Synthesis of Benzoxazoles Using Electrochemically Generated Hypervalent Iodine

Article abstract of DOI:10.1021/acs.joc.7b01686

The indirect ("ex-cell") electrochemical synthesis of benzoxazoles from imines using a redox mediator based on the iodine(I)/iodine(III) redox couple is reported. Tethering the redox-active iodophenyl subunit to a tetra-alkylammonium moiety allowed for anodic oxidation to be performed without supporting electrolyte. The mediator salt can be easily recovered and reused. Our "ex-cell" approach toward the electrosynthesis of benzoxazoles is compatible with a range of redox-sensitive functional groups. An unprecedented concerted reductive elimination mechanism for benzoxazole formation is proposed on the basis of control experiments and DFT calculations.

Full text of DOI:10.1021/acs.joc.7b01686

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Featured Article
Synthesis of Benzoxazoles Using
Electrochemically Generated Hypervalent Iodine
Olesja Koleda, Timo Broese, Jan Noetzel, Michael Roemelt, Edgars Suna, and Robert Francke
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01686 • Publication Date (Web): 11 Aug 2017
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Synthesis of Benzoxazoles Using Electrochemically Generated Hypervalent Iodine
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Olesja Koleda,† Timo Broese,‡ Jan Noetzel,§ Michael Roemelt,*§ǁ Edgars Suna*† and Robert Francke*‡
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† Latvian Institute of Organic Synthesis, Aizkraukles 21, LVꢀ1006, Riga, Latvia
‡ Institute of Chemistry, Rostock University, AlbertꢀEinsteinꢀStr. 3a, 18059 Rostock, Germany
§ Lehrstuhl für Theoretische Chemie, RuhrꢀUniversity Bochum, 44780 Bochum, Germany
ǁ
MaxꢀPlanck Institut für Kohlenforschung, KaiserꢀWilhelm Platz 1, 45470, Mülheim an der Ruhr,
Germany
michael.roemelt@theochem.ruhrꢀuniꢀbochum.de, edgars@osi.lv, robert.francke@uniꢀrostock.de
Abstract. The indirect (“exꢀcell”) electrochemical synthesis of benzoxazoles from imines using a redox
mediator based on the iodine(I)/iodine(III) redox couple is reported. Tethering the redox active
iodophenyl subunit to a tetra alkylammonium moiety allowed for anodic oxidation to be performed
without supporting electrolyte. The mediator salt can be easily recovered and reused. Our “exꢀcell”
approach toward the electrosynthesis of benzoxazoles is compatible with a range of redox sensitive
functional groups. An unprecedented concerted reductive elimination mechanism for benzoxazole
formation is proposed on the basis of control experiments and DFT calculations.
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Keywords: electrochemistry, hypervalent iodine, benzoxazole, reaction mechanism, density functional
theory (DFT).
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INTRODUCTION
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Aryliodonium species constitute a versatile and efficient class of reagents with numerous
applications in carbonꢀcarbon and carbonꢀheteroatom crossꢀcoupling reactions,1 in oxidative
rearrangements2 and as terminal oxidants in metalꢀcatalyzed syntheses.3 Stoichiometric amounts of preꢀ
formed aryliodonium reagents are routinely employed in these oxidative transformations, resulting in coꢀ
production of aryl iodide byꢀproduct together with the target molecule. Synthetic approaches relying on
the in situ generation of aryliodonium catalysts from subꢀstoichiometric amounts of iodoarenes and
terminal oxidants such as mꢀCPBA and Oxone have been recently developed to minimize the aryl iodide
byꢀproduct and to reduce loadings of relatively expensive iodine(III) reagents.4,5 Although the overall cost
may be reduced by the catalytic process, terminal oxidants still remain the source of stoichiometric waste.
Electrochemical synthesis provides an attractive solution to the waste reduction, the increase of atom
economy and costꢀefficiency, because inexpensive electric current is employed as the terminal oxidant for
the generation of I(III) reagents from iodoarenes.6,7 Further improvement of atom economy can be
accomplished by recovery and electrochemical reoxidation of the iodoarene species. Surprisingly, there
are only few examples of separation and multiple reuse of the redoxꢀactive iodoarene reagents. This has
been achieved by covalent attachment of iodoarene subunits to task specific ionic liquids8 or to a polymer
support.9 In addition, Francke and Broese have recently demonstrated that merging of the redoxꢀactive
iodoarene subunit with a tetraalkyl ammonium moiety not only facilitated efficient separation and reuse
of the iodoarene reagent, but also allowed for efficient electrochemical generation of I(III) reagent
without added external supporting electrolyte.10 Hence, the ionically tagged phenyl iodide served both as
redox mediator and supporting electrolyte in direct oxidative C–N and C–C bond forming reactions.10 As
a part of our ongoing research on electrochemical synthesis of heterocycles,11 we report herein an
application of the recyclable I(III) mediatorꢀelectrolyte system for electrosynthesis of 2ꢀsubstituted
benzoxazoles.
