Synthesis and photochromic properties of cycloalkylidene fulgides

Article abstract of DOI:10.1055/s-2005-917082

A series of cycloalkylidene fulgides have been synthesized using β,γ-unsaturated diesters, instead of the usual α,β- unsaturated diesters. A study of their photochromic properties revealed that an increase in the cycloalkylidene ring size caused a subsequ

Full text of DOI:10.1055/s-2005-917082

LETTER
2473
Synthesis and Photochromic Properties of Cycloalkylidene Fulgides
P
hotochromic Propertie
e
s
of Cycloa
i
-
e
Fulgid
W
es oon Wayne Lee,a,b Leong-Ming Gan,b Teck-Peng Loh*c
a
b
c
Department of Chemistry, 3 Science Drive 3, National University of Singapore, 117543, Singapore
Institute of Materials Research and Engineering, 3 Research Link, 117602, Singapore
Division of Chemistry and Biological Chemistry, Nanyang Technological University, 637616, Singapore
Fax +6563166984; E-mail: teckpeng@ntu.edu.sg
Received 31 May 2005
NaH, THF,
C6H10O,
0 °C to r.t., 16 h,
H2SO4, EtOH,
80 °C, 18 h
Abstract: A series of cycloalkylidene fulgides have been synthe-
sized using b,g-unsaturated diesters, instead of the usual a,b-unsat-
urated diesters. A study of their photochromic properties revealed
that an increase in the cycloalkylidene ring size caused a subsequent
decrease in the formation of the closed form from the open form.
O
O
O
OEt
OEt
OEt
EtO
72%
O
Key words: photochromic, fulgide, fulgimide, electrocyclic reac-
tions, microwave
7
9
tBuOK,
tBuOH,
Fulgides1a–c are one of the oldest known groups of organic
photochromic compounds and they continue to attract in-
terest, both academically and commercially. This is due to
their remarkable fatigue resistance combined with photo-
chromic properties, which can be modified by molecular
tailoring.
concd
H2SO4
C6H10O,
58%
15 °C, 1.5 h,
H2SO4, EtOH,
0 °C to r.t., 48 h
tBuOK/
NaH
O
O
O
O
OEt
OEt
OEt
OEt
+
O
Fulgides are usually synthesized through two successive
Stobbe condensations. The Stobbe condensation is an al-
dol-type reaction2 between carboxylic esters and alde-
hydes or ketones. In the presence of a strong base, the a-
carbon of a carboxylic ester can condense with the carbo-
nyl carbon of an aldehyde or ketone to give a b-hydroxy
ester,3 which may or may not be dehydrated to the a,b-un-
saturated ester.
OEt
O
O
8
10
8
(40%)
(9%)
Scheme 1
We expected the Stobbe condensation of diethyl succinate
with cyclohexanone to proceed smoothly to furnish the
desired a,b-unsaturated cyclohexylidene diethyl succinate
8 but obtained the b,g-unsaturated cyclohexenyl diethyl
succinate 9 instead. The migration of the double bond to
the b,g-position had been extensively reported by Johnson
et al. in the 1940s.6 Rao and Bagavant4 have also reported
the Stobbe condensation of succinic esters with various
aldehydes with much success about 20 years later.8
Attempts to effect the acid-catalyzed isomerization of the
double bond from the b,g-position to the a,b-position
resulted in the subsequent formation of the g,g-penta-
methyleneparaconate 10 as the major product and 8 as the
minor product.9 Compound 10 failed to condense with the
selected ketones in both NaH and t-BuOK over four days.5
Attempts to cause the ring-opening of 10 to afford 8 also
failed (Scheme 1).10
O
n
O
X
O
X = S, n = 1, 1; n = 2, 2; n = 3, 3
X = O, n = 1, 4; n = 2, 5; n = 3, 6
Figure 1 Depicting cycloalkylidene fulgides 1–6
There have been many comparisons of fulgides and
fulgimides with regards to the structural moieties attached
to the anhydride core, but a systematic study about the ef-
fects of the ring size on cycloalkylidene fulgides such as
1–6 have not been reported to date (Figure 1). Herein, we
report the synthesis of a series of cycloalkylidene fulgides
using either of the diesters 8 or 9 obtained from the use of
t-BuOK4 or NaH.5
The synthesis of the corresponding cycloalkylidene di-
ethyl succinic diesters 8, 11 and 12 was carried out using
the procedure reported by Rao and Bagavant.7 Careful
control of the reaction temperature afforded diesters with
yields ranging from 18% to 57%.11 The corresponding
cycloalkenyl diethyl succinic diesters 9, 13, 14 and 15
were obtained using NaH, affording yields ranging from
41% to 87% (Scheme 2).
