Photochemistry of 2-Nitroarenes: 2-Nitrophenyl-α-trifluoromethyl Carbinols as Synthons for Fluoroorganics

Article abstract of DOI:10.1021/jacs.9b07241

Facile synthesis of a new series of 2,2′-bis(trifluoroacetyl) azoxybenzene derivatives and trifluoromethylated benzo[c]isoxazoline systems, along with trifluoroacetyl nitrosobenzene derivatives was achieved by solvent controlled photolysis of appropriate

Full text of DOI:10.1021/jacs.9b07241

Article
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
pubs.acs.org/JACS
Photochemistry of 2‑Nitroarenes: 2‑Nitrophenyl-α-trifluoromethyl
Carbinols as Synthons for Fluoroorganics
†
,‡
,†,‡
‡
†,‡
Kavita Belligund, Thomas Mathew,*
Jonathan R. Hunt, Archith Nirmalchandar,
†
,‡
Jahan Dawlaty,‡ and G. K. Surya Prakash*
,†,‡
Ralf Haiges,
†Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California
9
‡
0089-1661, United States
Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
S Supporting Information
*
ABSTRACT: Facile synthesis of a new series of 2,2′-bis(trifluoroacetyl)
azoxybenzene derivatives and trifluoromethylated benzo[c]isoxazoline
systems, along with trifluoroacetyl nitrosobenzene derivatives was achieved
by solvent controlled photolysis of appropriate 2-nitrobenzyl alcohols.
Corresponding photoactive 2-nitrobenzyl chromophore plays a distinct role
in this photosynthetic process, while, quite unprecedented, pertinent
fluoromethyl substitution leads to high value fluoromethylated products,
whose direct access is not feasible by common synthetic protocols. The
significance of fluorine and fluoroalkyl substitution and its prominent
biological effects makes this new photochemical approach an important
discovery in synthetic methodology. Plausible mechanistic pathways
involved in the formation of the products during steady-state photolysis
are further established by picosecond laser flash photolysis experiments.
INTRODUCTION
Scheme 1. Intramolecular Photoredox Processes in o-
Nitrobenzylic Systems
■
The rich photochemistry of o-nitrobenzylic systems has been
extensively explored and utilized in the past few decades for
convenient application as effective photoremovable protecting
1
−7
groups,
which make these systems a vital tool in chemical
8
biology such as DNA polymerase technology and in the
9
−11
synthesis of photolabile caged compounds.
o-Nitrobenzylic
group has been effectively used for the safe photochemical
release of acids, alcohols, amines, phosphates, and ketones. In
solid state peptide synthesis, it has been used as a very efficient
photocleavable protecting group. In 1901, Ciamician and
1
2
Silber reported the intramolecular photoredox transforma-
tion of o-nitrobenzaldehyde to o-nitroso benzoic acid. Further
1
3
studies were carried out by Spiteller, Morrison and
1
4
Migadolf on similar systems. Time-resolved experiments by
2
0
15
16
small size, which is comparable to hydrogen. So far, over 20%
of approved pharmaceutical drugs contain one or more
fluorine atoms, while in the case of newly registered
George and Sciano, Yip and Sharma, Gilch and co-
1
7
workers have suggested that the primary process among
several elementary processes involved in the phototransforma-
tion of o-nitrobenzylic systems is the hydrogen transfer from
the substituent with C−H functionality in the ortho position to
the nitro group during irradiation (Scheme 1).
2
1,22
agrochemicals, it is even higher (∼30%).
Some well-
known fluorine containing drugs include the targeted chemo-
therapy drug sorafenib (Nexavar) A, selective Bcr-Abl kinase
inhibitor nilotinib (Tasigna) B, nonsteroidal anti-inflammatory
drug celecoxib (Celebrex) C, the cholesterol-lowering
compound atorvastatin (Lipitor) D, the antidepressant
fluoxetine (Prozac) E, and the antibiotic ciprofloxacin
There is a huge drive toward the synthesis of fluoroorganic
molecules as many of them are very valuable in medicinal and
material chemistry. In pharmaceutical chemistry, introduction
of fluorine and perfluoro groups in drug molecules generates
significant changes in conformation, lipophilicity, metabolic
stability, and pharmacokinetic properties that are highly
(
Ciprobay) F (Figure 1). Strong dipoles introduced by partial
1
8,19
desirable in medicinal chemistry.
These changes are
Received: July 8, 2019
attributed to the high electronegativity of fluorine and its
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 1. A few widely used fluorine-containing drugs.
Scheme 2. Photochemical Transformation of 2,2′-Dinitrodiphenylmethanes to N-Heterocycles
fluorination cause changes in electrical effects which are useful
to investigate the transformation occurring to 2-nitrophenyl-α-
trifluoromethylcarbinyl part and its synthetic utility.
in the development of ferroelectric, antiferroelectric, and liquid
2
3
crystal materials.
