Reactivity of tetrahydrochromeno[2,3-b]indoles: Chromic indicators of cyanide

Article abstract of DOI:10.1002/poc.3158

The synthesis and reactivity of a tetrahydrochromeno[2,3-b]indoles are reported. Evidence for reversible ring-opening is based on H/D exchange and trapping experiments. These compounds readily undergo reaction with tetra-n-butylammonium cyanide. The cyanide reaction is 10-100× faster when the solution is irradiated with 350 nm light. Reaction with trimethylsilyl cyanide occurs only with UV irradiation demonstrating photoreactivity. The rate of tetrahydrochromeno[2,3-b]indole ring-opening is greater for (i) Me substitution at the hemiaminal carbon (compared to Ph), and (ii) substitution of fluorine at the 9-position of the indole. Under acidic conditions, the ring-opened indolium ion is observed. Copyright

Full text of DOI:10.1002/poc.3158

Research Article
Received: 28 March 2013,
Revised: 24 May 2013,
Accepted: 29 May 2013,
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/poc.3158
Reactivity of tetrahydrochromeno[2,3-b]
indoles: chromic indicators of cyanide
Nicholas Douglasa, Charles J. Neefa, Robert A. Rogersa, Jake A. Stanleya,
Jacob Armitagea, Ben Martina, Todd W. Hudnalla and William J. Brittaina*
The synthesis and reactivity of a tetrahydrochromeno[2,3-b]indoles are reported. Evidence for reversible ring-opening is
based on H/D exchange and trapping experiments. These compounds readily undergo reaction with tetra-n-
butylammonium cyanide. The cyanide reaction is 10–100× faster when the solution is irradiated with 350 nm light.
Reaction with trimethylsilyl cyanide occurs only with UV irradiation demonstrating photoreactivity. The rate of
tetrahydrochromeno[2,3-b]indole ring-opening is greater for (i) Me substitution at the hemiaminal carbon (compared to
Ph), and (ii) substitution of fluorine at the 9-position of the indole. Under acidic conditions, the ring-opened indolium
ion is observed. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper
Keywords: acidolysis; chromeno; chromic; cyanide reaction; photoreactivity
OX (Scheme 1). This photochromic system demonstrated
fast ps switching times and no degradation after thousands
INTRODUCTION
of cycles. Synthesized by the adduct formation between 2-
hydroxy-5-nitrobenzyl chloride and substituted-3H-indoles,
substituents influenced the efficiency of the photochemical pro-
cess and isomerization kinetics.[11] OX undergoes a reversible
[C–O] bond cleavage to generate the colored 4-nitrophenolate
and indolium ion. Unlike SP, OX photoisomerization does not
involve cis–trans isomerization.
Like OX, the CR system reported in this work does not require
cis–trans isomerization as part of the photocycle, and we predict
that CR should demonstrate similar reactivity. One potential
advantage of CR relative to OX is versatile functionalization
chemistry at the indole nitrogen which can serve as a ‘tether’
location for incorporation into hybrid systems. In addition, it is
our expectation that reactivity studies of CR will add to the
general mechanistic understanding of heterolytic ring-opening.
We have studied CR reactivity with trifluoroacetic acid (TFA), and
two cyanide sources: (i) tetra-n-butylammonium cyanide (TBACN)
and (ii) trimethylsilyl cyanide (TMSCN). Cyanide is a good
nucleophile, and colorometric detection methods are advantageous
for sensitivity.[12] The potential sensor molecule should be selective
for cyanide in the presence of other anions and work in aqueous
media.[13,14] Shiraishi and co-workers[15–17] have studied CN
detection using SP where synthetic modification of SP allowed
Our iterest in use of chromic molecules for probing the
microenvironment of hybrid systems led us to examine
common chromophores. Spiropyran (SP) is a ubiquitous
photochromic system.[1–3] Like others, we observed significant
degradation of SP over time with repeated photoisomerization
cycles; this coupled with relatively slow kinetics of decoloration
prompted us to consider new chromic systems. Raymo, Sortino
and co-workers[4] reported a structurally analogous system
based [1,3]oxazines (OX) that posses
a fused structure
compared to the spirocyclic SP. Comparison of OX and SP
suggested that tetrahydrochromeno[2,3-b]indole (CR) may be
a potential useful chromic system. Scheme 1 compares the
three chromic systems and the structural relationship between
CR, SP and OX. All three systems possess a hemiaminal carbon
and generate 4-nitrophenolate upon ring-opening; the
structures differ in the indole ring location for the bridging
group and presence/absence of C=C bond between indole
and phenolate. The recognition of this structural similarity was
the impetus for the current study. In this communication, we
report the synthesis and structure of
a series of CR
compounds and the reactivity with acid and cyanide.