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Benzoxazole is frequently encountered in biologically active natural products12 and
pharmaceuticals.13 Several marketed drugs such as benoxaprofen, caboxamycin, flunoxaprofen, tafamidis
and pseudopteroxazole possess the benzoxazole subunit. Among a plethora of methods for synthesis of
benzoxazoles,14 electrochemical synthesis is one of the most appealing as it provides excellent atom
economy and sustainability. For instance, benzoxazoles have been recently prepared by direct
electrosynthesis of anilides under galvanostatic mode (eq 1).15 The developed approach is operationally
simple, however the method has been only demonstrated for substrates possessing specific substituents
(F, Cl or MeO) para to aniline nitrogen. Anodic oxidation of 2ꢀphenoxypirimidines followed by chemical
reaction of cyclized cationic intermediate with piperidine provided an access to 2ꢀaminobenzoxazoles (eq
2).16 Unfortunately, this approach features decreased atom economy due to the need of postꢀ
electrochemical functionalization step. Direct electrochemical oxidation of imines is also possible (eq 3),
however, it required addition of LiOMe to facilitate the formation of benzoxazoles.17 The presence of the
strongly basic methoxide decreases the functional group compatibility. Indirect electrosynthesis using
redox mediators such as DDQ18 or sodium iodide19 allows for electrochemical generation of benzoxazole
under considerably milder conditions (eq 3). However, stoichiometric additives such as carbonate buffer
(in NaI mediated reaction) or 2,6ꢀlutidine and supporting electrolyte (in DDQ mediated process) were
necessary to accomplish the indirect electrosynthesis. Furthermore, relatively electron rich imines were
only used in the oxidative cyclization (R=Me, Cl, see eq 3), and nitroꢀsubstituted imines were unreactive.
Herein we report an alternative approach which is based on the electrochemical generation of I(III)
mediator prior to the addition of imine (“exꢀcell” process). Furthermore, the redox active I(III) mediator
possesses a quaternary ammonium moiety, which serves as supporting electrolyte and facilitates
separation and reuse of the redoxꢀactive salt. The developed “exꢀcell” approach does not require any
additives, the oxidative formation of benzoxazoles proceeds under very mild conditions (room
temperature) and the method is compatible with a broad range of functional groups as will be
demonstrated below.20
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RESULTS AND DISCUSSION
Mediator properties. For the electrochemical generation of 2 from iodoarene 1, previously
reported optimized electrolysis parameters were applied (j = 15 mA cmꢀ2, Q = 1 F per mole 1, [1] = 0.2
M, rt).10 Due to its excellent anodic stability and its ability to stabilize iodine(III) species, the choice of
1,1,1,3,3,3ꢀhexafluoroisopropanol (HFIP) as a solvent for electrolysis turned out to be the key to a
successful oxidation of iodoarene 1 to 2 (Figure 1).10 Unfortunately, the exact structure of the
electrochemically prepared I(III) reagent 2 could not be determined because it undergoes decomposition
as soon as HFIP is removed, and all attempts to isolate 2 in a pure form were not successful. The 1Hꢀ
NMR spectrum of HFIP solution of 2 (acquired immediately after electrolysis with added 50 vol %
CH2Cl2–d2) shows signals corresponding to parent aryl iodide 1 (δ 7.95 and 7.67 ppm) together with a
downfieldꢀshifted paraꢀsubstituted aromatic spin system (δ 8.28 and 8.13 ppm; see Figure 1). The
downfield signals were assigned to the aromatic subunit of I(III) reagent 2 based on similarity between 1H
and 13C chemical shift values with those of hypervalent iodonium species 3 and 4, prepared by chemical
methods (Figure 1). Additional indirect support for the electrochemical formation of the I(III) reagent was
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obtained in a control experiment where electrochemically prepared HFIP solution of I(III) reagent 2
effected clean oxidation of hydroquinone to 1,4ꢀbenzoquinone within 15 min at room temperature.
Importantly, I(III) reagent 2 resulting from anodic oxidation of 1 is stable in HFIP solution at room
temperature for several days (entry 1, Table 1). The observed stability of 2 is unusual because hypervalent
I(III) species have been reported to oxidize secondary alcohols to the corresponding ketones.21 In fact,
relatively fast reduction of I(III) reagent 3 to aryl iodide 5 (ca. 40% after 15 min and ca. 65% after 20 h)
with concomitant oxidation of HFIP to hexafluoroacetone (as evidenced by appearance of a signal at –
82.9 ppm in 19F spectrum) was observed at room temperature (eq 1, Figure 1.).
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Figure 1. Indirect anodic oxidation of 1 to 2 in HFIP (15 mA cmꢀ2; WE – glassy carbon; CE – Pt sheet).
Several control experiments were performed to gain a better understanding of the unusual
stability of the electrochemically generated I(III) species 2 and the observed facile decomposition of
structurally related λ
3ꢀiodane 3 in HFIP solution (eq 1, Figure 1). We reasoned that formation of HCl in
the ligand exchange between 3 and HFIP could facilitate reductive elimination of 3 to iodoarene 5 and
hexafluoroacetone (Figure 1, eq 1). Indeed, addition of anhydrous HCl to electrochemically generated 2
resulted in rapid formation of aryl iodide 1 (entry 2, Table 1). The nature of the anion in the acid is more
important than the acidity of the proton, as evidenced by considerably slower conversion of 2 to 1 in the
presence of sulfuric acid (entry 3). Furthermore, addition of excess Bu4NCl (10 equiv) as a chloride
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source triggered the reductive elimination of 2 to 1 under essentially neutral conditions (entry 4).
Importantly, other halide anions were much more efficient (entries 5–7) with iodide effecting the most
rapid decomposition of 2 (entry 7).22 Addition of stoichiometric TEMPO did not affect the iodideꢀ
mediated conversion of 2 to 1 (entry 8), ruling out the reductive decomposition of 2 via a radical chain
process. Finally, stability of the electrochemically generated 2 in the presence of added tertiary amine
base (entry 10) as well as in the presence of a nonꢀnucleophilic hydrogen sulfate additive (entry 9) led us
to propose that nucleophilic reactivity of added halides is responsible for conversion of 2 to 1. Hence, a
plausible mechanism for halide anionꢀfacilitated reductive decomposition of 2 is proposed involving
addition of halide anion X to 2 to form equilibrating isomers of tetra coordinated [12ꢀIꢀ4] iodate 6
(scheme in Table 1).23 Subsequent intramolecular βꢀelimination results in the oxidation of HFIP and
concomitant reduction of I(III) species to iodoarene 1.24 The stability of electrochemically generated
iodonium (III) species 2 apparently is attributed to the lack of nucleophilic ligands in the electrolyte.