Our continued interest in the development of efficient
synthetic approaches for fluorination and fluoromethylation of
a wide range of organic substrates prompted us to search for
simple and convenient protocols. As earlier studies on the
photochemical transformation of 2-nitrobenzyl derivatives,
RESULTS AND DISCUSSION
■
Steady-State Photolysis of 2-Nitrophenyl-α-trifluor-
omethyl Carbinols in 2-Propanol: Synthesis of 2,2′-
Bis(trifluoroacetyl)azoxyarenes. As trifluoromethylated o-
nitrobenzyl alcohols can be easily synthesized by trifluor-
omethylation of the corresponding aldehydes using Ruppert−
Prakash reagent, we decided to examine initially the photo-
reaction of the simple trifluoromethylated alcohol, 2-nitro-
2
4−28
especially 2,2′-dintrodiphenylmethane derivatives 3,
showed that direct access to heterocycles such as diazepines,
diazepine-N-oxides, acridines, and their derivatives could be
achieved (Scheme 2), we became curious to examine the
photochemistry of α-trifluoromethylated 2-nitrobenzyl alco-
hols to see if we could exploit their rich photochemistry to
generate novel trifluoromethylated substituted arenes. While
there have been several approaches, where the trifluoromethy-
lated 2-nitrobenzyl systems have been used as photoremovable
groups, very few studies on their application as useful
photosynthons exist. Studies published recently on the use of
phenyl-α-trifluoromethyl carbinol 4a, synthesized by the
trifluoromethylation of 2-nitrobenzaldehyde.
29−31
As this
trifluoromethylated carbinol absorbs in the UV-B region, in
our initial studies, we irradiated 4a and its derivatives using a
medium pressure Hg lamp with a Pyrex glass filter. However,
Rayonet reactor with monochromatic lamps, being more
convenient for irradiation, was chosen for further studies.
Irradiation using 300 nm phosphorus lamps provided products
with similar or better yields depending on the nature of the
solvent. We carried out the photolysis in three solvents, 2-
propanol, dimethyl sulfoxide (DMSO), and acetonitrile.
2
-nitrophenyl-α-trifluoromethyl carbinol as an efficient photo-
1
1
removable group caught our attention and the effective
photocleavage/deprotection steps further sparked our interest
B
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
We started our photolytic studies using 2-nitrophenyl-α-
trifluoromethyl carbinol 4a by irradiating it in 2-propanol using
corresponding trifluoroacetyl group, eliminating the need for
an external oxidant. Azoxy compounds exhibit photochromic
properties, find applications in nonlinear optics and as dopants
1
00 W medium pressure Hg lamp with a Pyrex glass filter.
38−43
After irradiation for 1 h, aliquots of the reaction mixture were
analyzed by F NMR which showed the formation of a
mixture of products, though with low selectivity. Irradiation for
materials used in liquid crystals,
of heterocyclic compounds,
retinoid and antiandrogenic activity.
as substrates for synthesis
while some derivatives display
1
9
44,45
46,47
Therefore, direct
5
h could afford 20% of a major product, which was later
synthesis of trifluoroacetyl derivatives drew our keen attention.
It is evident that its formation occurs by an intramolecular
photoredox reaction in which the photooxidation of trifluor-
omethylcarbinol to trifluoroacetyl group by the excited nitro
group with its simultaneous photoreduction to nitroso group.
Nitrosoarenes, being significantly photoactive, undergoes
subsequent photoreductive coupling to form the correspond-
identified as 2,2-bis(trifluoroacetyl)azoxybenzene 5a. Since the
reaction was not very clean, we switched over to a Rayonet
reactor fitted with 300 nm monochromatic lamps. Irradiation
of a solution of 2-nitrophenyl-α-trifluoromethyl carbinol in 2-
propanol in the Rayonet photoreactor for 5 h resulted in the
formation of a red solution, which on 19F NMR analysis
showed the formation of a major product. After separation and
identification, we were very intrigued to know that it is the
corresponding 2,2′-bis(trifluoroacetyl)azoxybenzene 5a, same
as the one obtained during irradiation using Hg lamp but with
double the yield. To the best of our knowledge, this is the first
report on the synthesis of trifluoroacetylated azobenzene-N-
oxide by a simple one-step method as shown (Scheme 3).
48
ing azoxyarene product. Another product was also observed
in noticeable amount, but could not be separated due to
decomposition. These azoxy arenes are characterized by two
1
9
sharp F singlets with equal integration in the region −77 to
−71 ppm. The structures were completely characterized by
1
13
19
NMR ( H, C, F NMR) and were further established by X-
ray crystallographic analysis (Figure 2).
Table 1 shows the results of irradiation of the
trifluoromethylated carbinols 4a−h in 2-propanol. As shown,
the solutions of various substituted phenyl analogues 4a−d and
4f in 2-propanol on irradiation with 300 nm gave the
corresponding azoxy products 5a−d and 5f in moderate
yields. In the case of 4e with methoxy substitution at the para
position to the nitro group, the yield of the azoxy product was
reduced to 2−4%, giving the trifluoromethylated benzo[c]-
isoxazolone 6e as the major product. However, for 4f with two
methoxy substituents, para to both nitro and carbinol
functionalities, azoxy product 5f was obtained as the sole
product (Figure 3).
As seen in Table 1, apart from unsubstituted and halogen
substituted 2,2′-bis(trifluoracetyl)azoxybenzenes, direct syn-
thesis of 2,2′-bis(trifluoracetyl)azoxynaphthalene 5h was also
made possible by this very convenient photochemical method,
albeit in lower yield (Figure 3).
Scheme 3. Photolysis of 2-Nitrophenyl-α-trifluoromethyl
Carbinol 4a: Direct Access to 2,2′-
Bis(trifluoroacetyl)azoxybenzene 5a
While the general route to oxidation of the trifluoromethyl
carbinol functions to trifluoroacetyl groups involves the use of
32−36
harsh reaction conditions,
even mild reaction conditions
involve addition of oxidants in more than stoichiometric
3
0,37
amounts.
However, this intramolecular photoredox process
readily oxidizes the trifluoromethylated alcoholic group to the
Figure 2. 19F NMR spectrum and X-ray crystal structure of 5a.
