A two-stage continuous-flow synthesis of spirooxazine photochromic dyes

Article abstract of DOI:10.1071/CH12435

A continuous-flow process for the synthesis of several known and previously unreported spirooxazine photochromic dyes is reported. The process proceeds via an initial copper catalysed addition of substituted anilines to naphthalene-1,2-dione. This is followed by reaction with 1,3,3-trimethyl-2- methyleneindoline in the presence of hydroxylamine hydrochloride to give the desired spirooxazine products. The photochromic dyes were then cast into lenses to allow a preliminary evaluation of their properties.

Full text of DOI:10.1071/CH12435

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 172–177
Full Paper
http://dx.doi.org/10.1071/CH12435
A Two-Stage Continuous-Flow Synthesis of Spirooxazine
Photochromic Dyes
A B C D
, , ,
A
Mark York
and Adriana Edenharter
A
CSIRO Materials Science and Engineering, Clayton, Vic. 3169, Australia.
Cooperative Research Centre for Polymers, Notting Hill, Vic. 3168, Australia.
B
C
Advanced Polymerik Pty Ltd, Notting Hill, Vic. 3168, Australia.
D
Corresponding author. Email: mark.york@csiro.au
A continuous-flow process for the synthesis of several known and previously unreported spirooxazine photochromic dyes
is reported. The process proceeds via an initial copper catalysed addition of substituted anilines to naphthalene-1,2-dione.
This is followed by reaction with 1,3,3-trimethyl-2-methyleneindoline in the presence of hydroxylamine hydrochloride to
give the desired spirooxazine products. The photochromic dyes were then cast into lenses to allow a preliminary evaluation
of their properties.
Manuscript received: 25 September 2012.
Manuscript accepted: 9 November 2012.
Published online: 28 November 2012.
Introduction
The performance of synthetic transformations under continu-
ous-flow conditions (on either a micro- or mesoscale) is an area
of intense current interest. This interest can be explained, at least
in part, by the array of potential advantages that continuous-flow
processing presents over traditional batch processing. Such
advantages include the ease of scale-up, high reproducibility,
rapid mixing and heat transfer, and inherently higher safety due
to smaller reactor volumes and the containment of hazardous
intermediates.[1–3]
N
N
hν1
hν2 or heat
N
O
N
O
1
2
Colourless
Coloured
Scheme 1.
Spirooxazines are a commercially relevant class of photo-
chromic dyes which upon exposure to ultraviolet light undergo a
reversible colour change from the colourless spirocyclic isomer,
methanol.[9,10] Furthermore, such a method is not suitable for
use with sterically hindered anilines, giving no detectable
amounts of product even after extended reaction times for
reaction with N,N,3,5-tetramethylaniline.[12] A single report
exists of the formation of substituted naphthoquinones 5
under similar conditions in .80 % yield with a reaction time
of 4–5 h.[11] However, in our hands, this protocol gave a
,20 % yield of the desired products. The synthesis of 1,2-
naphthoquinones of the general structure 5 has also been
reported from the reaction of the corresponding anilines in the
presence of stoichiometric amounts of copper or nickel, with the
products being isolated in ,50 % yield.[13–15]
Our synthesis of substituted 1,2-naphthoquinones 5 was
performed by heating a solution of 1,2-naphthoquinone 3
(R1 ¼ H), aniline 4 and 10 mol-% copper (II) chloride in N,N-
dimethylacetamide (DMAc) at 1408C for 10 min using a com-
mercially available Vapourtec flow reactor (Scheme 3).[16]
In this way, reaction with N,N-diethylaniline gave an 80 %
yield of the corresponding naphthoquinone 5a. In the absence of
catalytic copper only 18 % of the product was isolated (Table 1,
entry 1). Performance of the reaction in a sealed tube under
microwave irradiation gave only a 54 % yield of the product
(Table 1, entry 1). The reason for this reduction in yield is
unknown although it may be a reflection of the greater operating
1
to the conjugated, coloured merocyanine isomer, 2
(Scheme 1).[4–8] Amongst these dyes, those substituted with
an arylamino functionality in the 60 position are of particular
interest due to their green coloration,[9–11] which contrasts with