Hence, electrosynthesis opens the door for preparation of new hypervalent I(III) species that are difficult
to access using chemical methods such as oxidation or ligands exchange.25
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Table 1. Stability of electrochemically generated I(III) species 2.
entry additive (equiv.)
time
10 days 12b
1, %a
conv. 2, %a
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none
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anhydrous HCl (1.4)
H2SO4 (1.4)
5 min
20c
12c
76c,d
12c
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Bu4NCl (10)
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Bu4NI (10)
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1:1 Bu4NI/TEMPO (1)
Bu4NHSO4 (10)
DIPEA (1)
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24 h
a Determined by 1H–NMR using 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione as internal standard. b Electrochemically generated
solution of 2 was stored at +4 oC. c CH2Cl2 was employed as the internal standard. Inseparable mixture of
d
unidentified sideꢀproducts was also formed.
Benzoxazole synthesis. Next, the electrochemically generated I(III) reagent 2 was employed for
oxidative cyclization of 2ꢀ(benzylideneamino)phenol 7 to benzoxazole 8. The redox couple 1/2 has a
higher oxidation potential (EP(1) = 2.2 V vs. Ag/AgNO3) as compared to that of imine 7 ((EP(7b) = 0.8 V
vs. Ag/AgNO3).26 Therefore, electrochemical generation of redoxꢀmediator 2 in the presence of 7 (an “inꢀ
cell” process) is not possible, because in this scenario the phenolic substrate 7 would be oxidized before
iodoarene 1. Consequently, imine 7 has to be added to the electrolyte after completed anodic conversion
of 1 to 2 (an “exꢀcell” process). Indeed, addition of imine 7a to electrochemically generated
stoichiometric amounts of I(III) mediator 2 afforded 2ꢀphenyl benzoxazole 8a (Figure 2) in 87% yield
(3.3 F/mole of passed charge with regard to the substrate 7a). The I(III)ꢀmediated „exꢀcell“
electrochemical cyclization is compatible with a broad range of functional groups in substrates such as
alkene moiety (7f,g,i), bromine (7b,o,q), nitro group (7c,m,o,p),27a ether moiety (7e,f,p), ester (7n) and
even carboxylic acid (7q). A variety of imines derived from nonꢀenolizable aldehydes such as electronꢀ
rich (7d–g,p) and electronꢀdeficient (7c) aromatic aldehydes, pyridylꢀ2ꢀaldehyde (7h), cinnamaldehyde
(7i) and pivalic aldehyde (7j) are suitable for the I(III)ꢀmediated cyclization (Figure 2). The formation of
benzoxazoles is not sensitive to steric hindrance in the imine moiety because orthoꢀsubstituted imines
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(7c,d,f,g) undergo facile oxidative cyclization (Figure 2).27b It should be noted that simple ester hydrolysis
in benzoxazole 8n leads to the formation of the FDAꢀapproved drug Tafamidis.28 Benzoxazoles 8 can be
also synthesized in a oneꢀpot sequential twoꢀstep process from orthoꢀaminophenol and nonꢀenolizable
aldehyde without isolation of intermediate imine 7. Accordingly, addition of I(III) mediator 2 to the in
situ formed imine 7b,j furnished the corresponding benzoxazoles in high yields (Figure 2). Finally, both
HFIP and 1 can be recovered after completion of the cyclization. After HFIP removal by distillation, the
redoxꢀactive iodoarene 1 possessing the tetraalkyl ammonium moiety can be recovered and purified by
dissolving the solid residue in acetone followed by precipitation upon addition of diethyl ether (typical
recovery yield is 90–95%).
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Figure 2. Scope of substrates.
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a Yield of sequential oneꢀpot twoꢀstep synthesis.
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Mechanistic studies. A series of control experiments have been carried out to elucidate the mechanism of
benzoxazole formation. First, a singleꢀelectron transfer (SET) from relatively electronꢀrich arene 7a–A to
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λ
3ꢀiodane 2 was considered as a possible mechanistic scenario (pathway A, Figure 3).29 The formed
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radical cation intermediate IIa,b would undergo another SET to form nitreniumꢀtype species IVb
affording benzoxazole 8a upon loss of a proton (Figure 3). A radical inhibition test was performed to
examine the possibility of benzoxazole formation via the SET pathway. Accordingly, the reaction of 7a–
A with 2 was performed in the presence of added radical scavengers such as TEMPO30 (1 equiv) or Nꢀ
tertꢀbutylꢀαꢀphenyl nitrone5b (1 equiv). However, neither of the additives influenced the yield of
benzoxazole 8a (87% yield in both cases; see Figure 2).
Figure 3. Plausible pathways for benzoxazole formation.
Next, imine 7g containing an orthoꢀallyl moiety as a radical clock probe was employed to test for
the intermediacy of radical cation species such as II in the synthesis of benzoxazoles (Figure 4). Based on
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the analogy with a previous study on the cyclization of 2ꢀallylbenzyl radicals where a rapid 5ꢀexoꢀtrig
cyclization was reported (rate constant k = 3 × 102 sꢀ1),31 one would expect the formation of 2ꢀmethylꢀ2,3ꢀ
dihydroꢀ1Hꢀindene VI after abstraction of a hydrogen atom from the medium (eq 1, Figure 4). However,
in our hands, benzoxazole 8g was obtained as the major product, and no detectable amounts of the
cyclization product VI were observed (eq 2, Figure 4). These data provide an evidence that the I(III)ꢀ
mediated benzoxazole formation occurs without involvement of benzyl radicals such as IIb (pathway A,
Figure 3).
