9H8ON = 146.0606, found = 146.0600.
4-Methylquinoline 1-oxide16 (2b)
4-Methylquinoline (5.4 g, 38 mmol) was dissolved in AcOH (40 mL), then NaBO3·4H2O (8 g,
59 mmol) was added portion-wise to the solution over 10 mins. The reaction was heated at
40 ˚C overnight. Most of the AcOH was removed in vacuo, then the reaction partitioned with
7

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
HCCl3 (50 mL) and H2O (150 mL), and the aqueous phase further extracted into HCCl3 (2×50
mL). The combined organic phases were washed with aq. 2 M NaOH, dried with MgSO4,
filtered, then concentrated in vacuo to produce an off-white deliquescent solid (2.7 g, 45%).
IR (thin film) ν/cm-1 = 3283br w, 1571m, 1514w, 1394s, 1313m, 1277m, 1206m, 1145s,
1057m, 1040w, 969w, 826w, 791s, 702m. 1H-NMR (400 MHz, D3COD): δ/ppm = 8.67 (d, J =
8.5 Hz, 1H), 8.58 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.82 (t, J =
7.5 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 2.75 (s, 3H). 13C-NMR (101 MHz, D3COD): δ/ppm =
141.20 (C), 141.06 (C), 137.66 (CH), 132.49 (CH), 131.19 (C), 130.23 (CH), 126.55 (CH),
122.88 (CH), 120.26 (CH), 18.49 (CH3). HRMS (ESI+) [M+H]+ calculated for C10H10ON =
160.0757, found = 160.0753.
2-(4-(Ethoxycarbonyl)phenyl)quinoline 1-oxide13b (3a)
Off-white solid 341 mg, 39%. IR (thin film) ν/cm-1 = 1709s, 1561w, 1343m, 1273s, 1206w,
1102m, 1027w, 892w, 820m, 763m, 737m, 699w. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.82
(d, J = 8.5 Hz, 1H), 8.17 (app. d, J = 7.5 Hz, 2H), 8.05 (app. d, J = 7.5 Hz, 2H), 7.87 (m, 1H),
7.83 – 7.73 (m, 2H), 7.65 (t, J = 7.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H),
1.42 (t, J = 7.0 Hz, 3H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 166.04 (CO), 143.99 (C), 142.20
(C), 137.66 (C), 131.08 (C), 130.76 (CH), 129.74 (C), 129.57 (CH), 129.38 (CH), 128.75 (CH),
128.08 (CH), 125.48 (CH), 123.02 (CH), 120.14 (CH), 61.17 (CH2), 14.32 (CH3). HRMS (ESI+)
[M+H]+ calculated for C18H16O3N = 294.1125, found = 294.1121. λmax (PhMe) = 346 nm, ε =
14.3 M-1cm-1.
2-(4-Fluorophenyl)quinoline 1-oxide17 (3b)
Off-white solid 221 mg, 31%. IR (thin film) ν/cm-1 = 1600m, 1563m, 1501s, 1453w, 1326s,
1299m, 1232s, 1205w, 1162m, 1149w, 1096w, 1060w, 1017w, 889m, 805s, 802s, 769m,
737s, 606m. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.80 (d, J = 6.5 Hz, 1H), 8.04 – 7.93 (m, 2H),
7.82 (d, J = 7.5 Hz, 1H), 7.79 – 7.67 (m, 2H), 7.61 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H),
7.22 – 7.08 (m, 2H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 163.17 (d, J = 250.5 Hz, CF), 144.14
(C), 142.13 (C), 131.81 (d, J = 8.5 Hz, CH), 130.76 (CH), 129.50 (C), 129.37 (d, J = 3.0 Hz, C),
128.51 (CH), 128.06 (CH), 125.75 (CH), 122.99 (CH), 120.07 (CH), 115.34 (d, J = 21.5 Hz, CH).
19F-NMR (376 MHz, CDCl3): δ/ppm = -110.40. HRMS (ESI+) [M+H]+ calculated for C15H11ONF =
240.0819, found = 240.0825.