C
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 1. Synthesis of 2,2-Bis(trifluoroacetyl)azoxyarenes by
the Photolysis of 2-Nitrophenyl-α-trifluoromethyl Carbinols
in 2-Propanol
intramolecular cyclization with the elimination of a molecule of
methanol occurred, leading to the formation of a trifluor-
omethylated benzo[c]isoxazol-5(3H)-one 6 (Scheme 4). More
Scheme 4. 2-Nitrophenyl-α-trifluoromethyl Carbinol, an
Efficient Photosynthon for Solvent-Controlled Synthesis of
2
,2′-Bis(trifluoroacetyl)azoxyarenes, 2-Trifluoroacetyl
Nitrosoarenes, and Trifluoromethylated Isoxazolines
intriguingly, changing the solvent to acetonitrile led to the
formation of 2-trifluoroacetyl nitrosoarenes and their hydrates
as the major products. Molecules containing the isoxazoline
49,50
core are found to exhibit significant antiplatelet activity.
These types of molecules also exhibit insecticidal properties;
Afoxolaner and Fluralaner are commercial drugs used to treat
51,52
fleas in mammals (Scheme 4).
Nitroso compounds serve
as reactants for various synthetic transformations such as those
5
3−55
56
involving nitroso aldol reactions,
ene reactions, cyclo-
5
4
addition, etc. They are also used as effective metal
coordinating ligands and antiviral compounds.
57
58
While irradiation of 4a in DMSO formed the corresponding
-trifluoroacetyl nitrosobenzene 7a through its hydrate 8a as
2
intermediate, 4e (with a methoxy group present para to the
nitro group) eventually formed the corresponding isoxazoline
derivative, 3-hydroxy-3-(trifluoromethyl)-benzo[c]isoxazol-
5(3H)-one 6e by the elimination of a molecule of methanol.
The 4,5-dimethoxy substituted carbinol 4f, which formed 2,2′-
bis(trifluoroacetyl)-4,4′,5,5′-tetramethoxy azoxybenzene 5f
previously in 2-propanol, is now transformed to 3-hydroxy-6-
methoxy-3-(trifluoromethyl)benzo[c]isoxazol-5(3H)-one 6f.
We were very delighted to see that the methoxy substituted
substrate 5i with an adjacent difluoromethoxy substituent also
formed the corresponding difluoromethoxy substituted iso-
xazoline 6i (Table 2). Formation of the isoxazolines were
1
9
identified by the formation of a distinct singlet in the F NMR
spectra between −85 to −83 ppm depending on the substrate
and solvent (Figure 4). Formation of the isoxazoline
derivatives, noticed during the irradiation in 2-propanol in
minute concentration, reached maximum concentration when
the solvent was switched to DMSO.
To obtain these compounds in substantial yields, after
irradiating the solution at a proper wavelength (300 nm) for a
specific period of time with monitoring the fading of substrate
concentration, the solution had to be kept undisturbed under
dark for a period of 48−168 h to avoid any secondary
photoprocesses. This allows the formation and rearrangement
of the cyclic intermediate with the elimination of a molecule of
Figure 3. X-ray crystal structures of 5f and 5h.
Synthesis of Trifluoromethylated Isoxazolines. To
explore the synthetic utility of this photoprocess, we continued
the study with a series of 2-nitrophenyl-α-trifluoromethyl
carbinols using different solvents. Therefore, as our next
approach, we chose the highly polar, aprotic solvent DMSO as
the solvent for irradiation. We observed an interesting
phenomenon when there was a methoxy group located para
to the nitro group. When the para-methoxy substituted (para
to nitro group) substrates were irradiated in DMSO as solvent,
D
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 2. Synthesis of Trifluoromethylated Benzo[c]isoxazol-
Evaporation of acetonitrile from the photolysates of 4c and
4d yielded solids, which were found to be the dimers 8c′ and
8d′ of the respective monomers 8c (hydrate of 7c) and 8d
5
(3H)-ones by the Photolysis of 2-Nitrophenyl-α-
a
trifluoromethyl carbinols in DMSO
(
hydrate of 7d). Solvent evaporation leads to increase in the
concentration of monomer hydrate 8c and 8d and promoted
dimerization to the corresponding N,N-dioxides 8c′ and 8d′.
The NMR spectra recorded for the solid 8d′ were found to be
similar to the intermediate observed during photolysis of 4e in
DMSO. The structure of the solid 8d′ was determined by X-
ray single crystal analysis (Scheme 5). However, when the
hydrate was left in CDCl or excess CHCl , it gradually
3
3
dissolved and formed the nonhydrated monomer, 2-triflluor-
oacteyl nitrosoarene 7d. This could be attributed to
dehydration due to the residual acidity of these solvents.
Transient Absorption Spectroscopy. To better under-
stand the mechanism of the photoreaction, femtosecond UV-
pump/vis-probe transient absorption spectroscopy was used to
study the transient intermediates involved in the reaction. The
details of the transient absorption apparatus are described
59
elsewhere. Study was conducted using 4a in 2-propanol and a
mixture of water and 2-propanol (Figure 5). At 300 fs, the
shortest delay resolved by our instrument, a broad spectrum is
seen that is assigned to the S1 state of the molecule. In the first
ten picoseconds, this spectrum evolves. The evolved spectrum,
consisting of a narrow short wavelength feature (∼430 nm)
and a broad long wavelength feature, is assigned as a mixed
population of the o-quinonoid singlet and the T1 triplet states.