SYNLETT 2005, No. 16, pp 2473–2477
0
4
.1
0
.2
0
0
5
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-917082; Art ID: D14305ST
© Georg Thieme Verlag Stuttgart · New York

2474
W.-W. W. Lee et al.
LETTER
tBuOK, tBuOH,
refluxing for approximately 18 hours. This was followed
by stirring in 20–25% aqueous NaOH for three hours.12
cycloketone*
n
15–20 °C, 1.5 h;
EtOH, H2SO4,
0 °C to r.t., 48 h
With reference to Scheme 3, the diesters were stirred in
THF in the presence of NaH with the selected ketones to
afford the half-acids. We discovered that the well known
classic synthetic pathway, involving ethanolic potassium
hydroxide and acetyl chloride, towards 2 or 5 resulted in
very low yields of the desired molecules (Scheme 3,
Route A), with 4% and 3%, respectively. Repeated at-
tempts to optimize the reaction were unsuccessful. We
suspected that the main reason behind the low yields
could be that the cycloalkyl motifs were actually causing
some steric hinderances during the course of the second
Stobbe condensation of the more bulky ketones when
compared with the less hindered cycloalkenyl diesters.
Since we were able to obtain appreciable yields for di-
esters 9, 13, 14 and 15, we decided to proceed with the
usage of the cycloalkenyl diesters as they had a more flex-
ible cyclic moiety, which would not pose as much of a
steric hindrance as the cycloalkylidene analogues.
O
EtO
OEt
O
*cycloketone used, 11 n = 1, 18%
8 n = 2, 57%
O
EtO
OEt
12 n = 3, 44%
O
NaH, cycloketone*,
n
THF, 0 °C to r.t.,
EtOH, H2SO4,
reflux, 24 h
O
EtO
OEt
O
*cycloketone used, 13, n = 1, 41%
9, n = 2, 72%
14, n = 3, 87%
15, n = 4, 80%
Scheme 2
When we applied our base-catalyzed isomerization strate-
gy, the reactions proceeded quite smoothly and we were
able to obtain the corresponding fulgides. The following
ring-closure was carried out by treatment of the diacid
with excess acetyl chloride, in the dark and stirring the re-
action mixture for approximately 4–6 hours. This led to
the formation of fulgides 1–6, with yields ranging from
7% to 80%. Repeated attempts to obtain the cyclooctyl
fulgide, from the cyclooctenyl diester, were unsuccessful.
After many attempts to cause the acid-catalyzed iso-
merization of the b,g-unsaturated double bond to afford
the diester with the desired a,b-double bond, we were not
satisfied with the yields obtained as more than 50% of the
starting diester was suspected to have decomposed under
such harsh acidic conditions. As such we decided to re-
look at the strategy of the isomerization of the double
bond and also to explore if we could somehow induce the
isomerization during the course of the reaction.
After successfully obtaining the above-mentioned
fulgides 1–6, we decided to study the implications on the
photochromic properties, caused by the larger cycloalkyl
rings, present on the fulgide core. With reference to
fulgides 18 and 19 as the key benchmark fulgides, based
on their intrinsic photochromic properties, the absorption
spectra of the fulgides in their open form have their
absorption maxima at approximately l = 342–346 nm.