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Figure 4. Control experiments.
In an alternative possibility, pathway B involves reaction of nucleophilic phenolic oxygen with 2
in a ligandꢀexchange process to form aryloxyꢀλ
3ꢀiodane III. Decomposition of III via oxidation of the
phenol followed by cyclization would afford intermediate IV, which is transformed into benzoxazole 8a
3ꢀiodane III in the benzoxazole
upon loss of a proton (Figure 3). To verify the intermediacy of aryloxyꢀ
λ
formation, substrates 7q and 9 that contain a propionic acid moiety para to the phenolic oxygen were
synthesized (eq 3 and 4, Figure 4). It is wellꢀknown that the tethered carboxylic acid is suitable as a
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nucleophile for intramolecular trapping of phenol oxidation products, derived from fragmentation of
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transient aryloxyꢀλ
3ꢀiodanes.32 Indeed, electrochemically generated I(III) reagent 2 reacted with phenol 9
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to form spirocycle 10 within 3h at rt (eq 3, Figure 4). In sharp contrast, structurally related 7q was
converted to benzoxazole 8q under similar conditions (2 h, rt, 90% yield) and none of the spirocyclization
products could be observed in the reaction mixture (eq 4, Figure 4). Hence, the involvement of aryloxyꢀ
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λ
3ꢀiodane III in the formation of benzoxazoles can be questioned.
As a third option, pathway C involves equilibrium formation of cyclic hemiaminal 7a–B from
imine 7a–A. Cyclic tautomer 7a–B reacts with I(III) species 2 to form a new hypervalent iodine (III)
intermediate V,33 which undergoes reductive elimination of ArꢀI to form 8a. Alternatively, benzoxazole
8a can be formed directly from cyclic hemiaminal 7a–B by a concerted reductive elimination via
transition state TS-1 (Figure 3). Although cyclic hemiaminal 7a–B has not been observed by NMR
methods in a 1:1 HFIPꢀCD2Cl2 solution of imine 7a–B (only signals at δ=8.67 (1H–C=N) and δ=159.1
(13C=N) could be seen), its equilibrium formation cannot be excluded. Furthermore, the cyclic tautomer
7a–B may react with I(III) reagent 2 considerably faster than does imine 7a–A (CurtinꢀHammett
conditions). In fact, such a scenario is in agreement with the observed distinct reactivity of phenols 7q–A
and 9 with I(III) reagent 2 (eq 3 and 4, Figure 4). To verify the involvement of the cyclic tautomer 7a–B
in the benzoxazole formation, structurally related ketimine 11 with tethered carboxylic acid was
synthesized. As anticipated, NMR spectra of ketimine 11 in 1:1 HFIPꢀCD2Cl2 solution only showed the
presence of the cyclic hemiaminal tautomer (evidenced by 13C signal at δ = 98.7, J = 32.2 Hz). Notably,
clean transformation of ketimine 11 to spirocycle 12 (as a 1:1 mixture of diastereomers) was observed
upon addition of I(III) reagent 2 under standard conditions (HFIP, rt, 10 min, 55% yield; see eq 5, Figure
4). Facile formation of spirocycle 12 from the cyclic ketimine 11 and the absence of spirocyclization
products for the nonꢀcyclic aldimine 7q–A renders the pathway C (Figure 3) as the most plausible
mechanism of benzoxazole formation. Further support for pathway C as the most viable mechanistic
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scenario as well as evidence in favor of the concerted reductive elimination (via transition state TS-1) as
opposed to intermediate V in the pathway C were obtained by theoretical investigations as shown below.
Computational studies. The proposed reaction pathways B and C (Figure 3) have been probed by
quantum chemical calculations on a model comprising substrate 7a, iodine reagent 1334 and an additional
solvent molecule (Figure 5). Technical details together with a description of the chosen theoretical
approach are provided in the Experimental Section and the SI. Computed reaction pathway B involved
transfer of a phenolic proton of 7a–A to the HFIP ligand of mediator 13 to induce a ligand substitution at
the I(III) center and formation of intermediate III (Figure 6). The substitution is computed to be
exothermic by 5.6 kcal molꢀ1. Furthermore, the corresponding transition state TS-2 could be identified. It
is associated with a reaction barrier of 7.2 kcal molꢀ1 and its reaction coordinate is dominated by the
proton transfer from the substrate to the HFIP ligand. After the substrate is bound to the I(III) center, a
reductive elimination from the iodine center triggers the ring closure to give intermediate IVa,b. The total
reaction enthalpy for this step accounts to ꢁG = ꢀ7.4 kcal molꢀ1 and is thus thermodynamically feasible.
Unfortunately, despite intense efforts, the optimization of the corresponding transition state did not meet
the convergence criteria. Nevertheless, our thorough search of the potential energy surface yielded a
configuration with a single imaginary harmonic frequency that is associated with a symmetric mode of
the iodineꢀoxygen bonds. Since such a motion eventually leads to the desired minima (as we have verified
by separate relaxed surface scans), we strongly believe that the obtained structure resembles the true
transition state. Thus, the obtained value of ꢁG‡ = 18.0 kcal molꢀ1 corresponding to TS-3 is a reasonable
approximation for the reaction barrier.
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Figure 5. The model system containing iodine(III) species 13, imine 7a and an additional HFIP molecule.