These assignments are made based on previous works by Yip
a
t = time of irradiation, t = time kept undisturbed in the dark.
i
s
methanol to form the 3-hydroxy-3-(trifluoromethyl)benzo[c]-
isoxazol-5(3H)-ones 6e,f,i (Table 2).
16,60,61
and Sharma,
who illustrated that the short wavelength
Fascinated by the reactions in DMSO as solvent, we decided
feature is associated with the o-quinonoid species and the long
wavelength feature is associated with the triplet state.
Overlapping absorption of these two states was similarly
observed by Yip and Sharma.
to change the solvent to CH CN, an aprotic solvent with lower
3
polarity. Irradiation of carbinol 4a−4e showed the formation
of one of the two major products, which were identified as 2-
trifluoroacetyl nitrosoarene 7 and its hydrate 8. Irradiation of
4
a, 4b, 4e formed the corresponding 2-trifluorocetyl nitro-
To probe the identities of these features experimentally,
water was gradually added to the 2-propanol solution to
observe its effects on the spectral evolution. Addition of water
soarene 7a, 7b, 7e, while 4c and 4d formed the respective
hydrates 8c and 8d as shown (Scheme 5, Table 3).
Figure 4. 19F NMR spectrum and X-ray crystal structure of 6e.
E
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 5. Photolysis of 4a−e in CH CN; Formation of 2-Trifluorocetyl Nitrosoarenes 7a, 7b, 7e and the Hydrates 8c, 8d; X-
3
ray Crystal Structure of 8d′ (the Dimer of the Hydrate 8d)
a
Table 3. 2-Trifluorocetyl Nitrosoarenes 7a−e and Their Hydrates 8a−e from the Irradiation of 4a−e in CH CN
3
aAn asterisk (*) indicates 19F NMR yield.
led to an increased prevalence of the short wavelength feature
in the transient absorption spectrum. This is consistent with
the short wavelength feature being assigned the o-quinonoid
species, since addition of water could aid in the proton transfer
process necessary for o-quinonoid generation. Oxygen was also
added to the solution to observe its effects on the spectral
evolution. Over the temporal range of our instrument (600 ps),
there were no spectral changes observed by the addition of
F
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 5. Transient absorption spectra of 2,2,2-trifluoro-1-(2-nitrophenyl)ethanol 4a in 2-propanol, 2-propanol with 1% water, and 2-propanol with
0% water
1
oxygen. While we expect the contributing T1 state to be
quenched by the presence of oxygen, it is possible that such
effects take place on longer time scales.
In 2-propanol, the cyclic intermediate 12 very likely opens to
give the corresponding trifluoroacetyl nitroso product 7, which
itself being highly photoactive undergoes photoreductive
coupling to form the trifluoroacetyl azoxy products. It is also
possible that in 2-propanol, part of 7 might get reduced to the
corresponding hydroxylamine followed by condensation with
nitroso product 7 to form trifluoroacetyl azoxy products. In 4e,
the presence of methoxy group in the para position enhances
the rate of formation of cyclic intermediate 12e during the
photoreaction and incites the elimination of a molecule of
Steady-State Photolysis in DMSO and Analysis of the
Photolysate. On irradiation of 4a in DMSO-d , an
6
intermediate, which was characterized by the formation of a
19
peak (quartet) at −84.35 ppm in the F NMR was detected.
As the reaction progressed, the peak corresponding to Cα (to
1
3
CF ) in the C spectrum moved from 65.21 ppm (J = 31.4
3
Hz) to 93.98 (J = 32.4 Hz) ppm on irradiation. This
intermediate finally gives rise to the 2-trifluoroacetyl nitro-
sobenzene 7a.
CH OH resulting in 6e. This process is highly favored in
3
DMSO.
It is quite intriguing to note that a mixture of the
nitrosoketone product 7 and its hydrate 8 are formed when
the reaction is carried out in acetonitrile. As the formation of
stable hydrates in the case of aldehydes, ketones and imines
On irradiation of 2,2,2-trifluoro-1-(5-methoxy-2-
nitrophenyl)ethanol 4e in DMSO, a similar transition was
observed. The compound on irradiation formed an inter-
mediate (evidenced by the appearance of a signal at −84.44
1
9
containing several electronegative substituents such as CCl3/
ppm in the F NMR spectrum), which on being left
CF group due to their strong electron withdrawing effect is
undisturbed transforms into 6e (Figure 6). As the reaction
3
6
3−68
progressed, monitoring the reaction with 13C NMR showed
well-known,
formation of the hydrates 8 is quite
reasonable. In fact, the hydration ability of trifluoromethylated
ketones has been exploited in the development of many
organic synthetic methodologies, recently for the development
the transformation of quartet corresponding Cα (to CF ) in
3
the alcohol 4e (65.24 ppm) to the one corresponding to Cα in
the intermediate (94.21 ppm) and finally to the one in
isoxazoline 6e (103.29 ppm) (Scheme 6, for detailed
procedure, see Supporting Information). This intermediate
was eventually characterized as the hydrated 2-trifluoroacetyl
nitrosoarene 8e.
69
of histone deacetylase (HDAC) inhibitors. However, as
expected, on workup and drying the product, conversion to the
nitroso product occurs gradually. Addition of chloroform/
CDCl3 pushes the equilibrium toward the nonhydrated
trifluoroacetyl nitrosoarene due the residual acidity of
Plausible Mechanism. On the basis of the laser flash
70−72
chloroform/CDCl3.
Thus, the formation of the photo-
photolysis studies, steady state analysis conducted (vide supra)
16,60−62
products could be rationalized based on these observations.