the dark blue to purple coloration exhibited by most spiroox-
azines reported.[4]
Results and Discussion
The published syntheses of such dyes are generally performed as
a three step process beginning with reaction of Folin’s reagent
(sodium 1,2-naphthoquinone-4-sulfonate, 3, R1 ¼ SOꢀ3 Naþ)
with a N,N-disubstituted aniline 4 (Scheme 2).[9–11]
During the course of our research into organic photochro-
mism we had reason to prepare several green colouring spir-
ooxazine dyes. We were initially drawn to investigate the
continuous-flow synthesis of these dyes due to the low yields
observed and the requirement for extended reaction times in the
initial coupling reaction between Folin’s reagent and substituted
anilines 4. These yields are typically less than 50 % with reaction
times in excess of 18 h and are performed by addition of
the aniline to a suspension of Folin’s reagent in aqueous
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

Continuous-Flow Synthesis of Spirooxazines
173
pressure of the continuous-flow system. The presence of a free
hydroxyl group in the aniline was well tolerated (Table 1, entries
2 and 5) as were substituents in the 3 position, which could
have been expected to provide a steric barrier to the coupling
reaction (Table 1, entries 2–4 and 6). Notably N,N,3,5-
tetramethylaniline, which failed to react under the standard
literature conditions,[12] gave the corresponding product 5f in
51 % yield (Table 1, entry 5).
With naphthoquinone derivatives 5 in hand we then turned
our attention to the conversion of these into the spirooxazine
photochromic dyes 7. This is typically done in two discreet
stages, with an initial conversion of the 4-substituted naphtho-
quinone 5 to the corresponding oxime 6 by treatment with
hydroxylamine hydrochloride, before reaction with a substituted
methylene indoline to deliver the spirooxazine photochromic
7 (Scheme 2).[10,11]
In order to avoid the necessity of two separate steps a
combined protocol was developed whereby a mixture of the
naphthoquinone 5 and hydroxylamine hydrochloride in 3 : 1 v/v
MeOH : THF was mixed with a second reagent stream contain-
ing a solution of N,N-diisopropylethylamine (DIPEA) and 1,3,3-
trimethyl-2-methyleneindoline in MeOH. The combined
reagent stream was then pumped through a series of four
10 mL tube reactors at 1208C with a total residence time of
20 min allowing the synthesis of the desired photochromics 7
without the need to isolate the intermediate oximes 6
(Scheme 4). The presence of DIPEA was required to deproto-
nate the oxime hydrochloride salt formed in the reaction. In its
absence only traces of product were observed.
As can be seen, the continuous flow method was successful
for the synthesis of both known (Table 2, entry 1) and novel
(Table 2, entries 2–3 and 5–8) spirooxazine photochromic dyes
in moderate yields. In this way oxime 5a gave the corresponding
spirooxazine in 55 % yield (Table 2, entry 1). The process could
also be performed in a sealed tube under microwave irradiation,
although in this case the yield was slightly lower than that
obtained under continuous-flow conditions (Table 2, entry 1).
In the case of the naphthoquinone bearing a free hydroxyl
functionality (5e) the reaction was not successful due to insuffi-
cient solubility of the starting quinone in the reaction medium
(Table 2, entry 4).
In order to undertake a preliminary evaluation of the photo-
chromic properties of novel compounds 7b, 7c, and 7e to 7h, in
comparison to known dye 7a, test lenses were prepared. The
lenses were composed of a matrix containing polyethylenegly-
col 400 dimethacrylate and bisphenol A ethoxylate dimethacry-
late in a 1 : 4 weight ratio with 0.4 % AIBN by mass as initiator.
The monomer was thoroughly mixed with 1.5 ꢁ 10ꢀ6 mol of
spirooxazine per gram of matrix and the lenses thermally cured.
The lenses, after irradiation at 365 nm with a handheld UV
source, can be seen in Fig. 1. Variations in the nitrogen
substituents of the aniline gave only very subtle changes in the
green coloration of the dyes (Fig. 1; 7a, 7 g, and 7h). Substi-
tuents in either the 3 or 5 position of the aniline tended to
produce dyes which were blue shifted (Fig. 1; 7b, 7c, 7e, and 7f).