2-(4-Chlorophenyl)quinoline 1-oxide17 (3c)
Off-white solid 344 mg, 45%. IR (thin film) ν/cm-1 = 1688w, 1598w, 1561 w, 1487m, 1336s,
1324s, 1298m, 1278m, 1149m, 1093s, 1015m, 890m, 821s, 769m, 729m. 1H-NMR (400 MHz,
CDCl3): δ/ppm 8.82 (d, J = 8.5 Hz, 1H), 7.94 (app. d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H),
7.82 – 7.72 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.50 – 7.46 (m, 3H). 13C-NMR (101 MHz, CDCl3):
δ/ppm = 143.93 (C), 142.17 (C), 135.55 (C), 131.76 (C), 131.01 (CH), 130.81 (CH), 129.61 (C),
128.65 (CH), 128.54 (CH), 128.07 (CH), 125.66 (CH), 122.90 (CH), 120.13 (CH). HRMS (ESI+)
8

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
[M+H]+ calculated for C15H11ON35Cl = 256.0524, found = 256.0525; C15H11ON37Cl = 258.0494,
found = 258.0496.
2-(4-Nitrophenyl)quinoline 1-oxide17 (3d)
Yellow solid 502 mg, 63%. IR (thin film) ν/cm-1 = 1591m, 1511s, 1324s, 1247w, 1103w, 892w,
843m, 810s, 755s, 734s, 694m. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.82 (d, J = 8.5 Hz, 1H),
8.35 (app. d, J = 8.0 Hz, 2H), 8.18 (app. d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (t, J =
7.0 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H). 13C-NMR (101 MHz, CDCl3):
δ/ppm = 147.95 (C), 142.77 (C), 142.30 (C), 139.70 (C), 131.11 (CH), 130.71 (CH), 130.00 (C),
129.22 (CH), 128.21 (CH), 125.70 (CH), 123.44 (CH), 122.65 (CH), 120.19 (CH). HRMS (ESI+)
[M+H]+ calculated for C15H11O3N2 = 267.0764, found = 267.0767.
2-Phenylquinoline 1-oxide18 (3e)
Off-white solid 232 mg, 35%. IR (thin film) ν/cm-1 = 1560m, 1491m, 1449w, 1348m, 1323m,
1283w, 1203w, 1133m, 1109m, 1061w, 888m, 761s, 733s, 695s, 609m, 567m, 540w. 1H-
NMR (400 MHz, CDCl3): δ/ppm = 8.86 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.88 (d, J =
8.0 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.67 (m, 1H), 7.56 – 7.44 (m, 5H). 13C-NMR (101 MHz,
CDCl3): δ/ppm = 145.24 (C), 142.40 (C), 133.60 (C), 130.77 (CH), 129.73 (CH), 129.70 (CH),
128.59 (CH), 128.45 (CH), 128.38 (C), 128.11 (CH), 125.52 (CH), 123.47 (CH), 120.43 (CH).
HRMS (ESI+) [M+H]+ calculated for C15H12ON = 222.0913, found = 222.0912.
2-(4-(Ethoxycarbonyl)phenyl)-4-methylquinoline 1-oxide – novel (3g)
Off-white solid 349 mg, 38%. IR (thin film) ν/cm-1 = 2980w, 1714s, 1607w, 1560w, 1385w,
1366w, 1339m, 1291s, 1210w, 1104m, 1020w, 765m. 1H-NMR (400 MHz, CDCl3): δ/ppm =
8.91 (d, J = 7.0 Hz, 1H), 8.18 (app. d, J = 7.5 Hz, 2H), 8.06 (app. d, J = 7.5 Hz, 2H), 7.99 (d, J =
8.0 Hz, 1H), 7.82 (m, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.35 (br s, 1H), 4.41 (q, J = 7.0 Hz, 2H), 2.71
(s, 3H), 1.43 (t, J = 7.0 Hz, 3H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 166.13 (CO), 141.72 (C),
137.74 (C), 134.00 (C), 131.04 (C), 130.50 (CH), 129.64 (CH), 129.49 (C), 129.37 (CH), 129.27
(C), 128.51 (CH), 124.69 (CH), 123.4 (CH). 120.74 (CH), 61.18 (CH2), 18.36 (CH3), 14.33 (CH3).
HRMS (ESI+) [M+H]+ calculated for C19H18O3N = 308.1281, found = 308.1282.