The photoreaction mixture would become more colored as the
reaction proceeds; hence, the low reaction yield could also be
attributed to the competitive absorption of the photoproducts.
and comparing the results with previous observations,
we suggest that the following plausible mechanism for the
transformations and the rearrangements involved in these
photoprocesses. On irradiation, the nitrochromophore in the
trifluoromethylated o-nitrobenzyl alcohol 4 undergoes n−π*
excitation to form both the excited singlet and triplet states.
Following intramolecular hydrogen abstraction, subsequent
formation of the primary intermediates consisting of the triplet
diradical 10 and the o-quinonoid singlet 11 occurs. Both 10
and 11 can advance to the cyclic intermediate 12, the former
by intersystem crossing to 11 (Scheme 7).
CONCLUSION
■
Through the described approach, the synthetic utility of α-
trifluoromethylated o-nitrobenzyl alcohols as efficient photo-
synthons toward the synthesis of new series of fluoroorganics
with versatile functional motifs such as trifluoromethylated
azoxy arenes, trifluoromethylated benzo[c]isoxazol-5(3H)-
G
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 6. 19F and 13C NMR taken at different intervals: (A) Solution of 4e in DMSO-d after irradiation for 2.5 h, showing the formation of
6
intermediate, 8e. (B) Irradiated mixture left undisturbed for 24 h showing transition of the intermediate 8e to product 6e. (C) After 72 h, showing
almost complete conversion of the intermediate, 8e to the product 6e.
H
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 6. Synthesis of Isoxazoline 6e by the Photolysis of
nitrobenzyl alcohols as photosynthons in addition to their
protecting and photodeprotecting ability. The authors also
anticipate that further studies in the area will provide key
synthetic pathways for direct access to many biologically active
small fluoroorganic molecules of great importance in the
pharmaceutical arena in the future.
2
,2,2-Trifluoro-1-(5-methoxy-2-nitrophenyl)-ethanol 4e in
DMSO
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b07241.
■
*
S
ones and trifluoroacetyl nitroso arenes is revealed. Mechanistic
studies by picosecond laser flash photolysis and monitoring of
the steady state photolysate by NMR spectroscopic analysis
shed light on the transient species and intermediates involved
in the reaction. This work is the first report underscoring the
importance of re-evaluating the potential of perfluorinated o-
Experimental Procedures and Spectral Data (PDF)
Summary of Data CCDC Numbers (PDF)
Crystal data for 5a (CIF)
Crystal data for 5f (CIF)
Scheme 7. Plausible Mechanism Leading to Photoproducts Observed during the Irradiation of 4a−i in Various Solvents
I
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(
14) Morrison, H.; Migdalof, B. H. Photochemical Hydrogen
Crystal data for 5h (CIF)
Crystal data for 6e (CIF)
Crystal data for 8d′ (CIF)
Abstraction by Nitro Group. J. Org. Chem. 1965, 30, 3996.
15) George, M. V.; Scaiano, J. C. Photochemistry of o-nitro-
benzaldehyde and related studies. J. Phys. Chem. 1980, 84, 492.
16) Yip, R. W.; Sharma, D. K.; Giasson, R.; Gravel, D.
(
(
Photochemistry of the o-nitrobenzyl system in solution: Evidence
for singlet state intramolecular hydrogen abstraction. J. Phys. Chem.
1985, 89, 5328.
AUTHOR INFORMATION
Corresponding Authors
tmathew@usc.edu
gprakash@usc.edu
■
(17) Laimgruber, S.; Schreier, W. J.; Schrader, T.; Koller, F.; Zinth,
*
W.; Gilch, P. The Photochemistry of o-nitrobenzaldehyde as seen by
femtosecond vibrational spectroscopy. Angew. Chem., Int. Ed. 2005,
*
ORCID
44, 7901.
Thomas Mathew: 0000-0002-2896-1917
Ralf Haiges: 0000-0003-4151-3593
Jahan Dawlaty: 0000-0001-5218-847X
G. K. Surya Prakash: 0000-0002-6350-8325
(18) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; Del Pozo, C.;
́
́
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
pharmaceutical industry: Fluorine-containing drugs introduced to the
Market in the last decade (2001−2011). Chem. Rev. 2014, 114 (4),
2
(
432.
19) Swallow, S. Fluorine in medicinal chemistry. Prog. Med. Chem.
2015, 54 (2), 65.
20) O’Hagan, D. Understanding Organofluorine Chemistry. An
Introduction to the C-F Bond. Chem. Soc. Rev. 2008, 37, 308.
21) Isanbor, C.; O’Hagan, D. Fluorine in Medicinal Chemistry: A
Review of anti-cancer agents. J. Fluorine Chem. 2006, 127, 303.
22) Begue,
Notes
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
(
Support by the Loker Hydrocarbon Research Institute and the
Department of Chemistry, University of Southern California is
gratefully acknowledged. The authors would also like to
acknowledge Ms. Alexandra Aloia for her valuable suggestions.
(
́
́
J. P.; Bonnet-Delpon, D. Recent advances (1995−2005)
in fluorinated pharmaceuticals based on natural products. J. Fluorine
Chem. 2006, 127, 992.
(23) Hiyama, T.; Yamamoto, H. Fluorine-Containing Materials. In
REFERENCES
Organofluorine Compounds; Yamamoto, H., Ed.; Springer: Berlin,
Heidelberg, 2000.
■
(
1
1) Pillai, V. N. R. Photoremovable protecting groups. Synthesis
980, 1980, 1.