The closed forms have their maximum absorption at l =
A detailed examination of the reaction scheme revealed
that we could possibly employ a base hydrolysis to obtain
the diacid during the second last step, as well as possibly
cause a base-induced isomerization of the double bond at
the b,g-position, to migrate to the a,b-position. We de-
cided to initiate the isomerization of the b,g-unsaturated
double bond to afford the diacid with the desired a,b-dou-
ble bond, with the usage of 5% w/v ethanolic NaOH,
Route A - classic pathway
excess
AcCl,
4–6 h
10% KOH/
EtOH,
reflux, 18 h
NaH, THF,
ketone,
0 °C to r.t., 16 h
O
O
O
O
O
O
n
OH
OH
n
OEt
OH
OEt
OEt
n
n
O
O
O
X
X
X
Route B - modified pathway
NaH, THF,
ketone,
0 °C to r.t., 16 h
5% w/v NaOH,
EtOH reflux, 18 h
20–25% NaOH, 3 h
O
O
O
OEt
OEt
OEt
OH
n
n
Route A: n = 2, 2, X = S, 4%; 5, X = O, 3%
Route B: n = 1, 1, X = S, 80%; 4, X = O, 46%
n = 2, 2, X = S, 14%; 5, X = O, 17%
O
X
n = 3, 3, X = S, 7%; 6, X = O, 22%
Scheme 3
Synlett 2005, No. 16, 2473–2477 © Thieme Stuttgart · New York

LETTER
Photochromic Properties of Cycloalkylidene Fulgides
2475
510–550 nm. With regards to the conversion percent of
the open E/Z-form to the closed (C) form, fulgide 18 dis-
played a conversion rate of almost 96%, which would
make it a potential candidate for use in optical memory
media. For fulgide 19, the conversion rate of close to 50%
displayed a drop of almost two-fold, when compared with
fulgide 18 (Scheme 4).
X
O
O
O
O
O
UV
Vis, UV
UV
UV
O
O
X
X
O
O
Z-form
X = O, 18; X = S, 19
E-form
C-form
As shown in Table 1, for the thiophene fulgides, the
difference of the absorption maxima of the colored form
between the isopropylidene (IPP)-based fulgide 19 and
the cycloheptyl analogue 3 was a 12 nm red shift.
Scheme 4
To conclude, an efficient synthesis of cycloalkylidene
fulgides have been achieved. With an increase in ring size,
there was a general increase in the wave number. Howev-
er, the percentage conversion of the opened form to the
closed form dropped significantly. This decrease could be
attributed to the larger steric hinderance of the cycloheptyl
Referring to Table 1, it was observed that for every addi-
tional carbon present in the ring for the thiophene ana-
logues, there will be a drop in formation of the colored
form by up to 12%. There was also an increase in the red
shift by up to 14 nm. As a comparison, for fulgide 19, the
difference of the absorption maxima for the open and
closed form is 196 nm. For the cyclothienyl fulgides, the
difference can be up to 220 nm (fulgide 2). The large red
shift of the closed form can be explained by the larger ster-
ic strain between the large cycloheptyl ring and the
thiophene moiety. Switching to the furyl fulgides, a simi-
lar trend could be seen between the IPP-based fulgide 18
and the cycloheptyl analogue 6. A bathochromic shift of
up to 16 nm was observed on UV irradiation of the open
fulgides. Replacing the furyl moiety of 6 with a thiophene
moiety (3) caused a red shift of approximately 24 nm. It
has been observed that for every additional carbon present
in the ring, for the furyl analogs, there was a drop in for-
mation of the colored form by 14%. There was also an in-
crease in the difference of the open and closed form, with
a red shift of 12 nm.
O
O
NaH, THF,
HCl
OEt
OH
OEt
OEt
S
S
O
O
O
13
5% w/v NaOH,
EtOH reflux, 18 h
20–25% NaOH, 3 h
O
O
O
OH
OH
AcCl, 6 h
O
S
O
S
1
Scheme 5
Table 1 UV/Vis Absorption Maxima (nm) in CH2Cl2 of Open and Closed Form of the Fulgides 1–6, 18 and 19
Fga
19
1b
l
maxO (nm)c
AO
l
maxC (nm)d
AC
Dlmax (nm)e
Conversion (%)f
46.8
342
1.48
538
0.69
196
Z: 342
E: 338
Z: 0.81
E: 0.93
Z: 544
E: 544
Z: 0.27
E: 0.45
Z: 202
E: 206
Z: 34.3
E: 48.3
2
332
342
346
350
346
350
2.00
1.45
0.97
0.74
0.76
0.96
552
550
510
514
514
526
0.48
0.16
0.92
0.49
0.39
0.36
220
208
164
164
168
176
24.8
11.0
95.6
66.8
51.9
37.9
3
18
4
5
6
a Fg = Fulgide.
b Compound 1 was obtained as a mixture of E- and Z-isomers with 2 distinct spots on TLC.
c Absorption maxima of open form (apart from 1, all other fulgides believed to be obtained in the Z-form due to steric hinderances).
d Absorption maxima of closed form (colored form).
e Difference of closed form over open form.
f Percentage of open form converted to closed form (ec/eo × 100). Note: [C] of stock solutions were prepared in 1–8 mmol and were repeated
in duplicate.
Synlett 2005, No. 16, 2473–2477 © Thieme Stuttgart · New York

2476
W.-W. W. Lee et al.
LETTER
O, 342 nm; C, 544 nm. HRMS (EI): m/z calcd for C17H18O3S [M+]:
302.0977; found: 302.0973; [M+ – CH3]: 287.0742; found:
287.0747.
groups caused when compared with the much smaller cy-
clopentyl group on the anhydride moiety, which in turns
caused an increase in the bleaching effect of the colored
fulgide. The decrease in conversion of the respective
fulgides, in descending order, is generally: IPP > cyclo-
pentyl > cyclohexyl > cycloheptyl. Yields of the fulgides
with larger cycloalkyl groups also generally decreased.
Preparation of Isopropylidene (IPP) Diethyl Succinate
(Scheme 6)
Diethyl succinate (33.5 mL, 0.200 mol, 1.00 equiv) was added to a
ice-cooled solution of NaH (55–65%, moistened with mineral oil;
7.2 g, 0.300 mol, 1.50 equiv) in THF and stirred for 10 min. Then,
2 drops of EtOH or MeOH were added to initiate the reaction. Ace-
tone (18.4 mL, 0.250 mol, 1.25 equiv) was added dropwise over 15
min and the reaction mixture was allowed to stir for 18 h at r.t. The
reaction was quenched with 4 M HCl and extracted with EtOAc
(3 × 50 mL). The combined organic layers were dried (MgSO4), fil-
tered, and the solvent was removed in vacuo. The resulting brown
syrup was dissolved in EtOH (200 mL) and acidified with concd
H2SO4 (ca. 5–10 mL) and stirred for 1 h at 0 °C. The reaction mix-
ture was warmed up to r.t. and refluxed for 16 h. The reaction mix-
ture was quenched with sat. aq NaHCO3 and extracted with EtOAc
(3 × 50 mL). The combined organic layers were dried (MgSO4), fil-
tered, and the solvent was removed in vacuo. Vacuum distillation
afforded isopropylidene (IPP) diethyl succinate as a clear colorless
oil (29.8 g, 69% yield). Rf = 0.46 (hexane–EtOAc = 4:1). 1H NMR
(300 MHz, CDCl3): d = 4.18 (q, J = 7.1 Hz, 2 H), 4.13 (q, J = 7.1
Hz, 2 H), 3.36 (s, 2 H), 2.14 (s, 3 H), 1.86 (s, 3 H), 1.27 (t, J = 7.1
Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (500 MHz,
CDCl3): d = 171.5, 167.9, 148.9, 120.7, 60.7, 60.2, 35.5, 23.3, 23.2,
14.2 ppm. FT-IR (film): 2983, 2938, 2909, 1738, 1719, 1642, 1446,
1369, 1335, 1283, 1223, 1178, 1135, 1079, 1032 cm–1. HRMS: m/z
calcd for C11H18O4 [M+]: 214.1205; found: 214.1207; [M+ – CH3]:
199.0970; found: 199.0971.
O
NaH, THF,
O
EtOH, H2SO4
OEt
OEt
O
OEt
+
EtO
O
O
Scheme 6
NaH, THF,
EtOH, H2SO4
O
O
O
O
OEt
OEt
OEt
+
EtO
O
7
13
Scheme 7
Preparation of 2,5-Dimethylthiophene Cyclopentylidene
Fulgide (1, Scheme 5)
Cyclopentenyl diethyl succinate (13, 1 equiv) was added into in a
solution of ice-cooled THF containing NaH (55–65%, moistened
with mineral oil, 1.5–1.8 equiv) prewashed with hexane and stirred
for 15 min. Then, 2–3 drops of EtOH were added into the reaction
mixture before dropwise addition of 3-acetyl-2,5-dimethyl
thiophene (1.1 equiv) over 30 min. The mixture was then allowed to
stir overnight followed by quenching of the reaction using ice-cold
water. After quenching of the reaction 10% Na2CO3 was used to ex-
tract the half-ester followed by the acidification of the basic solution
with 4 M HCl to liberate the acid-ester. Then, 4 × 25 mL of EtOAc
were used to extract the liberated acid-ester and the solvent was re-
moved in vacuo to afford a dark brown oil (crude NMR indicated
the presence of the half-ester). Saponification of the half-ester and
double bond isomerization of the b,g-unsaturation to the a,b-site
was initiated with 5% w/v NaOH in EtOH. The mixture was al-
lowed to stir for 1 h before refluxing for approximately 16 h. After
16 h, an aqueous solution (20–50 mL) of 25% NaOH was added and
the reaction mixture allowed to stir for an additional 3 h. A second
acid–base work up as before afforded the diacid as a brownish solid.