Photochromic molecules exist in two different states that exhibit
different absorption spectra, and at least one state must be photo-
induced.[1] Chromic molecules exhibit changes in absorption
spectra with a change in environment, but are often not reversible.
SPs are among the most studied chromic systems. First reported
by Fischer and Hirshberg,[5] the photoisomerization of SP to the
colored merocyanine (MC) isomer involves two consecutive
steps: (i) spirocyclic [C–O] bond cleavage in picoseconds (ps), and
(ii) cis–trans isomerization in milliseconds.[6,7] The thermal rever-
sion of MC back to SP is limited by the slow cis–trans isomerization
making the photoisomerization of SP susceptible to degradation
with repeated photoisomerization cycles.[8–10] Raymo, Sortino and
co-workers[4] reported the synthesis and study of photochromic
* Correspondence to: W. J. Brittain, Department of Chemistry and Biochemistry,
Texas State University - San Marcos, 601 University Drive, San Marcos, TX
78666, USA.
E-mail: wb20@txstate.edu
a N. Douglas, C. J. Neef, R. A. Rogers, J. A. Stanley, J. Armitage, B. Martin,
T. W. Hudnall, W. J. Brittain
Department of Chemistry and Biochemistry, Texas State University - San Marcos,
601 University Drive, San Marcos, TX, 78666, USA
J. Phys. Org. Chem. 2013
Copyright © 2013 John Wiley & Sons, Ltd.

N. DOUGLAS ET AL.
Scheme 1. Photoisomerization of spiro[chromene-2,2'indoline] (SP), benzo[5,6][1,3]oxazino[3,2-a]indole and tetrahydrochromeno[2,3-b]indole (CR);
the bold bond shows the bridging connection for the 4-nitrophenolate unit
cyanide reaction in water and used experimental conditions that
stabilized the MC. The reaction of cyanide reaction with SP
is selective with μmol detection limits.[17] This research group
also reported cyanide detection using a copolymer containing
SP[18] and fluorescence detection with a courmarin–SP conju-
gate.[19] SP–polythiophene conjugates have been reported for cya-
nide detection in photoswitchable sensors.[20] Light accelerates
cyanide reaction by increasing the MC concentration; cyanide reacts
102 faster with the MC isomer relative to SP.[15]
Scheme 2. Synthesis of tetrahydrochromeno[2,3-b]indoles 2a–e
OX also reacts with cyanide to form the colored nitrophenolate.
Sortino, Raymo and co-workers[21] studied an OX system with a
with an N-methyl-2,3-disubstituted indole (1a–e) to afford CR
4-nitrophenylazophenolate chromophore and were able to detect
μmol concentrations of cyanide ion. Ren and co-workers[22]
studied the cyanide reaction with a dinitro substituted OX and
reported fast (30 s) response for [CN–] ~ 10À6 M.
In this study, we report the cyanide reaction of CR and acid-cata-
lyzed ring-opening. We chose these two processes based on similar
studies performed for SP and OX. The strategy of compound
selection for this study is based on prior OX work where a lower rate
of ring-opening for R2 = C6H5 compared to R2 = CH3 and an increase
in quantum yield for fluorine substitution on the indole ring (R3 = F)
were reported.[11] CR 2e was prepared for comparison to CR 2a
to probe potential steric effects.
2a–e (Scheme 2). The synthesis of CR 2a was reported by
Spande and co-workers[23] in a study of Koshland's reagent;
however, detailed characterization was not performed. Although
not directly related to CR synthesis, the literature contains
reports of similarly fused ring systems.[24–28] Indoles 1a–e were
prepared by Fischer indole methods that include the
conventional ZnCl2-catalyzed reaction of a hydrazine and ketone
in acetic acid[29] and the use of ZnCl2-based ionic liquids.[30]
Compounds CR 2a–e were purified by flash chromatography
and characterized by NMR, UV–vis (Table 1 and Supplemental
Fig. S1), elemental analysis and X-ray crystallography.
Structure
RESULTS
In order to assess structural similarity to SP and OX, the X-ray
crystal structures of CR 2a,c–e[31] have been determined.
Despite repeated attempts, X-ray quality crystals for CR 2b
could not be obtained. Figure 1 shows the structures of CR
2a,d which are representative. The CR structures reveal a
Synthesis
The synthesis of tetrahydrochromeno[2,3-b]indole (CR) involves
the stoichiometric reaction of 2-hydroxy-5-nitrobenzyl bromide
Table 1. UV–vis and structural data for CR 2a–ea
Compound
R1
R2
R3
λmax (nm)
ϵ (mMÀ1cmÀ1
)
Dihedral angleb
2a
2b
2c
2d
2e
Me
Me
Me
Me
Me
Me
Ph
H
F
H
F
301
311
303
305
327
8.2 0.4
1.11 0.03
11°
-
18°
18°
11°
10
2
Ph
1.09 0.02
9.4 0.5
(CH2)4
H
aAbsorption data in CHCl3, 23°C.
bDihedral angle = angle between the plane of the phenolate C–O bond (σC-O orbital) and the perpendicular of the plane formed by
substituents on the indole nitrogen (2pz orbital), determined by X-ray crystallography.