2) Cameron, J. F.; Frechet, J. M. J. Photogeneration of Organic
Bases from o-Nitrobenzyl-Derived Carbamates. J. Am. Chem. Soc.
991, 113, 4303.
3) Marinzi, C.; Offer, J.; Longhi, R.; Dawson, P. E. An o-
Nitrobenzyl Scaffold for Peptide Ligation: Synthesis and Applications.
Bioorg. Med. Chem. 2004, 12, 2749.
4) Peng, L.; Goeldner, M. Synthesis and characterization of
(
24) Joshua, C. P.; Ramdas, P. K. Photochemistry of 2,2’-
Dinitrodiphenylmethanes: Irradiations in Neutral, Acidic and Alkaline
Media. Aust. J. Chem. 1976, 29, 865.
(
(25) Christudhas, M.; Joshua, C. P. Photochemistry of 2,2’-
1
(
Dinitrodiphenylmethanes. II: Irradiation of 5,5′-Dimethyl-2,2’-dini-
trodiphenylmethanes in Neutral, Acidic and Alkaline Media. Aust. J.
Chem. 1982, 35, 2377.
(26) Mathew, T.; Joshua, C. P. Photolysis of benzoyl esters of 2,2’-
(
dinitrodiphenylcarbinols in neutral and basic media. J. Photochem.
photolabile choline precursors as reversible inhibitors of cholines-
terases: Release of choline in the microsecond time range. J. Org.
Chem. 1996, 61, 185.
Photobiol., A 1991, 60, 319−324.
(
27) Mathew, T.; Joshua, C. P. Photolysis of acetyl esters of 2,2′-
dinitrodiphenyl-carbinols in protic and aprotic solvents. Res. Chem.
Intermed. 1991, 16, 189.
(
5) Watanabe, S.; Sueyoshi, T.; Ichihara, M.; Uehara, C.; Iwamura,
M. M. Reductive ring opening of o-nitrobenzylidene acetals of
monosaccharides: Synthesis and photolysis of some photolabile
sugars. Org. Lett. 2001, 3, 255.
6) Kim, M. S.; Diamond, S. L. Photocleavage of o-nitrobenzyl ether
derivatives for rapid biomedical release applications. Bioorg. Med.
Chem. Lett. 2006, 16, 4007.
7) Mathew, T.; Ajayaghosh, A.; Das, S.; Kamat, P. V.; George, M. V.
A new photodegradable polyamide containing o-nitrobenzyl chromo-
phore. Steady state and laser flash photolysis studies. Photochem.
Photobiol. A: Chem. 1993, 71, 181.
(28) Mathew, T.; Ramaiah, D.; Joshua, C. P.; Weir, D.; George, M.
V. Nanosecond and picosecond laser flash photolysis studies of 2,2’-
dinitrodiphenylmethanes. J. Photochem. Photobiol., A 1993, 70, 245.
(
(29) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. Synthetic
Methods and Reactions. 141. Fluoride-induced Trifluoromethylation
of Carbonyl Compounds with Trifluoromethyltrimethylsilane (TMS-
(
CF ). A Trifluoromethide Equivalent. J. Am. Chem. Soc. 1989, 111,
3
3
(
93.
30) Ramaiah, P.; Krishnamurti, R.; Prakash, G. K. S. 1-
(
8) Chaulk, S. G.; MacMillan, A. M. Caged RNA: Photo-control of a
ribozyme reaction. Nucleic Acids Res. 1998, 26 (13), 3173.
9) Albert, T. J.; Norton, J.; Ott, M.; Richmond, T.; Nuwaysir, K.;
Trifluoromethyl-1-cyclohexanol. Org. Synth. 1995, 72, 232.
(31) Prakash, G. K. S.; Yudin, A. K. Perfluoroalkylation with
Organosilicon Reagents. Chem. Rev. 1997, 97, 757.
(32) Linderman, R. J.; Graves, D. M. Oxidation of fluoroalkyl-
substituted carbinols by the Dess-Martin Reagent. J. Org. Chem. 1989,
54, 661.
(
Nuwaysir, E. F.; Stengele, K. P.; Green, R. D.; Richmond, T. Light-
directed 5′→3′ synthesis of complex oligonucleotide microarrays.
Nucleic Acids Res. 2003, 31, No. 35e.
(
10) Watanabe, S.; Sato, M.; Sakamoto, S.; Yamaguchi, K.; Iwamura,
(33) Liu, L.; Ireland, R. E. An Improved Procedure for the
Preparation of the Dess-Martin Periodinane. J. Org. Chem. 1993, 58,
2899.
(34) Frigerio, M.; Santagostino, M.; Sputore, S. A User-Friendly
Entry to 2-Iodoxybenzoic Acid (IBX). J. Org. Chem. 1999, 64, 4537.
(35) Stewart, R.; Lee, D. G. The Chromic Acid Oxidation of Aryl
Trifluoromethyl Alcohols: Isotope and Substituent Effects. Can. J.
Chem. 1964, 42, 439.
M. New dendritic caged compounds: Synthesis, mass spectrometric
characterization, and photochemical properties of dendrimers with α-
carboxy-2-nitrobenzyl caged compounds at their periphery. J. Am.
Chem. Soc. 2000, 122, 12588.
(
11) Specht, A.; Goeldner, M. 1-(o-Nitrophenyl)-2,2,2-trifluoroethyl
ether derivatives as stable and efficient photoremovable alcohol-
protecting group. Angew. Chem., Int. Ed. 2004, 43, 2008.