2-(4-Fluorophenyl)-4-methylquinoline 1-oxide – novel (3h)
Pale brown solid 253 mg, 33%. IR (thin film) ν/cm-1 = 1603m, 1510s, 1504s, 1398w, 1384w,
1338s, 1234s, 1208m, 1160m, 1150m, 1061w, 871w, 838s, 811w, 795w, 761m. 1H-NMR (400
MHz, CDCl3): δ/ppm = 8.90 (d, J = 8.5 Hz, 1H), 8.10-7.80 (m, 3H), 7.80 (m, 1H), 7.68 (m, 1H),
7.33 (m, 1H), 7.20 (m, 2H), 2.69 (s, 3H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 163.18 (d, J =
250.5 Hz, CF), 143.49 (C), 141.67 (C), 134.02 (C), 131.82 (d, J = 8.5 Hz, CH), 130.46 (CH),
129.48 (d, J = 3.5 Hz, C), 129.08 (C), 128.29 (CH), 124.63 (CH), 123.48 (CH), 120.73 (CH),
115.33 (d, J = 21.5 Hz, CH), 18.37 (CH3). 19F-NMR (376 MHz, CDCl3): δ/ppm = -110.66. HRMS
(ESI+) [M+H]+ calculated for C16H13ONF = 254.0976, found = 254.0977.
9

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
2-(4-Cyanophenyl)-4-methylquinoline 1-oxide – novel (3j)
Tan solid 226 mg, 29%. IR (thin film) ν/cm-1 = 3054w, 2226s, 1605m, 1565w, 1501m, 1383s,
1369w, 1339s, 1306w, 1234w, 1209m, 1151m, 869w, 840m, 759s, 731m, 559s. 1H-NMR (400
MHz, CDCl3): δ/ppm = 8.87 (d, J = 8.5 Hz, 1H), 8.10 (app. d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.5 Hz,
1H), 7.86 – 7.76 (m, 3H), 7.72 (t, J = 7.5 Hz, 1H), 7.32 (s, 1H), 2.71 (s, 3H, CH3). 13C-NMR (101
MHz, CDCl3): δ/ppm = 145.48 (C), 141.80 (C), 138.10 (C), 134.28 (C), 132.11 (CH), 130.83
(CH), 130.48 (CH), 129.58 (C), 128.98 (CH), 124.90 (CH), 123.15 (CH), 120.86 (CH), 118.67 (C),
112.99 (C), 18.56 (CH3). HRMS (ESI+) [M+H]+ calculated for C17H13ON2 = 261.1022, found =
261.1020.
4-Methyl-2-(o-tolyl)quinoline 1-oxide – novel (3k)
Dark brown amorphous solid 120 mg, 16%. IR (thin film) ν/cm-1 = 2924w, 1600w, 1561w,
1494w, 1457w, 1387m, 1368w, 1338s, 1282w, 1234m, 1209m, 1150m, 1060w, 910w, 871w,
758s, 729s. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.90 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.5 Hz,
1H), 7.80 (t, J = 7.5 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.41 – 7.28 (m, 4H), 7.20 (s, 1H), 2.69 (s,
3H), 2.26 (s, 3H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 146.34 (C), 141.53 (C), 137.77 (C),
134.00 (C), 133.51 (C), 130.34 (CH), 130.20 (CH), 129.44 (C), 129.36 (CH), 129.17 (CH),
128.35 (CH), 125.97 (CH), 124.79 (CH), 124.32 (CH), 120.91 (CH), 19.79 (CH3), 18.42 (CH3).
HRMS (ESI+) [M+H]+ calculated for C17H16ON = 250.1226, found = 250.1221.
Flow Photochemical Heterocyclic Metamorphosis
Ethyl 4-(benzo[d][1,3]oxazepin-2-yl)benzoate – novel (4a)
Tan solid 49 mg, 98%; large scale 1.935 g, 97%.
IR (thin film) ν/cm-1 = 1715s, 1661w, 1596w, 1407w, 1366s, 1207m, 1103m, 1034m, 761m.