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PHOTOREACTIVITY OF TETRAHYDROCHROMENO INDOLE
Figure 1. Single-crystal X-ray structures of CR-2a,d
bent structure in which the angle between the indole plane
and nitrophenolate plane varies from 72 to 89. The dihedral
angle between the 2pz orbital on the indole nitrogen and the
adjacent σC-O orbital ranges from 11 from 18°. Comparison of the
structures reveals that phenyl substitution at the hemiaminal carbon
increases the dihedral angle. The CR dihedral angle is similar to the
analogous SP systems (15–30°) and the OX where R3 = H, R2 = CH3
(Fig. 1) which has a dihedral angle of 9°.[4] This dihedral angle is
expected to favor electronic mixing between the two orbitals and
facilitate C–O bond cleavage. The OX system and CR share the same
bent geometry caused by the fused ring system with similar
envelope angles (87° for OX where R3 = H, R2 = CH3).
exchange under similar conditions consistent with proposed
mechanism. H/D exchange has also been observed in similar
systems such as indolospiropyrans[32] and 1,1’-diethyl-2,2’-
cyanine chloride.[33,34]
Acidolysis
The reaction of CR 2a–e with TFA was studied by 1H, 13C and 19
NMR. Addition of TFA produces the ring-opened 3H-indol-1-ium
ion where the 4-nitrophenolate has been protonated
F
5
(Scheme 4). The reaction with TFA proceeds in CDCl3, CD3CN
and acetone-d6. Figure 2 shows the 1H NMR spectra for TFA reac-
tion with CR 2a. The hydrogens of the indolium aromatic ring,
benzylic and N-Me shift to lower field. The cyclohexyl CR 2e
CR 2a–e have two chiral centers at the junction of the fused ring
system. Chromeno formation occurs by syn addition to form one
diastereomer. This geometry will likely constrain the ring-closure
step with regards to indolium ion facial selectivity.
1
displays a more complicated H NMR spectrum where chemical
shift differentiation of the axial and equatorial hydrogens is
observed (Supplemental Fig. S3). Fluorinated CR compounds
2b,d were synthesized to probe the electronic effects of fluorine
on ring-opening; however, they also serve a dual purpose
because 19F NMR provides complementary information for the
acid-catalyzed ring-opening. The 19F resonance for CR 2b,d
shifts downfield 15 ppm upon addition of TFA and is assigned
to 5b,d. The trifluoroacetate ion is observed at δ = À76.64
ppm. Buncel and co-workers[35] proposed an acid-catalyzed
process for conversion of SP similar to Scheme 4.
H/D exchange
H/D exchange is observed when a CDCl3 solution of CR 2a
containing D2O is irradiated with 350 nm light. The 1H NMR
resonance for the α-methyl to the hemiaminal (R2 in Scheme 2)
at 2.68 ppm decreases in intensity as exchange occurs. The 18C
NMR spectrum of the sample displays a septet (JC-D = 20 Hz) at
19.0 ppm for the α-methyl of CR 4a (Supplemental Fig. S2).
H/D exchange likely occurs via the vinylidene intermediate 3
(Scheme 3) that is formed following heterolytic C–O bond
cleavage of CR. H/D exchange is observed also for the fluoro
derivative 2b. No signals for either the ring-opened CR isomer or
3 were observed indicating an equilibrium process with ring-closed
CR being the strongly favored isomer. For comparison, we
synthesized 2-nitro-5a,6,6-trimethyl-5a,6-dihydro-12H–indolo[2,1b]
[1,3]benzoxazine (OX, R2 = CH3, R3 = H)3 and observed H/D
Reaction with cyanide reagents
The CR compounds are unreactive to the non-nucleophilic
base DBU (diazabicyclo[5.4.0]undec-7-ene). Darwish and
co-workers[36,37] observed decoloration of SP with DBU in
toluene and methanol and for a spirooxazine in methanol.
Raymo, Sortino, et al.[4] studied the reaction of OX with
Scheme 3. H/D exchange of tetrahydrochromeno[2,3-b]indoles 2a–e
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N. DOUGLAS ET AL.
Table 2. Half-life (t1/2) in min, determined by UV–visa
t1/2, min × 102
R1 R2 R3 TMSCN hυ TBACN hυ TBACN Δ
c
2a
2b
2c
2d
2e
Me Me
Me Me
Me Ph
Me Ph
–(CH2)4–
H
F
H
F
7
14
66
720
72
2
2
4
4
2
b
Scheme 4. Trifluoroacetic acid reaction with CR
17
14
H
72
tetra-n-butylammonium hydroxide and observed hemiaminal
formation from nucleophilic attack by hydroxide.
aHalf-life: TMSCN reaction – loss of starting material, TBACN
reaction – growth of product. The error in half-lives is 10–20%
for all values. CHCl3, 23°C. [CR] = 5 × 10–5 M, [trapping
agent]/[CR] = 50.