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At this point it should be noted that in order to obtain realistic reaction enthalpies for the
reductive elimination, it is of great importance to explicitly include an additional solvent molecule (see
Figure 5) that acts to stabilize the generated HFIP anion through formation of a strong hydrogen bond.
Another important aspect of the explicit inclusion of a HFIP molecule is that it is required as structural aid
during the ring closure. Without any solvent molecule in the vicinity of the imine group no ring closure is
observed. After the solvent–induced ring annulation, the formed nitrenium cation IV is stabilized by the
adjacent alkoxide ion (Xꢀ). However, this ion pair IVa,b is metastable. When the HFIP anion is manually
placed in the vicinity of the proton in αꢀposition to the nitrenium ion, the proton is abstracted without a
barrier resulting in the final product and a gain of ꢁG = ꢀ41.1 kcal molꢀ1. This manual procedure simulates
a solvent mediated motion of the HFIP anion which we anticipate to readily occur at room temperature.35
Alternatively, provided the concentration of mediator and substrate is sufficiently high, a HFIP anion
from a neighboring reaction center could act as the required base. In both cases the final product is
formed under considerable heat production.
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Figure 6. Summary of the computational results on the proposed pathways B and C (cf. Figure 3). The
structure of transition state TS-1 is inserted as sticks model (with iodine displayed violet, hydrogen white,
carbon grey, oxygen red, nitrogen blue and fluorine green). The black arrows indicate the corresponding
reaction coordinate which is dominated by the proton transfer from the substrate to its adjacent HFIP
anion.
Next, theoretical investigations of the two alternative reaction coordinates (TS-1 vs. intermediate
V) in pathway C were performed (cf. Figure 3). Intermediate V can be formed from imine 7a–A and 13
through tetracoordinated [12ꢀIꢀ4] iodate VII.20a However, stationary points on a potential energy surface
corresponding to intermediate VII could not be found (Figure 6). Alternatively, I(III) reagent 13 may
react with cyclic hemiaminal 7a–B to form iodate VI, which loses a HFIP molecule to afford intermediate
V (cf. Figure 3). The latter pathway involves cyclic hemiaminal 7a–B, a species that could not be
observed by 1HꢀNMR methods (vide supra). Notably, our calculations indicate that the tautomerization of
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imine 7a–A to hemiaminal 7a–B in the presence of I(III) species 13 is favored by 5.7 kcal molꢀ1 (see
Figure 6). As the relative stability is reversed when the Gibbs free energies of 7a-A and 7a-B are
calculated without 13 and an additional HFIP molecule (ꢁG(7a-A/7a-B) = 2.1 kcal molꢀ1) this suggests a
possible stabilization of the cyclic hemiaminal tautomer by I(III) species 13. In the meantime, calculations
did not lead to stationary points on the potential energy surface corresponding to intermediate VI.
Furthermore, intermediate V spontaneously undergoes reductive elimination when optimized with a
solvent molecule in the vicinity of its hemiaminal part. Hence, lack of evidence for the formation of
parent species VI and VII and its own instability puts in question the involvement of the key intermediate
V in the pathway C for benzoxazole formation. Instead, we have found that preꢀcoordination through
hydrogen bonding of N–H in 7a–B with Lewis basic oxygen of the HFIP ligand in 13 triggers a concerted
reductive elimination via TS-1 to form iodoarene and ion pair comprising nitrenium cation IVa,b and a
HFIP anion. The concerted reaction is exergonic with ꢁG = –7.9 kcal molꢀ1 and it has a relatively low
reaction barrier of ꢁG‡ = 7.6 kcal molꢀ1 (TS-1). Transition state TS-1 exhibits elongated I–O bonds (2.69
Å and 2.72 Å), whereas the N–H and O–H bond lengths are 1.18 Å and 1.31 Å, respectively. Hence, it
appears that at this point the reductive elimination is almost completed while the hydride transfer has yet
to take place. Accordingly, the corresponding reaction coordinate is mainly composed of the hydride
transfer movement accompanied by only a minor stretching of the I–O bonds (see stick model for
transition state TS-1 in Figure 6).
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The computed reaction barrier corresponding to transition state TS-1 (ꢁG‡ = 7.6 kcal molꢀ1,
pathway C) is considerably lower in energy as compared to that for TS-3 (ꢁG‡ = 18.0 kcal molꢀ1, pathway
B). Hence, our computational results support the pathway C (Figure 3) as the most plausible mechanism
for the observed oxidative cyclization as it involves only low kinetic barriers and each step is
thermodynamically favorable. Among the two possible scenarios within the pathway C, our results
strongly favor the concerted reductive elimination via transition state TS-1 as the most likely mechanism
for benzoxazole formation.
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CONCLUSIONS
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Anodic oxidation of iodoarenes in HFIP as a solvent allows for convenient preparation of I(III)
species under essentially neutral conditions and at room temperature. The electrochemically generated
9
dialkoxyꢀλ
3ꢀiodane is stable as a solution in HFIP for more than a week at +4o C (12% decomposition
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after 10 days). In the presence of nucleophilic anions such as halides, facile reductive elimination of I(III)
species to the corresponding aryl iodide, hexafluoroacetone and HFIP takes place. Poor compatibility of
dialkoxyꢀλ
3ꢀiodanes with nucleophiles renders anodic oxidation a convenient alternative to the traditional
approaches such as chemical oxidation or ligands exchange reaction for generation of HFIPꢀcontaining
I(III) species. Addition of electrochemically generated I(III) species to orthoꢀimino phenols results in
clean formation of benzoxazoles. The “exꢀcell” electrochemical synthesis of benzoxazoles is compatible
with a broad range of redox sensitive functional groups, including alkene, bromine and carboxylic acid.