Conclusion
In conclusion, a two stage, continuous-flow process for the
synthesis of spirooxazine photochromic dyes has been devel-
oped including a copper catalysed addition of substituted ani-
lines to 1,2-naphthoquinone. This method provides convenient
access to several both novel and previously unreported dyes,
including some which are not accessible using previously pub-
lished syntheses.
Experimental
Continuous-flow chemistry was performed on a Vapourtec R-4
flow reactor heater with a connected R2þ pumping module
using either DMAc (5) or MeOH (7) as flow solvent. NMR data
were collected on a Bruker AV200 (200 MHz) or Bruker AV400
(400 MHz) spectrometer using CDCl3 as the solvent and TMS as
internal standard. Positive ion EI mass spectra were collected
using a ThermoQuest MAT95XL mass spectrometer with an
O
O
O
NOH
O
R3
R4
N
N
R2
O
R3
N
R5
N
R5
O
N
R4
H2NOH⋅HCl
ϩ
R2
R4
R2
R4
R2
R1
N
N
R3
3
4
R3
7
5
6
Scheme 2.
O
O
O
R3
R4
N
O
75 psi 75 psi
ϩ
R2
R4
R1
R2
CuCl2 (10 mol-%)
N
3
4
R3
40 mL
140ЊC
10 min
5
0.6 M in DMA (wrt 3)
4 mL minϪ1
Scheme 3.

174
M. York and A. Edenharter
Table
1. Continuous-flow
synthesis
of
substituted
1,2-
ionisation energy of 70 eV. UV-Vis spectra were recorded using
a Hewlett Packard 8453 diode array spectrophotometer. Melting
points were obtained using a Gallenkamp capillary melting
point apparatus and are uncorrected. The anilines used to pre-
pare 5f and 5g were synthesised according to published proce-
dures.[17,18] All other starting materials were purchased from
commercial sources and used without further purification.
naphthoquinones 5
Entry
Aniline
Product
Yield [%]
80
18A
54B
1
2
3
5a
N
General Procedure for the Preparation of 4-Substituted
1,2-Naphthoquinones, 5
A solution of substituted aniline (3.35 mmol), copper (II) chlo-
ride (35 mg, 0.335 mmol) and 1,2-naphthoquinone (1.06 g,
6.70 mmol) in DMAc (total volume of solution ¼ 11.5 mL) was
pumped at a rate of 4 mL minꢀ1 through a series of 4 ꢁ 10 mL
reactor coils (PFA tubing, 1 mm i.d.) heated to 1408C. The
reagent stream was eluted through 2 ꢁ 75 psi back pressure
regulators into a mixture of ethyl acetate (50 mL) and water
(50 mL). The organic phase was separated, washed with a
further portion of water (30 mL), dried over magnesium sulfate
and evaporated under vacuum. The residue was then purified by
column chromatography over silica gel eluting with 0–20 % v/v
ethyl acetate/light petroleum 40–608C.
5b
5c
65
82
N
N
HO
4
5
6
5d
5e
5f
64
51
86
4-(4-(Diethylamino)phenyl)naphthalene-1,2-dione 5a is a
known compound; analytical data was in good agreement with
that reported previously.[9]
N
4’-(Dimethylamino)-[1,1’-binaphthalene]-3,4-dione 5b
N
Obtained as a dark brown solid in 65 % yield; mp 66–688C.
dH (400 MHz) 8.30 (d, J 8.4, 1H), 8.20 (dd, J 7.6 and 1.5, 1H),
7.65 (d, J 8.4, 1H), 7.53–7.49 (m, 1H), 7.49–7.44 (dt, J 7.6 and
1.2, 1H), 7.42–7.35 (m, 3H), 7.11 (d, J 7.7, 1H), 6.89 (dd, J 7.6
and 1.1, 1H), 6.52 (s, 1H), 2.97 (s, 6H). dc (100 MHz) 180.9,
179.8, 157.3, 152.7, 136.4, 135.5, 132.5, 131.5, 130.8, 130.3,
130.2, 129.1, 128.8, 128.6, 126.8, 126.4, 126.3, 125.8, 125.1,
113.3, 45.2. m/z (HREI) calc. for C22H17NO2 327.1254 (Mþꢂ),
found 327.1255.