(
12) Ciamician, G.; Silber, P. Chemische Lichtwirkungen (Chemical
light action). Ber. Dtsch. Chem. Ges. 1901, 34, 2040.
13) Spiteller, G. Der o-Effekt in den Massenspektren aromatischer
Verbindungen. Monatsh. Chem. 1961, 92, 1147.
(36) Cheng, H.; Pei, Y.; Leng, F.; Li, J.; Liang, A.; Zou, D.; Wu, Y.;
Wu, Y. Highly efficient synthesis of aryl and heteroaryl trifluoromethyl
ketones via o-iodobenzoic acid (IBX). Tetrahedron Lett. 2013, 54,
4483.
(
J
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(
37) Kelly, C. B.; Mercadante, M. A.; Hamlin, T. A.; Fletcher, M. H.;
(54) Yamamoto, H.; Momiyama, N. Rich chemistry of nitroso
compounds. Chem. Commun. 2005, 28, 3514.
Leadbeater, N. E. Oxidation of α-Trifluoromethyl alcohols using a
recyclable oxoammonium salt. J. Org. Chem. 2012, 77, 8131.
(
photochromism Based on Photoinduced Nitro-assisted Proton
Transfer. Chem. Mater. 2005, 17, 5394.
(55) Merino, P.; Tejero, T. Organocatalyzed Asymmetric α-
Aminoxylation of Aldehydes and Ketonesan Efficient Access to
Enantiomerically Pure α-Hydroxycarbonyl Compounds, Diols, and
Even Amino Alcohols. Angew. Chem., Int. Ed. 2004, 43, 2995.
(56) Adam, W.; Krebs, O. The Nitroso Ene Reaction: A
Regioselective and Stereoselective Allylic Nitrogen Functionalization
of Mechanistic Delight and Synthetic Potential. Chem. Rev. 2003, 103,
38) Naumov, P.; Sakurai, K.; Ohashi, Y.; Ng, S. W. Bifunctional
(
39) Otsuki, J.; Omokawa, N.; Yoshiba, K.; Yoshikawa, I.; Akasaka,
T.; Suenobu, T.; Takido, T.; Araki, K.; Fukuzumi, S. Synthesis and
Structural, Electrochemical, and Optical properties of Ru(II)
Complexes with Azobis(2,2′-Bipyridine). Inorg. Chem. 2003, 42,
4
(
131.
57) Cameron, M.; Gowenlock, B. G.; Vasapollo, G. Coordination
Chemistry of C-Nitroso-compounds. Chem. Soc. Rev. 1990, 19, 355.
58) Rice, W. G.; Schaeffer, C. A.; Harten, B.; Villinger, F.; South, T.
3
057.
(
40) Das, P.; Biswas, A. N.; Choudhury, A.; Bandyopadhyay, P.;
(
Haldar, P.; Mandal, P. K.; Upreti, S. Novel synthetic route to liquid
crystalline 4,4′-Bis(n-Alkoxy) Azoxybenzenes: Spectral Character-
isation, Mesogenic Behaviour and Crystal Structure of Two New
Members. Liq. Cryst. 2008, 35, 541.
L.; Summers, M. F.; Henderson, L. E.; Bess, J. W.; Arthur, L. O.;
McDougal, J. S.; Orloff, S. L.; Mendeleyev, J.; Kun, E. Inhibition of
HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds.
Nature 1993, 361, 473.
(
41) Folcia, C. L.; Alonso, I.; Ortega, J.; Etxebarria, J.; Pintre, I.; Ros,
(59) Driscoll, E.; Hunt, J. R.; Dawlaty, J. Proton capture dynamics in
M. B. Achiral Bent-Core Liquid Crystals with Azo and Azoxy
Linkages: Structural and nonlinear optical properties and photo-
isomerization. Chem. Mater. 2006, 18, 4617.
quinoline photobases: Substituent effect and involvement of triplet
states. J. Phys. Chem. A 2017, 121, 7099.
(60) Yip, R. W.; Sharma, D. K.; Giasson, R.; Gravel, D. Picosecond
(
42) Vix, A. B. E.; Muller-Buschbaum, P.; Stocker, W.; Stamm, M.;
excited-state absorption of alkyl nitrobenzenes in solution. J. Phys.
Chem. 1984, 88, 5770.
Rabe, J. P. Crossover between dewetting and stabilization of ultrathin
liquid crystalline polymer films. Langmuir 2000, 16, 10456.
(
behaviors of segmented azoxy polyester containing polyoxyethylene. J.
Appl. Polym. Sci. 1995, 55, 1217.
(
Annulation of azoxy compounds with alkynes: A regioselective
approach to 2H-Indazoles. Org. Lett. 2017, 19, 2781.
(61) Yip, R. W.; Wen, Y. X.; Gravel, D.; Giasson, R.; Sharma, D. K.
43) Huang, J. M.; Kuo, J. F.; Chen, C. Y. Studies on mesomorphic
Photochemistry of the o-nitrobenzyl system in solution: Identification
of the biradical intermediate in the intramolecular rearrangement. J.
Phys. Chem. 1991, 95, 6078.
44) Long, Z.; Yang, Y.; You, J. Rh(III)-Catalyzed [4 + 1]-
(62) Gravel, D.; Giasson, R.; Blanchet, D.; Yip, R. W.; Sharma, D. K.