Benzoxazoles can be also synthesized in a oneꢀpot sequential twoꢀstep process by addition of
electrochemically generated I(III) oxidant to the in situ formed imines. Our combined experimental and
theoretical approach suggests that oxidative cyclization of orthoꢀimino phenols to benzoxazoles proceeds
through 2,3ꢀdihydrobenzoxazole as the key intermediate. DFT studies of several conceivable pathways
indicate that a sequence via a concerted reductive elimination represents the most plausible mechanistic
scenario for the formation of benzoxazoles.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all chemicals were used as received from commercial
sources and all reactions were performed under nitrogen or argon atmosphere. Anhydrous CH2Cl2 was
obtained by passing commercially available anhydrous solvents through activated alumina columns.
Analytical thinꢀlayer chromatography (TLC) was performed on preꢀcoated silica gel Fꢀ254 plates.
Nuclear magnetic resonance spectra were recorded on NMR spectrometers at the following frequencies:
1H, 400 or 300 MHz; 13C{1H}, 100.6, 75 or 63 MHz; 19F, 376.3 MHz. Chemical shifts are reported in
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parts per million (ppm) relative to TMS or with the residual solvent peak as an internal reference. Highꢀ
resolution mass spectra (HRMS) were recorded on a mass spectrometer with a timeꢀofꢀflight (TOF) mass
analyzer using the ESI technique. Electrolysis was performed under galvanostatic control in an undivided
cell. Glassy carbon (SIGRADUR Gꢀplate, 10x50x5 mm) served as a working electrode; a Pt sheet
(10x50x0.1 mm) served as a counter electrode.
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Cyclic voltammetry. The experiments were carried out in a threeꢀelectrode cell using a glassy carbon
disc (diameter: 3 mm) as a working electrode and a platinum wire as a counter electrode. The glassy
carbon disc was polished using polishing alumina (0.05 µm) prior to each experiment. Ag/AgNO3
electrode (silver wire in 0.1 M NBu4ClO4/CH3CN solution; c(AgNO3) = 0.01 M) was used as a reference
and this compartment was separated from the rest of the cell with a Vycor frit. 0.1 M solution of
NBu4ClO4 (Electrochemical grade) in HFIP was used as electrolyte. The electrolyte was purged with
argon for at least five minutes prior to recording the CVs.
N-[4-(4-Iodophenyl)-4-oxobutyl]-N,N,N-trimethylammonium perchlorate (1) was synthesized in
three steps from iodobenzene and 4ꢀchlorobutanoyl chloride according to the procedure reported in the
literature.10 1HꢀNMR data are identical to those reported in the literature. 1H NMR (400 MHz, DMSO,
ppm) δ 7.96 – 7.94 (m, 2H), 7.75 – 7.72 (m, 2H), 3.33 – 3.29 (m, 2H), 3.12 (t, J = 6.8 Hz, 2H), 3.08 (s,
9H), 2.08 – 1.99 (m, 2H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 198.0, 137.7, 135.6, 129.6, 102.0,
64.7, 52.2, 34.4, 16.8. Anal. Calcd for C13H19ClINO5: C, 36.17; H, 4.44; N, 3.24. Found: C, 36.25; H,
4.38; N, 3.21.
Procedure for the Electrochemical Generation of I(III) Reagent 2. The electrolysis in an undivided
cell was performed following the procedure reported in literature.10 A glassy carbon piece (immersed
surface area: A = 1 cm2) served as a working electrode, a platinum sheet – as a counter electrode. The
experiment was carried out as follows: aryl iodide 1 (864 mg, 2 mmol) was dissolved in 1,1,1,3,3,3ꢀ
hexafluoroisopropanol (HFIP, 10 mL) and molecular sieves (4Å, 2.0 g) were added. After purging the cell
with argon, the clear solution was electrolyzed with a current density of 15 mA/cm2 until charge 1 F per
mol of 1 was passed. Upon completion of the electrolysis, an aliquot (0.3 mL) from the lightꢀyellow
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electrolysis solution was diluted with CD2Cl2 (0.3 mL). 1H NMR analysis of the aliquot helped to
determine the Faraday efficiency of 67% for the electrolysis. Accordingly, the concentration of the
electrolysis solution was 0.67 M in 2. 1H NMR (400 MHz, CD2Cl2, ppm) δ 8.32 – 8.29 (m, 2H), 8.16 –
8.13 (m, 2H), 4.39 (septet, J = 5.9 Hz, 2H), 3.40 – 3.32 (m, 2H, the signal overlaps with those of 1), 3.29
(t, J = 6.4 Hz, 2H), 3.17 (s, 9H), 2.31 – 2.19 (m, 2H, the signal overlaps with those of 1). 13C{1H} NMR
(100.6 MHz, CD2Cl2, ppm) δ 200.4, 140.0, 153.3, 132.0, 104.0 (the signal overlaps with those of 1), 67.9,
54.7 (the signal overlaps with those of 1), 35.5, 18.2. 19F NMR (376.3 MHz, CD2Cl2) δ –75.07 (d, J = 5.8
Hz).