TMSCN is an effective silylating agent for proton exchangeable
compounds.[38] It has also been used to trap iminium ions[39] and
zwitterionic peroxide intermediates in the singlet oxygen
reaction of electron-rich systems.[40] Malatesta and co-workers[41]
formed adducts with zwitterionic MC isomers of spirooxazines
and SPs in which the cyanide is attached to the spirocyclic
carbon and the phenolate is O-silylated. The adduct formed
rapidly with UV irradiation by reaction with the zwitterion; there
was no evidence for direct reaction with the SP.
bPhotochemical process for CR 2a was instantaneous.
cNo reaction.
nm and molar absorptivity (ϵ) of 8000 LmolÀ1cmÀ1. Kinetic
studies monitored the decrease in absorbance at 375 nm where
the product's absorbance is negligible. Figure 3 shows the plot of
time versus ln[A] and the effect of irradiation. The loss of CR
followed first-order kinetics with half-lives of 2–14 min; the ratio
of [TMSCN]/[CR] = 50 (Table 2).
Reaction with TMSCN
NMR and UV–vis spectroscopy were used to study the reaction
with TMSCN. Reaction kinetics (Table 2) were measured by
UV–vis with sample excitation using an arc-lamp fitted with a
340 nm broad bandpass filter. Malatesta, et al.[41] reported
degradation of TMSCN adducts of SP leading to desilylated
products; we also observed an increasing number of side-
products in the NMR for irradiations exceeding 20 min for
chloroform solutions with arc lamp irradiation. TMSCN does
not undergo photodegradation in chloroform solution. The
thermal reaction of TMSCN with CR 2a–e was negligible with
no conversion observed after 2 days under ambient labora-
tory conditions. However, heating to 60°C was sufficient to
induce complete reaction for all compounds within 30 min.
CR 2a,b,d,e formed TMSCN adducts upon irradiation; CR 2c
did not react with TMSCN under these conditions. Reactions
were run with 100 eq. of TMSCN and in the absence of oxygen.
The UV–vis spectrum of the adduct 7 is similar to CR
(Supplementary Fig. S4). 7c displays a peak maximum at 303
Reaction with TMSCN was also followed by NMR. Figure 4
1
displays H NMR spectra for the reaction of CR 2a with TMSCN
in CDCl3 where Ha and Hc shift upfield. Downfield shifts were
observed for the benzylic (Hj) and N-methyl (Hh) hydrogens
(Supplementary Fig. S5). Increased exposure times of samples
in quartz NMR tubes led to greater conversion. The fluorinated
compounds CR 2b,d displayed a new 19F resonance 0.2 ppm
downfield from the starting material which we have assigned
to 7b,d. Qualitative 1H NMR experiments on the effect of solvent
revealed greater conversion with increasing solvent polarity for
the reaction of CR 2a: CD3CN > CDCl3 > C6D6. The identity of
the TMSCN product was confirmed by NMR (Supplementary Figs.
S6 and S7). Characteristic peaks in the 13C NMR included 119.0
(CN), 3.6 (Me3Si) and 75.7 ppm (hemiaminal carbon, shifted 33
ppm upfield from CR). We obtained an X-ray structure
(Supplementary Fig. S8) of the hydrolyzed adduct (3-(2-hy-
droxy-5-nitrobenzyl)-1,2,3-trimethylindoline-2-carbonitrile)
Figure 2. 1H NMR of CR 2a (0.05M) before (a) and after (b) addition of 4 eq. TFA (CD3CN, 23°C)
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PHOTOREACTIVITY OF TETRAHYDROCHROMENO INDOLE
Figure 3. Reaction of CR 2a with TMSCN in CHCl3, 23°C. [CR] = 5 × 10À5
M, [TMSCN] = 2.5 × 10À3 M
Figure 5. UV–vis spectra of (a) CR 2a in CHCl3 (0.06 mM), (b) CR 2a and 6
eq. TBACN, (c) CR 2a and 12 eq. TBACN, and (d) tetra-n-butylammonium
4-nitrophenolate (5 μM). Stationary spectra taken 5 min after mixing
following unsuccessful attempts to obtain crystals of the
trimethylsilyl derivative; the crystal structure corresponds to
(2R,3R)-3-(2-hydroxy-5-nitrobenzyl)-1,2,3-trimethylindoline-2-
carbonitrile consistent with our mechanism.
and were fit to first-order kinetics based on CR concentration.