Preparation of Cyclopentenyl Diethyl Succinate (13, Scheme 7)
Synthesis was accomplished in a manner similar to that for the prep-
aration of isopropylidene (IPP) diethyl succinate. The cyclopen-
tanone was added into the stirring mixture of diethyl succinate and
NaH dropwise over 1 h. Usual esterification, work up and purifica-
tion of the crude reaction mixture using flash chromatography (8:1
hexane–EtOAc) afforded a clear colorless oil, 13 in 41% yield. Rf =
0.49 (hexane–EtOAc = 4:1). 1H NMR (500 MHz, CDCl3): d = 5.55
(s, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.67–
3.62 (m, 1 H), 2.97–2.88 (m, 1 H), 2.58–2.50 (m, 1 H), 2.35–2.30
(m, 4 H), 1.89–1.84 (m, 2 H), 1.28–1.22 (m, 6 H) ppm. 13C NMR
(500 MHz, CDCl3): d = 172.6, 171.7, 139.9, 127.5, 60.8, 60.5, 43.5,
35.4, 33.4, 32.3, 23.1, 14.1 ppm. FT-IR (film): 2981, 2935, 2907,
2850, 1738, 1647, 1446, 1371, 1275, 1161, 1096, 1031, 858 cm–1.
HRMS (EI): m/z calcd for C13H20O4 [M+]: 240.1362; found:
240.1358; [M+ – C2H6O]: 194.0943; found: 194.0944.
The crude reaction mixture was washed with brine and dried by Acknowledgment
standing in anhyd MgSO4. Solvents were removed in vacuo before
We would like to thank the A*STAR Graduate Fellowship for
the addition of excess acetyl chloride to the diacid in the dark to ini-
tiate the ring-closure to afford the desired fulgide. The mixture was
allowed to stir for approximately 5 h before removing the acetyl
chloride in vacuo. Purification of the crude reaction mixture using
flash chromatography (8:1 hexane–EtOAc) afforded 1 in 80% yield
(Z-isomer); yellow plates, mp 125–127 °C. The E-isomer was ob-
served to be present on TLC, but was not isolable. Rf = 0.61 (E-iso-
mer), 0.53 (Z-isomer) (hexane–EtOAc = 4:1). 1H NMR (500 MHz,
CDCl3): d = 6.56 (s, 1 H), 3.01–2.99 (m, 2 H), 2.42 (s, 3 H), 2.37–
2.34 (m, 2 H), 2.30 (s, 3 H), 2.13 (s, 3 H), 1.91–1.87 (m, 2 H), 1.83–
1.80 (m, 2 H) ppm. 13C NMR (500 MHz, CDCl3): d = 167.7, 164.3,
163.4, 148.8, 139.6, 137.7, 135.2, 125.8, 121.1, 117.5, 36.3, 35.2,
26.2, 25.6, 23.2, 15.1, 14.9 ppm. FT-IR (KBr): 3449, 2917, 2870,
1806, 1763, 1617, 1438, 1262, 1230, 1100, 927, 760 cm–1. UV/Vis:
funding this work.
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Synlett 2005, No. 16, 2473–2477 © Thieme Stuttgart · New York

LETTER
Photochromic Properties of Cycloalkylidene Fulgides
2477
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(9) Compound 10 was obtained in 40% yield and 8 in 9% yield,
respectively.
(10) As determined from crude 1H NMR of the reaction mixture.
(11) Attempts to obtain the cyclooctylidene succinic diester
resulted in the self-condensed product from the
cyclooctanone, which was only determined from crude 1H
NMR and not isolated. The cyclopentanone used to obtain
11 also tends to afford the self-condensed product quite
readily.
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(8) The observation of the migration of the double bond was
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(12) This was to ensure the complete formation of the diacid and
to maximize yield. Yields of synthesized fulgides were much
lower when this step was omitted.
Synlett 2005, No. 16, 2473–2477 © Thieme Stuttgart · New York