Photochemistry of the o-Nitrobenzyl System in Solution: Effects of
O···H Distance and Geometrical Constraint on the Hydrogen
Transfer Mechanism in the Excited State. Can. J. Chem. 1991, 69,
(
45) Long, Z.; Wang, Z.; Zhou, D.; Wan, D.; You, J. Rh(III)-
Catalyzed Regio- and Chemoselective [4 + 1]-Annulation of Azoxy
Compounds with Diazoesters for the Synthesis of 2H-Indazoles:
Roles of the Azoxy Oxygen Atom. Org. Lett. 2017, 19, 2777.
1
(
193.
63) Parrilla, A.; Villuendas, I.; Guerrero, A. Synthesis of
trifluoromethyl ketones as inhibitors of antennal esterases of insects.
Bioorg. Med. Chem. 1994, 2, 243.
(
46) Kagechika, H.; Himi, T.; Namikawa, K.; Kawachi, E.;
Hashimoto, Y.; Shudo, K. Retinobenzoic Acids. 3. Structure-Activity
Relationships of Retinoidal Azobenzene-4-Carboxylic Acids and
Stilbene-4-Carboxylic Acids. J. Med. Chem. 1989, 32, 1098.
(64) Guthrie, J. P. Carbonyl Addition Reactions: Factors Affecting
the Hydrate−Hemiacetal and Hemiacetal−Acetal Equilibrium Con-
stants. Can. J. Chem. 1975, 53, 898.
(
47) Takahashi, H.; Ishioka, T.; Koiso, M.; Hashimoto, Y. Anti-
(65) Liang, T. C.; Abeles, R. H. Complex of alpha-chymotrypsin and
androgenic activity of substituted azo- and azoxy-benzene derivatives.
Biol. Pharm. Bull. 2000, 23, 1387.
N-acetyl-L-leucyl-L-phenylalanyl trifluoromethyl ketone: structural
studies with NMR spectroscopy. Biochemistry 1987, 26, 7603.
(66) Bell, R. P. The Reversible Hydration of Carbonyl Compounds.
Adv. Phys. Org. Chem. 1966, 4, 1.
(67) Pedroni, J.; Cramer, N. Enantioselective C−H Functionaliza-
tion−Addition Sequence Delivers Densely Substituted 3-
Azabicyclo[3.1.0]hexanes. J. Am. Chem. Soc. 2017, 139, 12398.
(68) Stewart, R.; Linden, R. V. The Acidity of Some Aromatic
Fluoro Alcohols and Ketones. Can. J. Chem. 1960, 38, 399.
(69) Moreno-Yruela, C.; Olsen, C. A. Synthesis of Trifluoromethyl
Ketone Containing Amino Acid Building Blocks for the Preparation
of Peptide-Based Histone Deacetylase (HDAC) Inhibitors. Synthesis
(
48) Barltrop, J. A.; Bunce, N. J. Organic photochemistry. Part VIII.
The photochemical reduction of nitro-compounds. J. Chem. Soc. C
968, 1467.
49) Olson, R. E.; Sielecki, T. M.; Wityak, J.; Pinto, D. J.; Batt, D. G.;
1
(
Frietze, W. E.; Liu, J.; Tobin, A. E.; Orwat, M. J.; Di Meo, S. V.;
Houghton, G. C.; Lalka, G. K.; Mousa, S. A.; Racanelli, A. L.;
Hausner, E. A.; Kapil, R. P.; Rabel, S. R.; Thoolen, M. J.; Reilly, T. M.;
Anderson, P. S.; Wexler, R. R. Orally Active Isoxazoline Glycoprotein
IIb/IIIa Antagonists with Extended Duration of Action. J. Med. Chem.
1999, 42, 1178.
2
(
018, 50, 4037.
70) Margolin, Z.; Long, F. A. Acidic Behavior of Chloroform. J. Am.
Chem. Soc. 1973, 95, 2757.
71) Hine, J.; Peek, R. C.; Oakes, B. D. The Kinetics of the Base-
(
50) Quan, M. L.; Ellis, C. D.; Liauw, A. Y.; Alexander, R. S.; Knabb,
R. M.; Lam, G.; Wright, M. R.; Wong, P. C.; Wexler, R. R. Design and
Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2. J. Med.
Chem. 1999, 42, 2760.
(
catalyzed Deuterium Exchange of Chloroform in Aqueous Solution. J.
Am. Chem. Soc. 1954, 76, 827.
(
51) McTier, T. L.; Chubb, N.; Curtis, M. P.; Hedges, L.; Inskeep,
G. A.; Knauer, C. S.; Menon, S.; Mills, B.; Pullins, A.; Zinser, E.;
Woods, D. J.; Meeus, P. Discovery of Sarolaner: A novel, orally
administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.
Vet. Parasitol. 2016, 222, 3.
(
72) Hine, J.; Burske, N. W.; Hine, M.; Langford, P. B. The Relative
Rates of Formation of Carbanions by Haloforms. J. Am. Chem. Soc.
957, 79, 1406.
1
(
52) Shoop, W. L.; Hartline, E. J.; Gould, B. R.; Waddell, M. E.;
McDowell, R. G.; Kinney, J. B.; Lahm, G. P.; Long, J. K.; Xu, M.;
Wagerle, T.; Jones, G. S.; Dietrich, R. F.; Cordova, D.; Schroeder, M.
E.; Rhoades, D.F.; Benner, E. A.; Confalone, P. N. Discovery and
mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.
Vet. Parasitol. 2014, 201, 179.
(
53) Guillena, G.; Ramon, D. J. Enantioselective α-heterofunction-
alisation of carbonyl compounds: organocatalysis is the simplest
approach. Tetrahedron: Asymmetry 2006, 17, 1465.
K
DOI: 10.1021/jacs.9b07241
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX