Direct and Divergent Solid-Phase Synthesis of Azobenzene and Spiropyran Derivatives

Article abstract of DOI:10.1021/acs.joc.0c02375

Here, we report a solid-phase approach to synthesize azobenzene and spiropyran derivatives. The divergent synthesis process requires no purification steps to obtain the desired product with a 28-55% yield, depending on the specific compound. For the spiropyran compounds, solid-phase resin cleavage is performed under mild conditions to minimize spiropyran ring opening. The solid-phase method enables the synthesis of a library of azobenzene and spiropyran derivatives without the need to develop purification strategies for each derivative.

Full text of DOI:10.1021/acs.joc.0c02375

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Article
Direct and Divergent Solid-Phase Synthesis of Azobenzene and
Spiropyran Derivatives
Ravichandran H. Kollarigowda and Paul V. Braun*
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ABSTRACT: Here, we report a solid-phase approach to synthesize azobenzene and spiropyran derivatives. The divergent synthesis
process requires no purification steps to obtain the desired product with a 28−55% yield, depending on the specific compound. For
the spiropyran compounds, solid-phase resin cleavage is performed under mild conditions to minimize spiropyran ring opening. The
solid-phase method enables the synthesis of a library of azobenzene and spiropyran derivatives without the need to develop
purification strategies for each derivative.
INTRODUCTION
■
Favorable features of solid-phase organic synthesis include the
facile elimination and purification of intermediates, which
allows the rapid synthesis of libraries of compounds.1−3 In
solid-phase organic synthesis, the product purification is
simplified since filtration and washing rather than column
chromatography can be used. This enables reactions to be
driven to near completion by using excesses of reagents
without causing separation problems. Inspired by the
advantages of a solid-phase process, we developed a simple
solid-phase method to synthesize azobenzene and spiropyran
derivatives. We focus on azobenzene and spiropyran
chemistries specifically due to their stimuli-responsive nature.
These chemistries have been used for dyes and pigments,4
Figure 1. Synthetic pathways for azobenzene and spiropyrans
contrasting solution and solid-phase (this work) methods.
smart textiles,5 water purification,6 dynamic surfaces for
biological applications,7,8 sensors,9,10 and mechanophores.11,12
An alternative method is the electrolytic oxidation of
The conformational changes of azobenzene and spiropyran
aromatic amines; however, this only gave azo compounds in
chromophores upon exposure to external stimuli ranging from
light and heat to mechanical force have been a primary driver
of the interest in these systems.13−15
Received: October 7, 2020
Published: March 3, 2021
Solution synthesis of azobenzene and spiropyran derivatives
is well established from the last two decades.16
Classical methods of preparing azobenzenes include azo
coupling, Mills, oxidative, and Wallach reactions, which
provide yields of 62−90% (Figure 1).17−19
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a
Scheme 1. Examples of Solid-Phase Synthesis of (A) Azobenzene and (B) Spiropyran Compounds
a
In the final step, the product was cleaved from the polystyrene resin with TFA.
yields of 35−48%.20 The azo formation mechanism generally
a
Scheme 2. Preparation of the A Block
involves NN bond coupling with an aniline radical produced
by one-electron transfer, followed by two-electron oxidation of
hydrazobenzene.21 For a review of azo formation methods,
including recent advances, see Merino et al.22 The traditional
method of synthesizing spiropyran is the condensation of
methylene bases (or their precursors) with o-hydroxy aromatic
aldehydes. An alternative route is the condensation of o-
hydroxy aromatic aldehydes with the salts of heterocyclic
cations containing active methylene groups.23−26 Many
methods have been developed for the solution-phase synthesis
of azobenzenes and spiropyran.22−26 In most cases, the
solution syntheses proceed in a linear way, but they require
compound-specific purification steps. For each target, a unique
set of starting materials, the sequence of chemical reactions,
and purification procedures are generally required.
We suggest a solid-phase coupling approach may provide an
opportunity for a more facile synthesis of families of
azobenzenes and spiropyrans (Scheme 1), in particular, for
compounds for which purification strategies have not already
been developed. The solid-phase approach requires minimal
purification steps and enables rapid access to a diversity of
azobenzenes and spiropyrans in pure form. Moreover, this
process can be automated, which enable the use of many
reactions and starting materials and automation of generalized
platforms that make many different targets using common
coupling chemistry and building blocks.27,28 It is our hope that
these new strategies and methods for the synthesis of stimuli-
responsive molecules will broaden access to these important
chemistries.
a
Reaction conditions: (1a) ABA (3 mmol), TEA (5 mmol), Fmoc-cl
(3 mmol) in 30 mL of DCM, 24 h, rt; (1b) 1a (5 mmol), resin (1.1
mmol/g Cl loading), DMF/DCM, 12 h, rt.
unprotected acid functional group. Fmoc was cleaved with
20% (v/v) piperidine in dimethylformamide (DMF), forming
the piperidine adduct.29 Purification simply required washing
with DMF and DCM to remove unreacted precursors and
other noncovalent bonded impurities from the resin. The
piperidine adduct exhibits two distinct UV absorbance maxima
at λ = 301.0 and 289.8 nm. Absorption values measured at
either of the piperidine absorbance maxima can be used, in
combination with the respective molar absorption coefficient
(following Beer’s law), to calculate the substitution of Fmoc-
deprotected resins.2,29 The loading yield of the resin was over
60%.
Building block B (Table 1) was reacted with A to synthesize
the family of azobenzenes shown in Scheme 3. The
monosubstituted p-phenylenediamine was achieved at 0 °C
with the slow addition of Fmoc-Cl (B1, Table 1).
Monosubstitution (one-sided protection) with Fmoc was
quite challenging, but the condition was optimized with low
temperatures and with careful Fmoc addition. Lastly, the A and
RESULTS AND DISCUSSION
■
Building block A was synthesized using a solution method
followed by solid-phase coupling and deprotection (Scheme
2).
Briefly, 4-aminobenzoic acid was protected with chlorofor-
mic acid 9-fluorenylmethyl ester ((9-fluorenylmethyl)-
chloroformate (Fmoc-Cl)) forming compound 1a. Next, a
trityl chloride-functionalized resin was coupled with the
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B blocks were coupled following standard amine−amine diazo
coupling using silver oxide as a catalyst in DMF/DCM solvent
mixtures. Colorimetric Kaiser tests were performed to check
for reaction completion.30 Once the reaction was complete,
Fmoc was deprotected by following the piperidine procedure,
and the resin was cleaved with 15% trifluoroacetic acid, TFA.30
The synthesis of AZO 1 to AZO 6 was performed under
similar conditions. The yield of AZO 1 was 55% and AZO 2
was 50% (yields are almost equivalent to the solution
method).23 The yield of AZO 3 was 43%, AZO 4 was 40%,
AZO 5 was 30%, and AZO 6 was 38% (Table 1). In AZO 5
synthesis of B5, we suspect the two benzene rings in
[1,1′:3′,1″-terphenyl]-2′-amine] result in steric hindrance,
which lowers the yield.
Table 1. Azobenzene Building Blocks, Reaction Conditions,
and Yields for Final Azobenzene Products (X−OH, Y−Br)
a
We now describe the solid-phase synthesis of a library of
spiropyrans (Scheme S1). 1,3,3-Trimethyl-2-methyleneindo-
line-5-carboxylic acid (3a) was prepared using a reported
protocol.31 The resin was reacted with 3a to form building
block C. As a test, C was reacted with 2-hydroxy-5-
nitrobenzaldehyde, D1, Scheme 4 under classical basic
conditions,26 successfully yielding SP1.
Scheme 4. (a) Synthesis of Building Block C; (b) Solid-
Phase Reaction of C with Building Blocks D1−D6, Yielding
Spiropyrans SP1−SP6 (X−OH, Y−Br)
a
The yield was the average of 3 batches 4%.
For solid-phase SP1−SP6 spiropyran synthesis, building
blocks D1−D6 were reacted with C at 55 °C in a basic
(piperidine) DMF/DCM/EtOH solvent mixture (Scheme 4,
Table 2). An important consideration is the use of TFA to
Scheme 3. Synthesized Azobenzenes
Table 2. SP Building Blocks, Reaction Conditions, and
a
Yields for Final SP Products
a
building block D product no. yield (%)
conditions
D1
D2
D3
D4
D5
D6
SP1
SP2
SP3
SP4
SP5
SP6
45
40
40
28
40
35
DCM/DMF/EtOH; 55 °C
DCM/DMF/EtOH; 55 °C
DCM/DMF/EtOH; 60 °C
DCM/DMF/EtOH; 55 °C
DCM/DMF/EtOH; 55 °C
DCM/DMF/EtOH; 55 °C
a
The yield was the average of 3 batches 3%.
cleave SP from the resin. Acid can open the spiropyran ring
structure to the merocyanine (MC ∼ 8−10%) form, but we
found by using dilute TFA that this was minimized. We
noticed the formation of the merocyanine once the
concentration of TFA was increased. While, in principle,
treatment of the MC form with a base will lead to conversion
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beads were treated with 20% piperidine, and the deprotected FMOC
was calculated using Beer’s law. If the percentage substitution is lower
than expected, FMOC is reloaded to yield the desired substitution.
The amine-terminated resin was obtained after cleaving with 20%
piperidine, and the product was confirmed via the UV/Kaiser test.
Note, A is a resin and, thus, cannot be characterized via solution
NMR.
back to SP, we suggest avoiding this rather by the use of a low
concentration of acid to cleave SP from the resin.
The reported yield for the solution methods was about 72%
for the azobenzene derivatives and 65% for the spiropyran
derivatives with purities generally of +90%.21−26 The yield for
the solid-phase technique reported here was generally 40−
50%. One reason for the difference in the yield is that the
solution syntheses were run at 90 °C, but the solid-phase
syntheses were performed at 40−60 °C (the resin begins to
break at ∼70 °C). While a higher temperature resin might
provide an enhanced yield, we did not investigate this, as the
focus of this study was to use the solid-phase approach to
simplify the purification process and provide a high purity
product. Here we generally achieved +95% purity (see HPLC
reports in Supporting Information) without column chroma-
tography, indicating the solid-phase approach may be attractive
for the simple synthesis of pure forms of these types of
chromophores.
Synthesis of B1 (N-BOC-1,4-phenylenediamine). p-Phenylenedi-
amine (1.08 g, 10 mmol) and triethylamine (0.4 mL, 30 mmol) were
dissolved in 25 mL of dry tetrahydrofuran (THF). Di-tert-butyl
dicarbonate (4.35 g, 2 mmol) was dissolved in 15 mL of THF and
added dropwise to the reaction mixture at 0 to 4 °C. The reaction was
continued for 6 h. The reaction was monitored by TLC. Reaction
completion was confirmed by TLC. The mixture was washed with a
saturated solution of bicarbonate, and then the product was extracted
with DCM and washed again with a saturated sodium chloride
solution. Finally, the DCM layer was dried over sodium sulfate and
filtered. Further, purification of the product was done by column
chromatography with a mixture of hexane/ethyl acetate, 70:30 (v/v),
yielding an off-white powder. The yield was 0.91 g, 85%. The product
was characterized by MS and NMR. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C11H16N2O2Na, 231.1109; found, 231.1105. 1H NMR
(500 MHz, DMSO-d6): δ 9.16 (s, 1H), 7.30 (s, 2H), 1.46 (s, 9H).
13C{1H} NMR (126 MHz, DMSO-d6): δ 153.3, 134.46, 79.1, 28.6.
General Procedure for Azobenzene (AZO) Synthesis. A total of
500 mg of compound A resin was loaded and activated by washing
with DCM/DMF, and 300 mg (1.4 mmol) of B (B1, N-BOC-1,4-
phenylenediamine, B2, 4-aminophenol (215 mg, 2 mmol), B3, 3-
amino-5-bromophenol (335 mg, 1.8 mmol), B4, 3,5-dimethoxyaniline
(307 mg, 2 mmol), B5, [1,1′:3′,1′′-terphenyl]-2′-amine (615 mg, 2.5
mmol), B6, naphthalen-1-amine (267 mg, 2 mmol)), silver oxide
(0.21 mmol), and 5 mL of DMF/DCM 50:50 v/v were added. The
mixture was heated to 50 °C and kept for 12 h. A microwave oven can
also be used to provide this product, and the conversion is much
faster. After 12 h, any unreacted compound was washed out, and a few
beads were removed to check with the Kaiser reagent. The resin beads
and the solution turn dark blue when a primary amine is present,
which means there was still some unreacted resin present. In this
situation, we reload the compound and repeat the same procedure
until the primary amines are completely consumed. The resin beads
remain the same color, and the solution stays yellow when no free
primary amine is present (expected result after successful coupling). A
recoupling step is necessary when a slight blue color is detected in the
solution and/or on beads. In the final step, the resin was cleaved by
15% TFA in DCM. The resulting compound was analyzed with NMR
and mass spectrometry for product confirmation.
CONCLUSIONS
■
In summary, we have developed a simple and effective solid-
phase approach to synthesize a library of azobenzenes and
spiropyrans using a common protocol. The method described
requires minimal purification steps and enables rapid access to
a diversity of azobenzenes and spiropyrans in pure form.
EXPERIMENTAL SECTION
General Information. All chemicals and solvents were purchased
from Sigma-Aldrich at the highest purity available and used without
further purification unless otherwise indicated. Thin-layer chromatog-
■
1
raphy was performed on LC silica gel 60G F254 glass plates. H and
13C NMR spectra were recorded with a spectrometer operating at 500
MHz for proton and carbon nuclei, respectively, using either
tetramethylsilane or residual protons of the deuterated solvent used
(in parentheses) as an internal reference. High-resolution mass
spectra (HRMS) were obtained using positive electrospray ionization
by the TOF method. Compounds B2−B6 were purchased from
Sigma-Aldrich. Compounds D1, D2, D3, and D5 were purchased
from Sigma-Aldrich. Compounds D4 and D6 were purchased from
AKos Consulting & Solutions. A digital dry bath (heating mantle,
Thomas Scientific) was used for heating the reaction tubes.
Synthesis of 1a (Fmoc-aminobenzoic acid). 4-Aminobenzoic acid
(412 mg, 3 mmol) and triethyl amine (TEA, 0.69 mL, 5 mmol) were
dissolved in 30 mL of DCM. The solution of chloroformic acid 9-
fluorenylmethyl ester (778 mg, 3 mmol in 20 mL of DCM) was added
dropwise at 0 °C, and the reaction continued for 24 h at rt. The
reaction was monitored by thin-layer chromatography (TLC). The
mixture was washed with a saturated solution of bicarbonate, and then
the product was extracted with DCM and washed again with a
saturated sodium chloride solution. Finally, the DCM layer was dried
over sodium sulfate and filtered. The DCM was evaporated, yielding a
fluffy red powder. Further purification of the product was done by
column chromatography with a mixture of hexane/ethyl acetate,
70:30 (v/v). The yield was 360 mg, 88%. HRMS (ESI-TOF) m/z: [M
+ Na]+ calcd for C22H17NO4Na, 382.1055; found, 382.1050. 1H
NMR (500 MHz, DMSO-d6): δ 12.68 (d, J = 2.5 Hz, 1H), 10.08 (s,
1H), 7.92 (d, 2H, J = 7.6 Hz), 7.90−7.84 (m, 2H), 7.76 (d, 2H, J =
7.4 Hz), 7.56 (s, 2H), 7.43 (t, 2H, J = 7.4 Hz), 7.36 (td, 2H, J = 7.5,
1.1 Hz), 4.54 (d, 2H, J = 6.6 Hz), 4.34 (t, 1H, J = 6.5 Hz). 13C{1H}
NMR (126 MHz, DMSO-d6): δ 167.4, 153.7, 144.1, 143.7, 141.3,
130.9, 128.1, 127.6, 125.5, 124.8, 120.6, 117.9, 66.2, 47.0.
AZO 1 (4-((4-Aminophenyl)diazenyl)benzoic acid). The general
procedure resulted in a fluffy orange powder with 55% (132.5 mg)
yield of the title product. Mp: 248−255 °C. HRMS (ESI-TOF) m/z:
1
[M + Na]+ calcd for C13H11N3O2Na, 264.0749; found, 264.0745. H
NMR (500 MHz, DMSO): δ 7.76−7.74 (m, 1H), 7.69−7.65 (m,
2H), 7.51 (dd, 2H, J = 8.5, 7.0 Hz), 7.44−7.40 (m, 1H), 6.84−6.59
(m, 2H), 6.10 (s, 2H). 13C{1H} NMR (126 MHz, DMSO): δ 153.3,
152.9, 143.2, 129.8, 129.6, 125.6, 122.1, 113.8.
AZO 2 (4-((4-Hydroxyphenyl)diazenyl)benzoic acid)). The
general procedure resulted in an orange solid with 50% (121.3 mg)
yield of the title product. Mp: 270−280 °C. HRMS (ESI-TOF) m/z:
1
[M + Na]+ calcd for C13H10N2O3Na, 265.0589; found, 265.0585. H
NMR (500 MHz, DMSO): δ 10.46 (s, 1H), 8.19−8.06 (m, 2H),
7.93−7.82 (m, 4H), 7.03−6.94 (m, 2H). 13C{1H} NMR (126 MHz,
DMSO): δ 167.2, 162.1, 155.0, 145.7, 132.3, 131.0, 125.8, 122.5,
116.5.
AZO 3 (4-((3-Bromo-4-hydroxyphenyl)diazenyl)benzoic acid).
The general procedure resulted in an orange-reddish powder with
43% (137.66 mg) yield of the title product. Mp: 225−230 °C. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C13H10BrN2O3, 320.9875;
found, 320.9870. 1H NMR (500 MHz, DMSO): δ 9.88 (s, 1H),
8.38−8.28 (m, 2H), 8.22−8.14 (m, 1H), 7.13 (t, 1H, J = 8.0 Hz),
6.96−6.94 (m, 2H), 6.76 (ddd, 1H, J = 8.1, 2.3, 1.0 Hz). 13C{1H}
Synthesis of Compound A. A total of 500 mg of trityl chloride
resin (1.1 mmol/g Cl loading) was loaded, activated, and washed with
DMF/DCM. Compound 1a was loaded and allowed to react for 12 h.
After 12 h, the unreacted material is washed out, and the reaction was
monitored by UV absorption and a Kaiser test. The reacted resin
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NMR (126 MHz, DMSO): δ 166.2, 159.0, 150.5, 136.8, 131.6, 131.1,
124.2, 122.2, 122.1, 118.5, 115.0.
recoupling step is necessary when a slight blue color is detected in the
solution and/or on beads. In the final step, the resin was cleaved by
15% trifluoroacetic acid in DCM. The resulting compound was
analyzed via NMR and mass spectrometry for product confirmation.
SP1 (1′,3′,3′-Trimethyl-6-nitrospiro[chromene-2,2′-indoline]-5′-
carboxylic acid). The general procedure resulted in a dark green
powder with 45% (165 mg) yield of the title product. Mp: 177−180
°C. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N2O5,
367.1294; found, 367.1290. 1H NMR (500 MHz, DMSO): δ 8.22 (d,
1H, J = 2.8 Hz), 8.00 (dd, 1H, J = 9.0, 2.8 Hz), 7.23 (d, 1H, J = 10.4
Hz), 7.17−7.13 (m, 1H), 6.89 (d, 1H, J = 9.0 Hz), 6.81 (td, 1H, J =
7.4, 0.9 Hz), 6.62 (dd, 1H, J = 7.6, 1.1 Hz), 5.99 (d,1H, J = 10.4 Hz),
2.68 (s, 3H), 1.22 (s, 3H), 1.12 (s, 3H). 13C{1H} NMR (126 MHz,
DMSO): δ 163.5, 159.8, 147.8, 140.9, 136.3, 128.7, 128.1, 126.2,
123.2, 122.0, 121.9, 119.8, 119.3, 115.8, 107.5, 106.6, 52.3, 28.9, 26.1,
20.1.
SP2 (1′,3′,3′-Trimethylspiro[chromene-2,2′-indoline]-5′-carbox-
ylic acid). The general procedure resulted in a red powder with 40%
(128 mg) yield of the title product. Mp: 170−175 °C. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C20H19NO3Na, 344.1263; found,
344.1265. 1H NMR (500 MHz, DMSO): δ 7.17 (dd, 1H, J = 7.5, 1.7
Hz), 7.12−7.08 (m, 2H), 7.01 (d, 1H, J = 10.2 Hz), 6.83 (td, 1H, J =
7.4, 1.1 Hz), 6.77 (td, 1H, J = 7.4, 1.0 Hz), 6.66 (d, 1H, J = 8.1 Hz),
6.56 (d, 1H, J = 7.6 Hz), 5.76 (d, 1H, J = 10.2 Hz), 2.65 (s, 3H), 1.21
(s, 3H), 1.09 (s, 3H). 13C{1H} NMR (126 MHz, DMSO): δ 163.5,
154.4, 148.3, 136.7, 130.2, 129.7, 127.9, 127.3, 121.9, 120.6, 119.7,
119.3, 119.0, 114.7, 107.2, 104.2, 51.8, 29.0, 26.1, 20.3.
SP3 (1′,3′,3′,6-Tetramethylspiro[chromene-2,2′-indoline]-5′-car-
boxylic acid). The general procedure resulted in a red powder with
40% (135 mg) yield of the title product. Mp: 168−173 °C. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C21H21NO3Na, 358.1419;
found, 358.1416. 1H NMR (500 MHz, DMSO): δ 7.91 (d, 1H, J = 2.6
Hz), 7.66 (d, 1H, J = 2.6 Hz), 7.19 (d, 1H, J = 10.4 Hz), 7.17−7.09
(m, 2H), 6.81 (td,1H, J = 7.4, 1.1 Hz), 6.62 (d, 1H, J = 7.8 Hz), 5.97
(d, 1H, J = 10.4 Hz), 3.78 (s, 3H), 2.69 (s, 3H), 1.74 (s, 1H), 1.20 (s,
3H), 1.10 (s, 3H). 13C{1H} NMR (126 MHz, DMSO): δ 169.2,
169.1, 157.3, 155.5, 151.3, 148.7, 140.3, 137.1, 136.6, 131.4, 123.2,
123.0, 122.9, 120.9, 97.6, 57.5, 51.7, 49.1, 44.5, 43.9, 43.5, 31.1, 31.1,
2.1, 23.9, 23.2, 22.0.
AZO 4 (4-((2,6-Dimethoxyphenyl)diazenyl)benzoic acid). The
general procedure resulted in an orange solid with 40% (114.5 mg)
yield of the title product. Mp: 175−180 °C. HRMS (ESI-TOF) m/z:
1
[M + Na]+ calcd for C15H14N2O4Na, 309.0851; found, 309.0849. H
NMR (500 MHz, acetone-d6): δ 8.43−8.36 (m, 2H), 8.34−8.28 (m,
2H), 6.69 (d, 2H, J = 2.3 Hz), 6.54 (t, 1H, J = 2.2 Hz), 3.88 (d, 6H, J
= 1.3 Hz). 13C{1H} NMR (126 MHz, DMSO): δ 168.1, 161.4, 153.5,
134.7, 131.7, 117.3, 113.1, 107.0, 99.7, 56.0.
AZO 5 (4-([1,1′:3′,1′′-Terphenyl]-2′-yldiazenyl)benzoic acid).
The general procedure resulted in a red powder with 30% (113
mg) yield of the title product. Mp: 350−360 °C. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C25H19N2O2, 379.1447; found, 379.1443. 1H
NMR (500 MHz, acetone-d6): δ 8.40−8.34 (m, 2H), 8.32−8.26 (m,
2H), 7.92 (t, 1H, J = 1.8 Hz), 7.79−7.64 (m, 8H), 7.58 (t, 1H, J = 7.7
Hz), 7.54−7.47 (m, 2H), 7.44−7.37 (m, 1H). 13C{1H} NMR (126
MHz, acetone): δ 205.2, 166.9, 153.0, 141.8, 140.7, 140.3, 140.1,
131.8, 131.5, 129.5, 129.0, 128.8, 127.5, 127.0, 126.3, 125.7, 125.4,
121.2, 117.8, 112.9.
AZO 6 (4-(Naphthalen-1-yldiazenyl)benzoic acid). The general
procedure resulted in a red powder with 38% (89 mg) yield of the
title product. Mp: 290−295 °C. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C17H12N2O2Na, 299.0796; found, 299.0791. 1H NMR (500
MHz, DMSO): δ 15.78 (s, 1H), 8.56 (dd, J = 8.2, 1.1 Hz, 1H), 7.98
(d, J = 9.4 Hz, 1H), 7.91−7.85 (m, 2H), 7.80 (dd, J = 7.8, 1.3 Hz,
1H), 7.63 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.59−7.52 (m, 2H), 7.52−
7.44 (m, 1H), 7.43−7.36 (m, 1H), 6.94 (d, J = 9.3 Hz, 1H). 13C{1H}
NMR (126 MHz, DMSO): δ 169.2, 163.7, 145.5, 140.4, 133.2, 130.3,
129.6, 129.6, 129.3, 128.5, 128.3, 126.3, 124.3, 121.7, 119.4.
General Procedure for Azobenzene (AZO) Solution Synthesis. A
total of 300 mg (1.4 mmol) of B (B1, N-BOC-1,4-phenylenediamine,
AZO 1; B2, 4-aminophenol (215 mg, 2 mmol), AZO 2; B3, 3-amino-
5-bromophenol (335 mg, 1.8 mmol), AZO 3; B4, 3,5-dimethoxyani-
line (307 mg, 2 mmol), AZO 4; B5, [1,1′:3′,1′′-terphenyl]-2′-amine
(615 mg, 2.5 mmol), AZO 5; B6, naphthalen-1-amine (267 mg, 2
mmol), AZO 6), silver oxide (0.21 mmol), and 15 mL of acetone at 4
°C (for AZO 5 and AZO 6, THF, and heated at 85 °C) were reacted
for 24 h. The reaction was monitored by TLC. Reaction completion
was confirmed by TLC. The purification of the product was done by
column chromatography with a mixture of dichloromethane/
methanol, 90:10 (v/v), yielding the resultant compound. The yield
was 193 mg (80% AZO 1), 192 mg (80% AZO 2), 228 mg (71%
AZO 3), 214.7 mg (75% AZO 4), 227 mg (60% AZO 5), and 182.2
mg (66% AZO 6).
Synthesis of C. A total of 500 mg of trityl chloride resin (1.1
mmol/g Cl loading) was loaded, activated, and washed with DMF/
DCM. Compound 3a (synthesized by following the procedure from
ref 31) (650 mg, 3 mmol) and triethyl amine (TEA, 0.65 mL, 5
mmol) were dissolved in 30 mL of DCM. This mixture was loaded
onto the resin and allowed to react for 12 h. After 12 h, unreacted
material is washed out. The reaction was monitored by UV absorption
and the Kaiser test. Note that C is a resin and, thus, cannot be
characterized via solution NMR.
Synthesis of Spiropyran (SP1) General Procedure. A total of 500
mg of compound C resin was loaded and activated by washing with
DCM/DMF/EtOH, 300 mg (1.8 mmol) of D (D1, 2-hydroxy-5-
nitrobenzaldehyde; D2, 2-hydroxybenzaldehyde (244 mg, 2 mmol);
D3, 2-hydroxy-5-methylbenzaldehyde (273 mg, 2 mmol); D4, Boc-
amino-2-hydroxybenzaldehyde (475 mg, 2 mmol); D5, 2,4-dihydrox-
ybenzaldehyde (276 mg, 2 mmol); D6, 2-bromo-4,6-dihydroxyben-
zaldehyde (434 mg, 1.9 mmol)). Piperidine (85 mg, 1 mmol) was
added, and the reaction was heated to 60 °C for 6 h. The unreacted
compound was washed out, and a few beads were taken out with the
Kaiser reagent. The resin beads and the solution turn dark blue when
a primary amine is present, which means some unreacted resin is
present. In this situation, we reload the compound and repeated the
same procedure until no unreacted resin is present. The resin beads
retain their color, and the solution stays yellow when no free primary
amines are present (expected result after successful coupling). A
SP4 (6-Amino-1′,3′,3′-trimethylspiro[chromene-2,2′-indoline]-
5′-carboxylic acid). The general procedure resulted in a reddish-
range powder with 40% (134 mg) yield of the title product. Mp:
175−178 °C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
C20H20N2O3Na, 359.1372; found, 359.1370. H NMR (500 MHz,
DMSO): δ 7.77−7.71 (m, 1H), 7.56 (d, 1H, J = 2.7 Hz), 7.16−7.10
(m, 3H), 6.80 (t, 1H, J = 7.4 Hz), 6.61 (d, 1H, J = 7.7 Hz), 5.94 (d,
1H, J = 10.2 Hz), 3.85 (s, 1H), 3.02 (d, 1H, J = 18.3 Hz), 2.83 (s,
1H), 2.68 (s, 3H), 1.21 (s, 3H), 1.10 (s, 3H). 13C{1H} NMR (126
MHz, DMSO): δ 163.6, 148.5, 148.0, 145.1, 140.2, 136.4, 128.8,
128.0, 122.0, 121.9, 119.6, 119.4, 111.2, 107.3, 106.0, 52.2, 28.8, 26.2,
19.9.
SP5 (7-Hydroxy-1′,3′,3′-trimethylspiro[chromene-2,2′-indoline]-
5′-carboxylic acid). The general procedure resulted in a red solid
powder with 40% (135 mg) yield of the title product. Mp: 169−173
°C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H19NO4Na,
360.1211; found, 360.1215. 1H NMR (500 MHz, DMSO): δ 9.87 (s,
1H), (d, 2H, J = 1.7 Hz), 7.75−7.52 (m, 3H), 7.16 (d, 1H, J = 10.4
Hz), 6.71 (d, 1H, J = 8.2 Hz), 6.05 (d, 1H, J = 10.4 Hz), 2.79 (s, 3H),
1.30 (s, 3H), 1.16 (s, 3H). 13C{1H} NMR (126 MHz, DMSO): δ
167.8, 155.6, 151.5, 136.3, 135.3, 131.2, 129.7, 128.4, 123.9, 123.3,
122.9, 121.7, 112.5, 106.7, 106.0, 52.0, 28.9, 25.9, 20.4.
SP6 (5-Bromo-7-hydroxy-1′,3′,3′-trimethylspiro[chromene-2,2′-
indoline]-5′-carboxylic acid). The general procedure resulted in a
red powder with 30% (125 mg) yield of the title product. Mp: 160−
164 °C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
C20H18BrNO4Na, 438.0317; found, 438.0319. H NMR (500 MHz,
DMSO): δ 10.27 (s, 1H), 8.29 (d, 1H, J = 16.1 Hz), 8.19 (d,1H, J =
2.8 Hz), 8.01 (d, 1H, J = 16.2 Hz), 7.87 (d, 1H, J = 2.8 Hz), 7.65 (d,
1H, J = 8.7 Hz), 7.15 (d, 1H, J = 2.3 Hz), 6.95 (dd, 1H, J = 8.7, 2.3
Hz), 3.97 (s, 3H), 1.71 (s, 6H). 13C{1H} NMR (126 MHz, DMSO):
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δ 179.4, 170.2, 169.0, 159.3, 147.8, 145.9, 137.3, 137.2, 134.4, 125.5,
122.0, 116.2, 115.8, 111.7, 110.2, 105.12 51.7, 46.2, 34.2, 26.6, 9.1.
Synthesis of Spiropyran (SP) General Solution Method.
Compound 3a (synthesized by following the procedure found in ref
31) (434 mg, 2 mmol), 334 mg (2 mmol) of D (D1, 2-hydroxy-5-
nitrobenzaldehyde; D2, 2-hydroxybenzaldehyde (244 mg, 2 mmol);
D3, 2-hydroxy-5-methylbenzaldehyde (273 mg, 2 mmol); D4, Boc-
amino-2-hydroxybenzaldehyde (475 mg, 2 mmol); D5, 2,4-dihydrox-
ybenzaldehyde (276 mg, 2 mmol); D6, 2-bromo-4,6-dihydroxyben-
zaldehyde (434 mg,1.9 mmol)), and piperidine (85 mg-1 mmol) were
added, and the reaction was heated to 90 °C for 6 h. The reaction was
monitored by TLC. The purification of the product was done by
column chromatography with a mixture of dichloromethane/
methanol, 90:10 (v/v), yielding a resultant compound. The yield
was 281 mg (76% SP 1), 250 mg (77% SP 2), 238 mg (70.9% SP 3),
200 mg (59.4% SP 4), 249 mg (73% SP 5), and 260 mg (62% AZO
6).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02375.
■
sı
NMR, mass spectra, and HPLC of azo and spiropyran
derivatives (PDF)
FAIR data, including the primary NMR FID files, for
compounds AZO 1−6 and SP1−6 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Paul V. Braun − Beckman Institute for Advanced Science and
Technology, Department of Materials Science and
Engineering, Department of Chemistry, and Materials
Research Laboratory, University of Illinois at
Urbana−Champaign, Urbana, Illinois 61801, United States;
orcid.org/0000-0003-4079-8160; Email: pbraun@
illinois.edu
Author
Ravichandran H. Kollarigowda − Beckman Institute for
Advanced Science and Technology, Department of Materials
Science and Engineering, and Materials Research Laboratory,
University of Illinois at Urbana−Champaign, Urbana,
Illinois 61801, United States; orcid.org/0000-0001-
8376-218X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02375
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Department of Defense/
US Army W911NF-17-1-0351 through the Materials Research
Laboratory at the University of Illinois. The authors thank to
Ms. Chen Chen for helping with NMR analysis.
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