O
N
7
8
5g
5h
81
66
N
4-(4-(Diethylamino)-2-methylphenyl)
naphthalene-1,2-dione 5c
Obtained as a dark blue solid in 82 % yield; mp 148–1498C.
dH (400 MHz) 8.15 (dd, J 7.5 and 1.6, 1H), 7.54–7.49 (dt, J 7.6
and 1.5, 1H), 7.49–7.44 (dt, J 7.5 and 1.3, 1H), 7.12 (dd, J7.6 and
1.2, 1H), 7.05–7.00 (m, 1H), 6.60–6.55 (m, 2H), 6.35 (s, 1H),
3.39 (q, J 7.1, 4H), 2.16 (s, 3H), 1.20 (t, J 7.1, 6H). dc (100 MHz)
180.9, 180.2, 158.5, 148.6, 136.8, 136.4, 135.4, 131.6, 130.6,
N
AReaction performed in the absence of CuCl2.
BReaction performed in a sealed tube under microwave irradiation.
O
O
N
R2
R3
R4
75 psi 75 psi
O
N
N
R2
H2NOH⋅HCI
N
R4
R3
7
40 mL
120ЊC
20 min
DIPEA
5
N
0.2 M in 3:1 v/v MeOH:THF (wrt 5)
1.64 mL minϪ1
8
1.05 M in MeOH (wrt 8)
0.36 mL minϪ1
Scheme 4.

Continuous-Flow Synthesis of Spirooxazines
175
Table 2. Continuous-flow synthesis of substituted spirooxazines 7
Entry Oxime
Product
Yield [%]
N
7a
7f
7b
7g
7c
7e
55
41A
N
O
O
O
N
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
7a
7b
7c
7d
7e
7f
N
N
N
7h
N
N
71
63
Fig. 1. Test lenses containing spirooxazine compounds 7a–7c and 7e–7h
after UV irradiation.
and 1.6, 1H), 7.52–7.47 (m, 1H), 7.34 (dd, J 7.8 and 1.2, 1H),
7.10 (d, J 8.6, 1H), 6.47 (s, 1H), 6.41 (dd, J 8.6 and 2.5, 1H), 6.27
(d, J 1.5, 1H), 4.89 (br s, 1H), 3.02 (s, 6H). dc (100 MHz) 180.6,
180.2, 155.2, 154.4, 153.2, 135.4, 135.2, 131.8, 131.1, 130.8,
130.2, 130.1, 127.8, 111.2, 105.3, 99.7, 40.4. m/z (HREI) calc.
for C18H13NO3 291.0890 (Mþꢂ), found 218.0899.
N
N
N
N
N
N
N
N
N
N
N
N
NDB
O
O
O
O
O
4-(4-(Dimethylamino)-2,6-dimethylphenyl)
naphthalene-1,2-dione 5e
HO
Obtained as a dark brown solid in 51 % yield; mp 180–1828C.
dH (400 MHz) 8.18–8.15 (m, 1H), 7.50–7.46 (m, 2H), 6.92–6.88
(m, 1H), 6.50 (s, 2H), 6.32 (s, 1H), 2.99 (s, 6H), 2.11 (s, 6H). dc
(100 MHz) 180.9, 179.9, 158.2, 150.6, 136.1, 136.0, 135.8,
131.6, 130.8, 130.1, 129.0, 128.7, 123.8, 111.5, 40.4, 20.6. m/z
(HREI) calc. for C20H19NO2 305.1410 (Mþꢂ), found 305.1409.
N
N
N
N
68
4-(4-(Dimethylamino)-2-methoxyphenyl)
naphthalene-1,2-dione 5f
45
Obtained as a dark purple solid in 86 % yield; mp 172–1748C.
dH (400 MHz) 8.10 (dd, J 7.6 and 1.4, 1H), 7.52–7.46 (dt, J 7.6
and 1.5, 1H), 7.45–7.39 (dt, J 7.5 and 1.2, 1H), 7.17 (dd, J 7.6
and 1.0, 1H), 7.10 (d, J 8.5, 1H), 6.40 (s, 1H), 6.37 (dd, J 8.5 and
2.2, 1H), 6.27 (d, J 2.2, 1H), 3.73 (s, 3H), 3.04 (s, 6H).
dc (100 MHz) 180.8, 180.4, 158.1, 156.2, 153.2, 136.0, 134.8,
131.5, 130.9, 130.2, 129.9, 129.7, 127.9, 113.5, 104.6, 95.4,
55.4, 40.5. m/z (HREI) calc. for C19H17NO3 307.1203 (Mþꢂ),
found 307.1203.