Half-lives ranged from 2 to 760 min. 1H, 13C and 19F NMR analysis
of the reaction is consistent with the product structure in
Scheme 5. For CR 2b,d, the 19F resonance shifted upfield 0.14
ppm. No reaction was observed with other TBA salts that include
phenolate, acetate, benzoate and azide. All of the work on
cyanide was performed in organic media; we did not examine
aqueous conditions or mixed solvents with water.
Reaction with TBACN
TBACN reacts with CR 2a–e in CHCl3 at 23°C under ambient
lighting, but proceeds at rates 10–100 greater with irradiation
(Table 2). Products 8a–e are highly colored due to the
nitrophenolate group. Figure 5 shows UV–vis spectrum for
CR 2c before and after addition of 6 and 12 eq. TBACN
and the spectrum of TBA 4-nitrophenolate (λmax =411 nm,
ϵ = 27,000 L MÀ1cmÀ1). Raymo, Sortino, et al.[4] reported
DISCUSSION
λ
max =425 nm, ϵ = 32,500 L MÀ1cmÀ1 for TBA 4-nitrophenolate
A new structural class of chromic compounds based on
tetrahydrochromeno have been synthesized and characterized.
Reaction of TBACN with CR 2a–e produced an instantaneous
chromic response to form the 4-nitrophenolate ion. CRa,b
undergo H/D exchange with D2O or CD3OD to form 4a,b in
CD3CN and acetone-d6; H/D exchange in CDCl3 is accelerated
by 350 nm light. H/D exchange is consistent with a mechanism
in which reversible heterolytic ring-opening forms an indolium
ion which undergoes reversible proton exchange.
in acetonitrile; these workers concluded that the UV–vis
spectrum of compounds like 8 represents the sum of the
indole and 4-nitrophenolate absorptions. The data reported in
Table 2 correspond to experimental ratios of [TBACN]/[CR] = 50
Acidolysis with TFA instantaneously forms the corresponding
3H-indol-ium ions 5a–e. The CR compounds undergo facile
Figure 4. 1H NMR spectra for CR 2a and TMSCN in CDCl3 for different
times of exposure to 254 nm irradiation – (a) No UV, (b) 5 min UV and
(c) 10 min UV (see Fig. S5 for aliphatic region)
Scheme 5. CR reaction with TBACN and TMSCN
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N. DOUGLAS ET AL.
Ocean Optics component system with a HR2000+ detector, qpodTM
sample holder, DH 2000 source and Spectra Suite software for data
collection. Solutions were degassed via three freeze–pump–thaw cycles.
Trapping experiments used air-sensitive techniques for addition of
trapping agent. Photochemical kinetic experiments used Oriel 66901
50-200W Research Arc Lamp; the output was cooled with a water filter
and passed through a bandpass filter (350 nm center, 70 nm FWHM).
The sample cell was temperature controlled to 23°C and magnetically
stirred. Kinetic experiments were run with a data capture rate of one
spectrum/100 ms. If necessary, air-sensitive handling techniques were
used to degass samples and add reagents to a sealed optical cell.
Elemental analysis was performed by Galbraith Laboratories, Inc. X-ray
crystallography was performed on a Rigaku SCX-Mini Single Crystal
X-ray Diffractometer.
reaction with TBACN both thermally and photochemically with a
10–100× increase in conversion with exposure to UV. We argue
the photoinduced pathway first involves heterolytic bond
cleavage followed by cyanide trapping. Two pathways for the
thermal process are possible: (i) ring-opening followed by
cyanide trapping, or (ii) a second-order, nucleophilic attack by
cyanide. The phenyl substituted derivatives (CR 2b,d) are the
least reactive which we ascribe to a steric effect. These results
suggest an early transition state as the phenyl group would
conjugatively stabilize the ring-opened indolium ion. These
results are similar to Sortino, Raymo, et al.[4] where they observed
a 500× rate difference for phenyl versus methyl (faster)
substitution at the hemiaminal carbon in OX.
Additional evidence for photoactivity of CR is the reaction with
TMSCN where no reaction is observed without irradiation at room
temperature. Phenyl-substituted CR 2c does not react with TMSCN
even with irradiation. The 9-fluorophenyl-substituted derivative CR
2d does react. The effect of fluorine substitution is observed in the
shorter half-life for CR 2b compared to the nonfluorinated analog
CR 2a. Raymo, Sortino, et al.[4] reported that fluorine substitution
on the indole ring para to the indole nitrogen increased the
quantum yield by 3×. The effect of fluorine on the photochemical
reaction with TBACN is similar for the phenyl substituted
compounds (2d versus 2b) while the opposite effect is observed
for the methyl substituted compounds (2a versus 2c). NMR studies
of TMSCN reaction in different solvents reveal higher conversion in
more polar solvents consistent with a polar intermediate in the
trapping process.
General procedure for N-alkylation of indoles
To a solution of 2,3-dimethylindole (1.90 g, 1.30 mmol) in 20 mL
anhydrous THF was added NaH (0.325 g, 1.35 mmol). The reaction was
performed in a high pressure tube at 80°C for 2 h. MeI (860 uL, 1.38
mmol) was added the mixture and heating applied at 80°C for 1 h.
Methanol was added to quench excess base. Volatiles were removed in
vacuo and the product isolated by two-phase extraction with CH2Cl2.
Drying the combined CH2Cl2 extracts over anhydrous MgSO4 and
removal of volatiles afforded 1.85 g 1,2,3-trimethyl-1H-indole (dark red
oil, 89% yield); 1H NMR (400 MHz, CDCl3) δ: 7.72 (d, 1H), 7.41 (t, 1H),
7.36 (t, 1H), 7.32 (t, 1H), 3.00 (s, 3H), 2.07 (s, 3H), 1.87 (s, 3H).[42] Purification
of the N-methyl indole is easily performed via flash chromatography
using CH2Cl2:hexanes mixtures. Often the crude product was used
without purification in the next step.
The cyclohexyl derivative 2e adopts a conformation with the
lowest dihedral angle (11°) consistent with a tricyclic structure.
However, this more ‘open’ structure is not manifested by higher
reactivity. Reactions of 2e with TMSCN or TBACN are slower than
the dimethyl analog 2a but faster relative to the phenyl-
substituted CR compounds.
Our original impetus for this study was to assess the relative
reactivity of CR relative to OX and SP. We have concluded that CR
is a viable chromic system with similar reactivity to OX. The faster
reaction of CR with TMSCN with 350 nm light suggests a trapping
mechanism that has been observed with SP – increased concentra-
tion of the more reactive zwitterion with irradiation. Transient
absorption studies are in progress to confirm the trapping experi-
ments reported here and further characterize the reactivity of
CR. We are also expanding the library of tetrahydrochromeno
compounds to better understand substituent effects and evaluate
these compounds as colorometric sensors and probe molecules
for determination of microenvironmental polarity. For colorometric
detection in aqueous media, we are synthesizing functionalized
derivatives to facilitate solubility.
General procedure for CR formation
5a,6,10b-Trimethyl-2-nitro-5a,6,10b,11-tetrahydrochromeno[2,3-b]
indole (2a)
1,2,3-trimethyl-1H-indole (1 g, 06.2 mmol), 2-(bromomethyl)-4-nitrophenol
(1.45 g, 6.2 mmol) and K2CO3-7H2O (0.865 g, 6.2 mmole) were combined in
2:1 (v/v) acetone:H2O. The mixture was sonicated for 15 min and stirred
overnight. The acetone was removed in vacuo and the product isolated
via two-phase extraction with CH2Cl2. Flash chromatography using
1:1 (v/v) CH2Cl2:hexanes gave 1.29 g (67%) of a yellow powder (Rf = 0.3,
mp = 119–120°C). 1H NMR (400 MHz, CDCl3) δ: 7.88 (s, 1H), 7.83 (d, 1H),
7.01 (t, 1H), 6.89 (d, 1H), 6.65 (t, 1H), 6.64 (d, 1H), 6.41 (d, 1H), 3.18, 3.00
(dd, 2H), 2.94 (s, 3H), 1.73 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz)
δ: 161.8, 149.3, 141.2, 133.2, 128.5, 124.5, 124.5, 124.3, 121.7, 119.6, 116.4,
107.2, 105.9, 47.9, 34.0, 28.0, 26.2, 19.5.
Anal. Calcd. for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.98;
H, 5.95; N, 8.73.
9-Fluoro-5a,6,10b-trimethyl-2-nitro-5a,6,10b,11-tetrahydrochromeno
[2,3-b]indole (2b)
Te method of Abbott and co-workers[30] was used to prepare 5-
fluoro-3-methyl-2-phenyl-1H-indole using an ionic liquid prepared by
heating 16 g ZnCl2 and 8.2 choline chloride together until a homogeneous
fluid was obtained. To this was added 1.3 g (19.8 mmol) of 2-butanone and
3.22 g (19.8 mmol) (4-fluorophenyl)hydrazine hydrochloride and the mixture
heated at 120°C for 2 h. Aqueous workup and extraction with CH2Cl2 afforded
product. Flash chromatography using 1:1 (v/v) CH2Cl2:hexane gave 2.1 g
(47%, brown solid) of 5-fluoro-3-methyl-2-phenyl-1H-indole (Rf = 0.3). 1H NMR
(400 MHz, CDCl3) δ: 7.64 (broad s, 1H), 7.13 (m, 2H), 6.85 (m, 1H), 2.36
(s, 3H), 2.19 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ: 158.1 (JCF = 233 Hz),
131.1, 131.9, 130.2, 110.8, 109.1, 107.8, 103.3, 12.0, 8.8 ppm; 19F NMR (376
MHz, CDCl3) δ: À126.98 ppm.
EXPERIMENTAL SECTION
General information
Unless otherwise noted, all reagents were obtained from commercial
sources and used without purification. Exceptions include: TMSCN
(Aldrich) which was distilled before use and chloroform (UV grade) was
dried over CaH2. Solutions of TBACN and TMSCN were freshly prepared
for NMR and absorption experiments. Flash chromatography used Agela
60Å gel and TLC was performed using EMD Millipore silica plates with
fluorescent indicator. NMR spectra were obtained using a Bruker
Advance III 400 spectrometer. 1H and 13C NMR shifts are reported relative
to TMS and 19F shifts are relative to CFCl3. Absorption measurements
were performed using either a Cary 100 Bio UV–vis spectrometer or an
Anal. Calcd. for C10H10FN: C, 73.60; H, 6.18; N, 8.58. Found: C, 73.02;
H, 5.98; N, 8.39.
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J. Phys. Org. Chem. 2013

PHOTOREACTIVITY OF TETRAHYDROCHROMENO INDOLE
161.9, 157.9(1JCF = 235 Hz), 145.8, 145.8, 141.6, 137.0, 134.5, 134.5, 129.3,
128.7, 128.2, 124.7, 124.6, 116.5, 114.7, 110.3, 109.6, 108.3, 108.3 49.6, 33.1,
30.1, 27.9; 19F NMR (376 MHz, CD3CN) δ: À126.71 ppm.
Anal. Calcd. for C23H19FN2O3: C, 70.76; H, 4.91; N, 7.18. Found: C, 70.56;
H, 5.12; N, 7.22.
Indole 1b was prepared by the general alkylation procedure.[44] Flash
chromatography using 2:98 (v/v) CH2Cl2:hexane gave 5-fluoro-1,3-dimethyl-
2-phenyl-1H-indole as a light yellow powder in 80% yield (Rf = 0.6). 1H NMR
(400 MHz, CDCl3) δ: 7.12 (m, 2H), 6.89 (m, 1H), 3.63 (s, 3H), 2.35 (s, 3H), 2.23
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ: 158.0 (1JCF = 232 Hz), 134.8, 133.4,
109.0, 108.5, 106.7, 103.2, 30.0, 10.6, 9.1 ppm; 19F NMR (376 MHz, CDCl3)
δ: À126.27 ppm.
6-Methyl-2-nitro-6,11-dihydro-5a,10b-butanochromeno[2,3-b]in-
dole (2e)
Anal. Calcd. for C11H12FN: C, 74.55; H, 6.83; N, 7.90. Found: C, 75.01; H,
6.66; N, 7.78.
2b was prepared by the general procedure; after flash chromatography
with 1:2 (v/v) CH2Cl2:hexane gave a yellow powder in 62% yield (Rf = 0.25,
mp = 128–130°C). 1H NMR (400 MHz, acetone-d6) δ: 8.01 (s, 1H), 7.89 (d, 1H),
6.94 (d, 1H), 6.75 (m, 2H), 6.48 (m, 1H), 3.16, 3.50 (dd, 2H), 2.99 (s, 3H), 1.82
(s, 3H), 1.46 (s, 3H) ppm; 13C NMR (100 MHz, acetone-d6) δ: 163.3, 158.3 (1JCF
= 295 Hz), 147.3, 136.9, 126.2, 125.7, 125.2, 117.6, 115.2 (2JCF = 25 Hz), 111.1
Phenylhydrazine (6.6 mL, 66.5 mmol), 5g (36.6 mmol) ZnCl2 and 2.32 mL
(22.3 mmol) were combined with 33 mL glacial acetic acid in a high
pressure tube. The mixture was heated at 120°C for 3 h. After cooling,
100 mL H2O was added the product extracted with CH2Cl2. The
combined extracts were washed 1× NaHCO3(aq) and 1× H2O. The
organic phase was dried over MgSO4 and volatiles removed in vacuo to
afford 3.43 g (90% yield) of 2,3,4,9-tetrahydro-1H-carbazole[46] which
was used without further purification. Using the general alkylation
procedure, 9-methyl-2,3,4,9-tetrahydro-1H-carbazole and matched
literature data[47] The product was used without purification.
Using the general procedure for CR formation, 2e was obtained in
87% yield after flash chromatography using 1:1 (v/v) CH2Cl2:hexane
(colorless solid, Rf = 0.45, mp = 138–140°C). 1H NMR (400 MHz, C6D6) δ:
7.83 (s, 1H), 7.55 (d, 1H), 6.98 (t, 1H), 6.68 (m, 2H), 6.37 (d, 1H), 6.23
(d, 1H), 2.60 (s, 3H), 2.58, 2.47 (dd, 2H), 1.97 (m, 1H), 1.29 (m, 6H), 1.04
(m, 1H) ppm; 13C NMR (100 MHz, C6D6) δ: 161.1, 149.8, 141.8, 135.5,
125.9, 124.2, 122.0, 121.5, 120.4, 116.6, 109.2, 104.2, 46.0, 38.8, 29.4,
29.2, 27.9, 23.6, 21.7.
(2JCF = 25 Hz), 108.8 (3JCF = 8 Hz), 107.9, 49.4, 33.9, 29.0, 26.6, 20.1 ppm; 19
NMR (376 MHz, acetone-d6) δ: À126.98 ppm.
F
Anal. Calcd. for C18H17FN2O3: C, 65.84; H, 5.22; N, 8.53. Found: C, 65.65;
H, 5.07; N, 8.41.
6,10b-Dimethyl-2-nitro-5a-phenyl-5a,6,10b,11-tetrahydrochromeno
[2,3-b]indole (2c)
Phenylhydrazine (7.20 g, 22.3 mol), propiophenone (3 g, 22.3
mmoles) and ZnCl2 (5 g, 36.6 mmol) were combined with 33 mL
glacial acetic acid in a high pressure tube. The reaction mixture
was heated at 120°C for 5 h. Two-phase extraction using water and
CH2Cl2 followed by flash chromatography (1:99, v/v, ethyl acetate:
hexane) afforded 3.24 g (70% yield, yellow powder, Rf = 0.25). 1H
and 13C NMR spectra matched literature values for 3-methyl-2-phenyl-1H-in-
dole.[43] 1,3-Dimethyl-2-phenyl-1H-indole was prepared by the general
alkylation procedure above. The product was a red oil and was purified via
flash chromatography (2:98, v/v, ethyl acetate:hexane) to afford 3.1 g of a
yellow powder (90% yield, Rf = 0.3); 1H and 13C NMR spectra matched
literature values.[45] 2c was prepared by the general procedure above and
after chromatography with 1:1 (v/v) CH2Cl2:hexane afforded 75% of a yellow
powder (Rf = 0.4, mp = 148–150°C). 1H NMR (400 MHz, acetone-d6) δ: 8.05 (s,
1H), 7.97 (d, 1H), 7.55 (m, 5H), 7.10 (m, 2H), 6.95 (d, 1H), 6.68 (m, 2H), 3.49, 3.12
(dd, 2H), 2.96 (s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ: 163.5,
151.2, 143.0, 138.8, 134.4, 130.4, 129.9, 129.7, 127.0, 125.8, 125.4, 123.4,
121.20, 117.8, 111.3, 109.3, 51.0, 33.9, 28.9 ppm.
Anal. Calcd. for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.11;
H, 6.02; N, 8.39.
X-ray crystallography
Single crystals of 2a–e were grown from vapor diffusion of i-Pr2O into a
MeCN solution of CR.
SUPPORTING INFORMATION
1H, 13C and 19F NMR spectra, UV–vis absorption spectra and crys-
tallographic data (.cif files provided separately) are included in
supplementary material.
Anal. Calcd. for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 74.08;
H, 5.39; N, 7.23.
Acknowledgements
9-Fluoro-6,10b-dimethyl-2-nitro-5a-phenyl-5a,6,10b,11-tetrahydrochromeno
[2,3-b]indole (2d)
WJB thanks the National Science Foundation (PREM Center for
Interfaces in Materials, DMR-1205670) and the ACS Petroleum
Research Fund (51997UR7) for financial support of this research.
BM thanks the National Science Foundation (CAREER DMR-
0748140). The authors also acknowledge the support of the National
Science Foundation for X-ray and NMR instrumentation (CRIF:
MU-0946998 and MRI-0821254) and the Welch Foundation
(AI-0045) for support.
Using the same process as described for CR 2b, 5-fluoro-3-methyl-2-phenyl-
1H-indole was prepared in 73% yield (brown solid). 1H NMR (400 MHz, CDCl3)
δ: 7.99 (s, 1H), 7.57 (m, 2H), 7.49 (t, 2H), 7.38 (m, 1H), 7.26 (m, 2H), 6.95 (m, 1H),
2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ: 158.1 (1JCF = 233 Hz), 136.3,
133.4, 132.6, 130.9, 130.9, 129.2, 128.0, 111.6, 111.0, 110.7, 109.2, 104.3,
104.1, 10.0 ppm; 19F NMR (376 MHz, CDCl3) δ: À124.51 ppm.
The product from the first step was used without purification; using the
general alkylation procedure, 5-fluoro-1,3-dimethyl-2-phenyl-1H-indole obtained
in 76% yield (brown solid, Rf = 0.5) after flash chromatography with 1:3 (v/v)
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