1H-NMR (400 MHz, CDCl3): δ/ppm = 8.16 (app. d, J = 8.5 Hz, 2H), 8.09 (app. d, J = 8.5 Hz, 2H),
7.30 – 7.24 (m, 2H), 7.13 (m, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.28 (d, J = 5.5 Hz, 1H), 6.00 (d, J =
5.5 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H). 13C-NMR (101 MHz, CDCl3):
δ/ppm =166.06 (CO), 152.75 (C), 144.82 (C), 144.50 (CH), 136.74 (C), 132.80 (C), 130.07 (C),
129.53 (CH), 129.26 (CH), 129.06 (CH), 128.64 (CH), 128.25 (CH), 126.18 (CH), 117.50 (CH),
61.29 (CH2), 14.32 (CH3). HRMS (ESI+) [M+H]+ calculated for C18H16O3N = 294.1125, found =
294.1128.
2-(4-Fluorophenyl)benzo[d][1,3]oxazepine – novel (4b)
Tan solid 46 mg, 92%. IR (thin film) ν/cm-1 = 1662m, 1634m, 1595m, 1504s, 1484w, 1444w,
1261m, 1207s, 1193s, 1151m, 1113m, 1098m, 843w, 761s. 1H-NMR (400 MHz, CDCl3):
δ/ppm = 8.12 (app. dd, J = 8.5, 5.5 Hz, 2H), 7.27 – 7.23 (m, 2H), 7.15 – 7.06 (m, 4H), 6.28 (d, J
= 5.5 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 165.06 (d, J =
252.5 Hz, CF), 152.97 (C), 145.17 (C), 144.63 (CH), 131.62 (d, J = 9.0 Hz, CH), 130.05 (C),
129.34 (CH), 129.11 (d, J = 3.0 Hz, C), (C), 128.50 (CH), 128.32 (CH), 125.89 (CH), 117.71 (CH),
10

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
115.60 (d, J = 22.0 Hz, CH). 19F-NMR (376 MHz, CDCl3): δ/ppm = -108.1. HRMS (ESI+) [M+H]+
calculated for C15H11ONF = 240.0819, found = 240.0827.
2-(4-Chlorophenyl)benzo[d][1,3]oxazepine – reported but with no NMR9c (4c)
Off-white solid 47 mg, 95%. IR (thin film) ν/cm-1 = 1661m, 1633w, 1592s, 1571w, 1488w,
1445w, 1401w, 1285m, 1259m, 1207w, 1183w, 1113, 1090s, 1032w, 761s, 523w. 1H-NMR
(400 MHz, CDCl3): δ/ppm = 8.04 (app. d, J = 8.5 Hz, 2H), 7.40 (app. d, J = 8.5 Hz, 2H), 7.28 –
7.22 (m, 2H), 7.16 – 7.04 (m, 2H), 6.27 (d, J = 5.5 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H). 13C-NMR
(101 MHz, CDCl3): δ/ppm = 145.04 (C), 144.61 (CH), 137.87 (C), 131.43 (C), 130.65 (CH),
130.10 (C), 129.36 (CH), 129.18 (CH), 128.80 (C), 128.58 (CH), 128.35 (CH), 126.05 (CH),
117.68 (CH). HRMS (ESI+) [M+H]+ calculated for C15H11NO35Cl = 256.0524, found = 256.0530;
C15H11NO37Cl = 258.0494, found = 258.0501.
2-(4-Nitrophenyl)benzo[d][1,3]oxazepine – novel (4d)
Due to solubility difficulties this transformation required a 1:1 MeCN:PhMe solvent system.
A residence time of 15 min was used as a compromise between conversion and
photodecomposition. Orange solid 33 mg, 66%. IR (thin film) ν/cm-1 = 1660w, 1598m, 1519s,
1482w, 1360s, 1261w, 1208w, 111w, 1036w, 1012w, 854m, 756m, 712w. 1H-NMR (400
MHz, CDCl3): δ/ppm = 8.26 (app. s, 4H), 7.29 – 7.25 (m, 2H), 7.16 (m, 1H), 7.08 (d, J = 7.5 Hz,
1H), 6.26 (d, J = 6.0 Hz, 1H), 5.98 (d, J = 6.0 Hz, 1H). 13C-NMR (101 MHz, CDCl3): δ/ppm =
151.54 (C), 149.58 (C), 144.53 (C), 144.40 (CH), 138.77 (C), 130.21 (C), 130.14 (CH), 129.54
(CH), 129.06 (CH), 128.63 (CH), 126.90 (CH), 123.68 (CH), 117.57 (CH). HRMS (ESI+) [M+H]+
calculated for C15H11O3N2 = 267.0764, found = 267.0767.
2-Phenylbenzo[d][1,3]oxazepine11,19 (4e)
Off-white solid 46 mg, 95%. IR (thin film) ν/cm-1 = 3059w, 1651s, 1631m, 1448w, 1208m,
1197m, 1113w, 1037w, 1020w, 758m, 691w. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.14 –
8.10 (m, 2H), 7.51 – 7.39 (m, 3H), 7.31 – 7.23 (m, 2H), 7.15 – 7.06 (m, 2H), 6.30 (d, J = 5.5 Hz,
1H), 6.02 (d, J = 5.5 Hz, 1H). 13C-NMR (101 MHz, CDCl3): δ/ppm = 153.95 (C), 145.31 (C),
144.79 (CH), 132.87 (C), 131.64 (CH), 130.12 (C), 129.35 (CH), 129.28 (CH), 128.53 (CH),
128.49 (CH), 128.22 (CH), 125.79 (CH), 117.76 (CH). HRMS (ESI+) [M+H]+ calculated for
C15H12ON = 222.0913, found = 22.0916.
Ethyl 4-(5-methylbenzo[d][1,3]oxazepin-2-yl)benzoate – novel (4g)
Off-white solid 47 mg, 95%. IR (thin film) ν/cm-1 = 1716s, 1655w, 1634w, 1367w, 1301s,
1202w, 110s, 1011m, 761w. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.19 (app. d, J = 8.5 Hz, 2H),
8.10 (app. d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.22 (m, 1H), 6.33
(q, J = 1.0 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 2.02 (d, J = 1.0 Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H). 13C-
NMR (101 MHz, CDCl3): δ/ppm = 166.19 (CO), 154.62 (C), 144.81 (C), 140.66 (CH), 136.58
(C), 132.95 (C), 132.12 (C), 129.73 (CH), 129.07 (CH), 128.16 (CH), 128.00, (CH) 126.70 (CH),
11

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
125.69 (CH), 125.28 (C), 61.41 (CH2), 15.35 (CH3), 14.43 (CH3). HRMS (ESI+) [M+H]+ calculated
for C19H18O3N = 308.1281, found = 308.1282.
2-(4-Fluorophenyl)-5-methylbenzo[d][1,3]oxazepine – novel (4h)
Off-white solid 47 mg, 98%. IR (thin film) ν/cm-1 = 1655m, 1597s, 1503s, 1480m, 1441w,
1410w, 1284m, 1258m, 1225m, 1202m, 1153m, 1095m, 1010w, 841w, 763m. 1H-NMR (400
MHz, CDCl3): δ/ppm = 8.19 – 8.10 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.20
(m, 1H), 7.17 – 7.08 (m, 2H), 6.33 (s, 1H), 2.03 (s, 3H). 13C-NMR (101 MHz, CDCl3): δ/ppm =
164.96 (d, J = 252.5 Hz, CF), 154.61 (C), 144.90 (C), 140.59 (CH), 131.90 (C), 131.39 (d, J = 9.0
Hz, CH), 128.75 (C), 128.01 (CH), 127.70 (CH), 126.56 (CH), 125.21 (CH), 125.17 (C), 115.58
(d, J = 22.0 Hz, CH), 15.26 (s, CH3). 19F-NMR (376 MHz, CDCl3): δ/ppm = 108.0. HRMS (ESI+)
[M+H]+ calculated for C16H13ONF = 254.0976, found = 254.0982.
4-(5-Methylbenzo[d][1,3]oxazepin-2-yl)benzonitrile – novel (4j)
Off-white solid 49 mg, 98%. IR (thin film) ν/cm-1 = 3063w, 2228m, 1659m, 1634w, 1596w,
1564w, 1500w, 1483w, 1441w, 1407w, 1283w, 1259m, 1203s, 1093s, 1073m, 1026w, 1012s,
863w, 843w, 762s. 1H-NMR (400 MHz, CDCl3): δ/ppm = 8.23 (app. d, J = 8.5 Hz, 2H), 7.73
(app. d, J = 8.5 Hz, 2H), 7.42 – 7.13 (m, 4H), 6.30 (s, 1H), 2.03 (s, 3H). 13C-NMR (101 MHz,
CDCl3): δ/ppm = 153.61 (C), 144.49 (C), 140.46 (CH), 136.82 (C), 132.36 (CH), 132.11 (C),
129.59 (CH), 128.34 (CH), 128.13 (CH), 126.82 (CH), 126.08 (CH), 125.39 (C), 118.55 (C),
114.75 (C), 15.40 (CH3). HRMS (ESI+) [M+H]+ calculated for C17H13ON2 = 261.1022, found =
261.1026.
5-Methyl-2-(o-tolyl)benzo[d][1,3]oxazepine – novel (4k)
Off-white solid 38 mg, 75%. IR (thin film) ν/cm-1 = 2956w, 2923w, 1652m, 1633w, 1597w,
1570w, 1483m, 1454w, 1440w, 1254m, 1193s, 1095s, 1071w, 1002s, 981w, 758s, 726m. 1H-
NMR (400 MHz, CDCl3): δ/ppm = 7.92 (d, J = 7.0 Hz, 1H), 7.43 – 7.24 (m, 6H), 7.21 (m, 1H),
6.33 (q, J = 1.0 Hz, 1H), 2.69 (s, 3H), 2.04 (d, J = 1.0 Hz, 3H). 13C-NMR (101 MHz, CDCl3):
δ/ppm = 156.12 (C), 145.21 (C), 140.67 (CH), 139.83 (C), 134.43 (C), 132.03 (C), 131.82 (CH),
130.78 (CH), 130.59 (CH), 127.99 (CH), 127.86 (CH), 126.62 (CH), 125.89 (CH), 125.26 (CH),
125.04 (C), 22.75 (CH3), 15.34 (CH3). HRMS (ESI+) [M+H]+ calculated for C17H16ON = 250.1226,
found = 250.1227.
References
1.
Campbell IB, Macdonald SJF, Procopiou PA. Drug Discov Today. 2018; 23: 219–234.
2.
Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. Chem Soc Rev. 2016; 45: 546–
576.
3.
(a) Fier PS, Hartwig JF. J Am Chem Soc. 2014; 136: 10139–10147; (b) Fujiwara Y, Dixon
JA, O’Hara F, Funder ED, Dixon DD, Rodriguez RA, Baxter RD, Herlé B, Sach N, Collins
12

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
MR, Ishihara Y, Baran PS. Nature. 2012; 492: 95–99.
4.
(a) Gensch T, Hopkinson MN, Glorius F, Wencel-Delord J. Chem Soc Rev. 2016; 45:
2900–2936; (b) Durak LJ, Payne JT, Lewis JC. ACS Catal. 2016; 6: 1451–1454. (c) Zhou
Q, Gui J, Pan C-M, Albone E, Cheng X, Suh EM, Grasso L, Ishihara Y, Baran PS. J Am
Chem Soc. 2013; 135: 12994–12997; (d) Wencel-Delord J, Glorius F. Nat Chem. 2013;
5: 369–375.
5.
6.
(a) Nogi K, Yorimitsu H. Chem Commun. 2017; 53: 4055–4065; (b) Yorimitsu H, Vasu
D, Bhanuchandra M, Murakami K, Osuka A. Synlett. 2016; 27: 1765–1774.
Butini S, Gemma S, Campiani G, Franceschini S, Trotta F, Borriello M, Ceres N, Ros S,
Coccone SS, Bernetti M, De Angelis M, Brindisi M, Nacci V, Fiorini I, Novellino E,
Cagnotto A, Mennini T, Sandager-Nielsen K, Andreasen JT, Scheel-Kruger J, Mikkelsen
JD, Fattorusso C. J Med Chem. 2009; 52: 151–169.
7.
(a) Afzal O, Kumar S, Haider MR, Ali MR, Kumar R, Jaggi M, Bawa S. Eur J Med Chem.
2015; 97: 871–910; (b) Marella A, Tanwar OP, Saha R, Ali MR, Srivastava S, Akhter M,
Shaquiquzzaman M, Alam MM. Saudi Pharm J. 2013; 21: 1–12.
8.
9.
(a) Kaneko C, Yamada S, Yokoe I, Ishikawa M. Tetrahedron Lett. 1967; 8: 1873–1877.
(b) Kaneko C, Yamada S. Chem Pharm Bull (Tokyo). 1966; 14: 555–557.
(a) Buchardt O, Duffield AM, Djerassi C, Liljeqvist G, Lindberg AA, Jansen G, Lamm B,
Samuelsson B. Acta Chem Scand. 1969; 23: 126–136; (b) Buchardt O, Jensen B, Larsen
IK, Levstek I, Eržen V, Blinc R, Paušak S, Ehrenberg L, Dumanović J. Acta Chem Scand.
1967; 21: 1841–1854; (a) Buchardt O. Tetrahedron Lett. 1966; 7: 6221–6228.
10. (a) Albini A, Fasani E, Frattini V. J Chem Soc Perkin Trans 2. 1988: 235–240; (b) Albini
A, Fasani E, Dacrema LM. J Chem Soc Perkin Trans 1. 1980: 2738–2742; (c) Albini A,
Fasani E, Buchardt O. Tetrahedron Lett. 1982; 23: 4849–4852; (d) Albini A, Bettinetti
GF, Minoli G. Tetrahedron Lett. 1979; 20: 3761–3764.
11. Le Roux J-P, Desbene P-L, Cherton J-C. J Heterocycl Chem. 1981; 18: 847–849.
12. McKillop A, Sanderson WR. Tetrahedron. 1995; 51: 6145–6166.
13. (a) Yuan J-W, Liu S-N, Qu L-B. Tetrahedron. 2017; 73: 2267–2275; (b) Colleville AP,
Horan RAJ, Olazabal S, Tomkinson NCO. Org Process Res Dev. 2016; 20: 1283–1296;
(c) Liu S, Tzschucke CC. European J Org Chem. 2016: 3509–3513; (d) Campeau L-C,
Stuart DR, Leclerc J-P, Bertrand-Laperle M, Villemure E, Sun H-Y, Lasserre S, Guimond
N, Lecavallier M, Fagnou K. J Am Chem Soc. 2009; 131: 3291–3306; (e) Harrowven DC,
Sutton BJ. In Progress in Heterocyclic Chemistry Elsevier, 2005; pp 27–53.
14. (a) Cochran JE, Waal N. Org Process Res Dev. 2016; 20: 1533–1539; (b) Elliott LD,
Knowles JP, Koovits PJ, Maskill KG, Ralph MJ, Lejeune G, Edwards LJ, Robinson RI,
Clemens IR, Cox B, Pascoe DD, Koch G, Eberle M, Berry MB, Booker-Milburn KI. Chem
13

Flow Photochemical Heterocyclic Metamorphosis
C. D. Smith
ACCEPTED MANUSCRIPT
- A Eur J. 2014; 20: 15226–15232; (c) Harrowven DC, Mohamed M, Gonçalves TP,
Whitby RJ, Bolien D, Sneddon HF. Angew Chemie - Int Ed. 2012; 51: 4405–4408; (d)
Knowles JP, Elliott LD, Booker-Milburn KI. Beilstein J Org Chem. 2012; 8: 2025–2052.;
(e) Hook BDA, Dohle W, Hirst PR, Pickworth M, Berry MB, Booker-Milburn KI. J Org
Chem. 2005; 70: 7558–7564.
15. Jha AK, Jain N. Chem Commun. 2016; 52: 1831–1834.
16. Bering L, Antonchick AP. Org Lett. 2015; 17: 3134–3137.
17. Yuan J-W, Li W-J, Xiao Y-M. Tetrahedron. 2017; 73: 179–186.
18. Cho SH, Hwang SJ, Chang S. J Am Chem Soc. 2008; 130: 9254–9256.
19. Buchardt O, Jensen B, Larsen IK. Acta Chem Scand. 1967; 21: 1841–1854.
14