O
5g
7g
59
4-(1-Methyl-1,2,3,4-tetrahydroquinolin-6-yl)
naphthalene-1,2-dione 5g
8
5h
7h
53
Obtained as a dark blue solid in 81 % yield; mp 1658C. dH
(400 MHz) 8.14 (d, J 7.4, 1H), 7.59–7.53 (m, 2H), 7.50–7.44
(m, 1H), 7.20 (dd, J 8.5 and 2.2, 1H), 7.09–7.06 (m, 1H), 6.60
(d, J 8.6, 1H), 6.38 (s, 1H), 3.33 (t, J 5.7, 2H), 2.97 (s, 3H), 2.78
(t, J 6.3, 2H), 2.04–1.95 (m, 2H). dc (100 MHz) 180.6, 180.3,
157.6, 148.4, 135.5, 134.8, 132.1, 130.5, 130.3, 130.0, 129.2,
128.4, 125.5, 123.3, 122.6, 110.2, 51.2, 38.9, 28.0, 22.0. m/z
(HREI) calc. for C20H17NO2 303.1254 (Mþꢂ), found 303.1251.
AReaction performed in a sealed tube under microwave irradiation.
BReaction unsuccessful, starting material insufficiently soluble. ND ¼ not
determined.
130.1, 130.0, 128.1, 123.1, 113.2, 109.1, 44.5, 21.1, 12.8. m/z
(HREI) calc. for C21H21NO2 319.1567 (Mþꢂ), found 319.1562.
4-(4-(Benzyl(ethyl)amino)phenyl)naphthalene-
4-(4-(Dimethylamino)-2-hydroxyphenyl)
1,2-dione 5h
naphthalene-1,2-dione 5d
Obtained as a dark violet gum in 66 % yield. dH (400 MHz)
8.14 (d, J 7.7, 1H), 7.59–7.51 (m, 2H), 7.50–7.44 (m, 1H),
7.35–7.30 (m, 4H), 7.28–7.21 (m, 3H), 6.75 (d, J 9.0, 2H), 6.38
Obtained as a dark purple solid in 64 % yield; mp 182–1858C.
dH (400 MHz) 8.16 (dd, J 7.4 and 1.6, 1H), 7.58–7.53 (dt, J 7.6

176
M. York and A. Edenharter
(s, 1H), 4.60 (s, 2H), 3.56 (q, J 7.1, 2H), 1.27 (t, J 7.5, 3H). dc
(100 MHz) 180.5, 180.3, 157.4, 150.1, 138.1, 135.4, 134.8,
132.0, 130.5, 130.4, 130.3, 129.9, 128.9, 127.2, 126.4, 125.7,
123.5, 111.7, 53.8, 45.5, 12.3. m/z (HREI) calc. for C25H21NO2
367.1567 (Mþꢂ), found 367.1560.
1.97 (d, J 6.0, 6H), 1.44 (d, J 12.6, 6H). dc (100 MHz) 152.6,
147.8, 140.7, 138.3, 136.2, 133.9, 131.9, 128.1, 127.0, 126.0,
125.5, 125.0, 124.0, 122.23, 121.7, 119.9, 111.8, 107.3, 99.4,
52.0, 40.9, 29.9, 25.6, 21.2, 21.1. m/z (HREI) calc. for
C32H33N3O 475.2618 (Mþꢂ), found 475.2614.
3-Methoxy-N,N-dimethyl-4-(1,3,3-trimethylspiro
[indoline-2,2’-naphtho[1,2-b][1,4]oxazin]-6’-yl)
aniline 7f
General Procedure for the Preparation of Substituted
Spirooxazines, 7
A solution of substituted 1,2-naphthoquinone 5 (0.98 mmol) and
hydroxylamine hydrochloride (75 mg, 1.08 mmol) in 3 : 1 v/v
MeOH : THF (total volume of solution ¼ 5 mL), pumped at a
rate of 1.64 mL minꢀ1 was mixed at ambient temperature via a
T-piece with a solution of 1,3,3-trimethyl-2-methyleneindoline
(204 mg, 1.18 mmol) and DIPEA (188 mL, 1.08 mmol) in MeOH
(total volume of solution ¼ 1.1 mL), pumped at a rate of
0.36 mL minꢀ1. The combined reagent stream was then passed
through a series of series of 4 ꢁ 10 mL reactor coils (PFA tubing,
1 mm i.d.) heated to 1208C before elution through 2 ꢁ 75 psi
back pressure regulators. The eluent was then evaporated under
vacuum and the residue was then purified by column chroma-
tography over silica gel eluting with 0–10 % v/v ethyl acetate/
light petroleum 40–608C.
Obtained as a khaki foam in 45 % yield; mp 108–1108C. lmax
614 nm. dH (400 MHz) 8.09–8.04 (m, 1H), 7.75 (d, J 6.2, 1H),
7.64–7.60 (m, 1H), 7.51 (d, J 4.3, 1H), 7.40–7.30 (m, 2H), 7.26
(t, J 7.7, 1H), 7.20 (dd, J 8.3 and 1.2, 1H), 7.14 (t, J 7.4, 1H), 6.95
(dt, J 7.3 and 2.0, 1H), 6.64 (t, J 8.2, 1H), 6.54–6.42 (m, 2H),
3.72 (s, 3H), 3.07 (s, 6H), 2.87 and 2.83 (2 s, 3H), 1.46–1.41
(m, 6H). dc (100 MHz) 158.3, 152.5, 151.9, 148.0, 140.8, 136.3,
133.9, 132.8, 130.2, 128.1, 127.5, 127.0, 126.6, 125.3, 124.6,
123.8, 122.1, 121.7, 119.9, 107.3, 104.9, 99.6, 99.1, 66.0, 55.7,
52.0, 51.7, 40.9, 30.0, 25.8, 23.3, 21.3. m/z (HREI) calc. for
C31H31N3O2 477.2411 (Mþꢂ), found 477.2401.
1,3,3-Trimethyl-6’-(1-methyl-1,2,3,4-
tetrahydroquinolin-6-yl)spiro[indoline-2,2’-naphtho
[1,2-b][1,4]oxazine] 7g
N,N-Diethyl-4-(1,3,3-trimethylspiro[indoline-2,20-naphtho
[1,2-b][1,4]oxazin]-60-yl)aniline 7a is a known compound;
analytical data was in good agreement with that reported
previously.[9]
Obtained as a cream solid in 59 % yield; mp 205–2068C. lmax
628 nm. dH (400 MHz) 8.06 (dd, J 7.7 and 2.1, 1H), 7.98 (dd, J
7.7 and 2.0, 1H), 7.74 (s, 1H), 7.50 (s, 1H), 7.43–7.35 (m, 2H),
7.26–7.22 (m, 2H), 7.15–7.13 (m, 2H), 6.95 (t, J 6.1, 1H), 6.73
(d, J 8.4, 1H), 6.62 (d, J 7.7, 1H), 3.33 (t, J 5.6, 2H), 2.98 (s, 3H),
2.86 (t, J 6.3, 2H), 2.82 (s, 3H), 2.11–2.05 (m, 2H), 1.41 (d, J 6.5,
6H). dc (100 MHz) 152.5, 147.8, 146.0, 140.5, 136.2, 133.7,
133.1, 130.8, 129.0, 128.1, 127.9, 126.8, 126.6, 126.3, 125.5,
124.6, 122.8, 122.2, 121.7, 119.9, 110.8, 107.3, 99.4, 51.8, 51.5,
39.3, 29.9, 28.0, 25.6, 22.6, 21.1. m/z (HREI) calc. for
C32H31N3O 473.2462 (Mþꢂ), found 473.2441.
N,N-Dimethyl-4-(1,3,3-trimethylspiro[indoline-2,2’-
naphtho[1,2-b][1,4]oxazin]-6’-yl)naphthalen-
1-amine 7b
Obtained as a sage foam in 71 % yield; mp 171–1738C. lmax
607 nm. dH (400 MHz) 8.39 (d, J 8.4, 1H), 8.13 (d, J 8.5, 1H),
7.78 (d, J 2.5, 1H), 7.60 (d, J 2.7, 1H), 7.51–7.44 (m, 3H), 7.35–
7.16 (m, 7H), 6.96 (dt, J 8.9 and 1.2, 1H), 6.66 (t, J 7.6, 1H), 3.04
(s, 6H), 2.92 and 2.86 (2 s, 3H), 1.47–1.13 (m, 6H). dc
(100 MHz) 152.8, 152.5, 147.9, 141.3, 136.2, 134.4, 134.3,
131.6, 128.9, 128.3, 128.2, 127.9, 127.3, 127.0, 126.9, 125.6,
125.2, 124.7, 124.5, 123.7, 122.2, 121.7, 120.0, 113.8, 107.3,
99.7, 99.4, 52.1, 52.0, 45.5, 30.0, 29.9, 25.7, 21.2. m/z (HREI)
calc. for C34H31N3O 497.2462 (Mþꢂ), found 497.2463.
N-Benzyl-N-ethyl-4-(1,3,3-trimethylspiro[indoline-2,2’-
naphtho[1,2-b][1,4]oxazin]-6’-yl)aniline 7h
Obtained as a dark green foam in 53 % yield; mp 116–1178C.
lmax 623 nm. dH (400 MHz) 8.07 (dd, J 6.9 and 1.8, 1H), 7.98
(dd, J 7.1 and 1.6, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.42–7.25
(m, 11H), 7.14 (dd, J 7.3 and 0.9, 1H), 6.95 (t, J 7.5, 1H), 6.84
(d, J 8.8, 1H), 6.62 (d, J 7.7, 1H), 4.64 (s, 2H), 3.59 (q, J 7.1, 2H),
2.83 (s, 3H), 1.42 (d, J 7.0, 6H), 1.33 (t, J 6.0, 3 H). dc (100 MHz)
152.6, 147.9, 147.8, 140.5, 139.4, 136.2, 133.6, 133.1, 131.2,
128.8, 128.1, 127.8, 127.0, 126.8, 126.7, 126.5, 126.4, 125.5,
124.7, 124.0, 122.2, 121.7, 199.9, 112.0, 107.3, 99.4, 54.2, 51.9,
45.4, 29.9, 25.7, 21.1, 12.4. m/z (HREI) calc. for C37H35N3O
537.2775 (Mþꢂ), found 537.2767.
N,N-Diethyl-3-methyl-4-(1,3,3-trimethylspiro[indoline-
2,2’-naphtho[1,2-b][1,4]oxazin]-6’-yl)aniline 7c
Obtained as a pale green solid in 63 % yield; mp 147–1488C.
max 612 nm. dH (400 MHz) 8.10–8.07 (m, 1H), 7.76 (d, J 3.7,
l
1H), 7.56–7.51 (m, 1H), 7.45 (d, J 3.3, 1H), 7.38–7.35 (m, 2H),
7.27 (t, J 7.6, 1H), 7.16–7.12 (m, 2H), 6.95 (t, J 7.4, 1H), 6.68–
6.62 (m, 3H), 3.45 (q, J 7.0 4H), 2.87 and 2.83 (2 s, 3H), 2.07
(s, 3H), 1.46–1.31 (m, 6H), 1.27 (t, J 7.1, 6H). dc (100 MHz)
152.7, 152.3, 147.9, 147.5, 140.7, 138.0, 136.2, 134.1, 133.2,
131.9, 128.1, 127.0, 126.8, 125.4, 124.6, 123.7, 122.2, 121.7,
119.9, 112.9, 109.2, 107.3, 99.5, 99.2, 52.0, 51.8, 44.5, 29.9,
25.6, 21.1, 13.0. m/z (HREI) calc. for C33H35N3O 489.2775
(Mþꢂ), found 497.2764.
General Procedure for the Preparation of Test Lenses
A matrix composed of polyethyleneglycol 400 dimethacrylate
and bisphenol A ethoxylate dimethacrylate in a 1 : 4 weight ratio
with 0.4 % AIBN by mass as initiator was thoroughly mixed
with 1.5 ꢁ 10ꢀ6 mol of spirooxazine per gram of matrix. The
lenses were then added to a mould and thermally cured with a
gradient heating profile (408C for 60 min followed by an
increase of 0.28C per minute for 275 min followed by 958C for
180 min). The lenses thus formed had a diameter of 15 mm and a
thickness of 1 mm.
N,N,3,5-Tetramethyl-4-(1,3,3-trimethylspiro[indoline-
2,2’-naphtho[1,2-b][1,4]oxazin]-6’-yl)aniline 7e
Obtained as a pale green foam in 68 % yield; mp 190–1928C.
lmax 605 nm. dH (400 MHz) 8.09 (dt, J 7.7 and 1.5, 1H), 7.76
(s, 1H), 7.39–7.26 (m, 5H), 7.15 (dd, J 7.3 and 0.9, 1H), 6.96 (dt,
J 7.4 and 0.9, 1H), 6.66–6.62 (m, 3H), 3.05 (s, 6H), 2.87 (s, 3H),

Continuous-Flow Synthesis of Spirooxazines
177
Supplementary Material
[8] M. York, Tetrahedron Lett. 2012, 53, 2226. doi:10.1016/J.TETLET.
2012.02.082
[9] M. York, R. A. Evans, Synth. Commun. 2010, 40, 3618. doi:10.1080/
00397910903457423
[10] D. A. Clarke, B. M. Heron, C. D. Gabbutt, J. D. Hepworth,
S. M. Partington, S. N. Corns, U. S. Patent 6 303 673 2001.
[11] M. Rickwood, S. D. Marsden, V. E. Askew, U. S. Patent 5 446 150
1995.
1H and 13C NMR for compounds 5a–5h, 7b–7c, and 7e–7h and
UV-Vis spectra for compounds 7a–7c and 7e–7h are available
on the Journal’s website.
Acknowledgements
The authors thank the Co-operative Research Centre for Polymers,
Advanced Polymerik Pty Ltd, and CSIRO Materials Science and Engi-
neering for their support.
[12] A mixture of sodium 1,2-naphthoquinone-4-sulfonate (0.3 g,
1.153 mmol) and N,N,3,5-tetramethylaniline (0.17 g, 1.153 mmol) in
20 % aqueous methanol (8.5 mL) was stirred for 72 h at room temper-
ature. Analysis of the mixture showed none of the desired product had
formed.
References
[1] J. Yoshida, H. Kim, A. Nagaki, ChemSusChem 2011, 4, 331.
doi:10.1002/CSSC.201000271
[2] D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675. doi:10.1039/
C0SC00381F
[3] J. Wegner, S. Ceylan, A. Kirschning, Chem. Commun. 2011, 47, 4583.
doi:10.1039/C0CC05060A
[4] V. Lokshin, A. Samat, A. V. Metelitsa, Russ. Chem. Rev. 2002, 71,
893. doi:10.1070/RC2002V071N11ABEH000763
[5] H. Bouas-Laurent, H. Durr, Pure Appl. Chem. 2001, 73, 639.
doi:10.1351/PAC200173040639
[13] Y. Ooyama, T. Okamoto, T. Yamaguchi, T. Suzuki, A. Hayashi,
K. Yoshida, Chem. – Eur. J. 2006, 12, 7827. doi:10.1002/CHEM.
200600094
[14] Y. Ooyama, S. Nagano, K. Yoshida, Tetrahedron 2009, 65, 1467.
doi:10.1016/J.TET.2008.12.003
[15] Y. Ooyama, Y. Kagawa, Y. Harima, Eur. J. Org. Chem. 2007, 3613.
doi:10.1002/EJOC.200700247
[16] www.vapourtec.co.uk.
[17] P. R. de Oliveira, D. S. Ribeiro, R. Rittner, J. Phys. Org. Chem. 2005,
18, 513. doi:10.1002/POC.896
[18] H. Ahlbrecht, E. O. Dueber, J. Epsztajn, R. M. K. Martcinowski,
[6] N. Malic, J. A. Campbell, A. S Ali, M. York, A. D’Souza, R. A. Evans,
Macromolecules 2010, 43, 8488. doi:10.1021/MA101051M
[7] M. York, R. A. Evans, Tetrahedron Lett. 2010, 51, 2195. doi:10.1016/
J.TETLET.2010.02.105
Tetrahedron 1984, 40, 1157. doi:10.1016/S0040-4020(01)99321-4