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1-(4-(Dichloro-λ
3-iodanyl)phenyl)ethan-1-one (3) was synthesized according to the literature
procedure.36 Thus, 4’ꢀiodoacetophenone (492 mg, 1 mmol) was dissolved in MeCN (4 mL) and aqueous
5.84% NaOCl solution (12 mL) was added, followed by the slow addition of aqueous concentrated HCl
(4 mL). Light yellow precipitate was formed. After 20 min at room temperature the precipitate was
filtered off and washed with H2O and hexanes. Drying at room temperature overnight in the dark afforded
the title compound 3 as a light yellow solid (620 mg, 98% yield). Pure material was obtained by
recrystallization from hexanes/CH2Cl2, mp 76.5 – 75.5 oC (decomp.). 1H NMR (400 MHz, CD2Cl2, ppm)
δ 8.33 – 8.30 (m, 2H), 8.03 – 7.99 (m, 2H), 2.63 (s, 3H). 13C{1H} NMR (100.6 MHz, CD2Cl2, ppm) δ
196.7, 140.2, 134.6, 131.5. 129.5, 27.2. HRMS (ESIꢀTOF) m/z: [M]+ Calcd for C8H7ClIO+ 280.9230;
Found 280.9234.
(4-Acetylphenyl)(hydroxy)-λ
3-iodanyl 4-methylbenzenesulfonate (4). To a stirred solution of 4’ꢀ
iodoacetophenone (49 mg, 0.2 mmol) in 1:1 CH2Cl2/TFE (2 mL) was added mCPBA (49 mg, 0.2 mmol),
followed with TsOH*H2O (38 mg, 0.2 mmol). The resulting yellow solution was stirred at room
temperature for 1 hour and then concentrated under a stream of air. Et2O (4 mL) was added to the
remaining residue and the resulting precipitate was filtered off to afford iodane 4 as an offꢀwhite solid (62
mg, 71%). Pure material was obtained after precipitation from a mixture of MeOH/CH2Cl2/hexanes. 1H
NMR (400 MHz, DMSOꢀd6, ppm) δ 8.32ꢀ 8.29 (m, 2H), 8.11 – 8.09 (m, 2H), 7.49 – 7.47 (m, 2H), 7.13 –
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7.11 (m, 2H), 2.63 (s, 3H), 2.28 (s, 3H). 13C{1H} NMR (100.6 MHz, DMSOꢀd6, ppm) δ 197.5, 145.4,
139.2, 137.9, 134.4, 130.5, 128.2, 127.7, 125.6, 27.1, 20.9. Anal. Calcd for C15H15IO5S: C, 41.49; H, 3.48.
Found: C, 41.54; H, 3.49.
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General Procedure A for the Synthesis of Imines 7a–q.37 Benzaldehyde (2 mmol, 1.0 equiv.) was
added to a mixture of orthoꢀaminophenol (2 mmol, 1.0 equiv), anhydrous Na2SO4 (3 equiv), and
anhydrous CH2Cl2 (5 mL) under argon atmosphere. The suspension was stirred at room temperature for
16 h whereupon Na2SO4 was removed by filtration. The filtrate was concentrated under reduced pressure
and the crude solid residue was recrystallized from EtOH to afford the corresponding imine.
General Procedure B for the Synthesis of Imines 7a–q.37 A mixture of orthoꢀaminophenol (2 mmol,
1.0 equiv.) and aldehyde (2 mmol, 1.0 equiv.) was stirred under reflux in anhydrous EtOH (4 mL) for 4
hours. After cooling to room temperature and concentration under reduced pressure, the crude solid
residue was recrystallized from EtOH to afford the corresponding imine.
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General Procedure C for the Synthesis of Imines 7a–q.38 A mixture of
orthoꢀaminophenol (2 mmol, 1.0 equiv.) and aldehyde (2.4 mmol, 1.2 equiv.) was stirred at 70 oC in
anhydrous MeOH (4 mL) in the presence of molecular sieves 4Å (1.5 g) for 20 hours. After being cooled
to ambient temperature the reaction mixture was filtered to remove the molecular sieves, and the filtrate
was concentrated under reduced pressure. The crude product was recrystallized from MeOH, EtOH or a
mixture of MeOH/CH2Cl2/hexanes to yield the corresponding imine.
(E)-2-(Benzylideneamino)phenol (7a) was obtained as a light yellow amorphous solid (319 mg, 81%)
according to general procedure A. 1HꢀNMR spectral data are identical to those reported in the literature.39
1H NMR (300 MHz, CDCl3, ppm) δ 8.71 (s, 1H), 7.97 – 7.92 (m, 2H), 7.54 – 7.49 (m, 3H), 7.33 (dd, J =
7.9, 1.5 Hz, 1H), 7.29 (br s, 1H), 7.25 – 7.20 (m, 1H), 7.05 (dd, J = 8.1, 1.1 Hz, 1H), 6.96 – 6.91 (m, 1H).
13C{1H} NMR (75 MHz, CDCl3, ppm) δ 157.1, 152.3, 135.8, 135.5, 131.7, 128.9, 128.8, 128.7, 120.1,
115.82, 115.0.
(E)-2-(4-Bromobenzylideneamino)phenol (7b) was obtained as a yellow solid (447 mg, 81%) according
to general procedure A. Pure material was obtained by recrystallization from EtOH, mp 127–128 oC. IR
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(film, cm–1) 3312 (O–H), 1626 (C=N). 1H NMR (400 MHz, CD2Cl2, ppm) δ 8.68 (s, 1H), 7.85 – 7.801
(m, 2H), 7.67 – 7.62 (m, 2H), 7.34 (dd, J = 8.0, 1.4 Hz, 1H), 7.26 – 7.15 (m, 2H), 6.99 (dd, J = 8.1, 1.4
Hz, 1H), 6.92 (td, J = 7.7, 1.4 Hz, 1H). 13C{1H}NMR (100.6 MHz, CDCl3, ppm) δ 155.7, 152.5, 135.2,
134.9, 132.3, 130.2, 129.4, 126.4, 120.3, 115.9, 115.3. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C13H11BrNO 276.0024; Found 276.0032.
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(E)-2-(2-Nitrobenzylideneamino)phenol (7c) was obtained as a yellow solid (391 mg, 54%) according
to general procedure B from orthoꢀaminophenol (3 mmol) and 2ꢀnitrobenzaldehyde (3 mmol). 1HꢀNMR
spectral data are identical to those reported in the literature.40 1H NMR (300 MHz, CDCl3, ppm) δ 9.18 (s,
1H), 8.28 (dd, J = 7.7, 1.5 Hz, 1H), 8.08 (dd, J = 8.2, 1.2 Hz, 1H), 7.79 – 7.74 (m, 1H), 7.68 – 7.62 (m,
1H), 7.37 (dd, J = 7.9, 1.5 Hz, 1H), 7.30 – 7.24 (m, 1H), 7.15 (s, 1H), 7.05 (dd, J = 8.1, 1.3 Hz, 1H), 6.97
– 6.92 (m, 1H). 13C{1H} NMR (63 MHz, CDCl3, ppm) δ 152.8, 152.0, 149.4, 134.7, 133.4, 131.4, 130.5,
130.2, 129.5, 124.7, 120.4, 116.4, 115.5.
(E)-2-((2,4,6-Trimethylbenzylidene)amino)phenol (7d) was obtained as a brown amorphous solid (84
mg, 70%) according to general procedure C from orthoꢀaminophenol (0.5 mmol) and 2,4,6ꢀ
trimethylbenzaldehyde (0.5 mmol). 1HꢀNMR spectral data are identical to those reported in the
literature.38 1H NMR (400 MHz, CDCl3, ppm) δ 9.09 (s, 1H), 7.28 – 7.26 (m, 1H), 7.23 – 7.19 (m, 1H),
7.05 – 7.03 (m, 1H), 6.97 (s, 2H), 6.97 – 6.92 (m, 1H), 2.58 (s, 6H), 2.35 (s, 3H). 13C{1H} NMR (100.6
MHz, CDCl3, ppm) δ 157.9, 152.2, 140.6, 139.2, 137.0, 130.3, 130.1, 128.7, 120.2, 115.6, 114.9, 21.7,
21.4.
(E)-2-(4-Methoxybenzylideneamino)phenol (7e) was obtained as a yellow amorphous solid (186 mg,
41%) according to general procedure A. 1H NMR spectral data are identical to those reported in the
literature.41 1H NMR (300 MHz, CDCl3, ppm) δ 8.63 (s, 1H), 7.91 – 7.86 (m, 2H), 7.30 – 7.27 (m, 1H),
7.21 – 7.15 (m, 1H), 7.03 – 6.99 (m, 3H), 6.94 – 6.88 (m, 1H), 3.90 (s, 3H). 13C{1H} NMR (63 MHz,
CDCl3, ppm) δ 162.5, 156.6, 152.0, 135.9, 130.6, 128.9, 128.3, 120.0, 115.7, 114.8, 114.3, 44.5.
(E)-2-((2-(Allyloxy)benzylidene)amino)phenol (7f) was obtained as a dark brown oil (493 mg, 99%
yield) according to general procedure C. IR (film, cm−1) 3412 (O–H), 1594 (C=N). 1H NMR (400 MHz,
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CDCl3, ppm) δ 9.22 (s, 1H), 8.17 (dd, J = 7.7, 1.8 Hz, 1H), 7.44 (m, 1H), 7.32 (dd, J = 7.9, 1.5 Hz, 1H),
7.14 (td, J = 7.8, 1.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.02 (dd, J = 8.1, 1.4 Hz, 1H), 6.96 (d, J = 8.4 Hz,
1H), 6.91 (td, J = 7.7, 1.4 Hz, 1H), 6.16 – 6.06 (m, 1H), 5.46 (dd, J = 17.2, 1.6 Hz, 1H), 5.35 (dd, J =
10.5, 1.5 Hz, 1H), 4.66 (d, J = 5.2 Hz, 2H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 158.8, 153.3,
152.4, 136.4, 133.0, 132.9, 128.7, 127.6, 124.8, 121.2, 120.2, 118.1, 116.2, 114.9, 112.7, 69.4. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C16H16NO2 254.1181; Found 254.1180.
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(E)-2-((2-Allylbenzylidene)amino)phenol (7g) was obtained as a brown oil (260 mg, 90%) according to
general procedure C from orthoꢀaminophenol (1.5 mmol) and 2ꢀallylbenzaldehyde42 (1.2 mmol). IR (film,
cm−1) 3412 (O – H), 1587 (C=N). 1H NMR (400 MHz, CDCl3, ppm) δ 8.96 (s, 1H), 8.12 (dd, J = 7.7, 1.5
Hz, 1H), 7.44 (td, J = 7.4, 1.5 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.29 – 7.23 (m, 2H), 7.22 – 7.18 (m, 1H),
7.02 (dd, J = 8.1, 1.3 Hz, 1H), 6.93 – 6.89 (m, 1H), 6.08 (ddt, J = 17.1, 10.2, 5.8 Hz, 1H), 5.17 – 5.11 (m,
1H), 5.02 – 4.94 (m, 1H), 3.75 (d, J = 5.8 Hz, 2H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 156.0.
152.5, 1410.4, 137.3, 136.3, 133.9, 131.6, 131.0, 129.0, 128.5, 127.1. 120.2, 116.6, 116.0, 115.1, 37.4.
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H16NO 238.1232; Found 238.1236.
(E)-2-((Pyridin-2-yl)methyleneamino)phenol (7h) was obtained as a green solid (282 mg, 47%)
according to general procedure B from 2ꢀpyridinecarboxaldehyde (3 mmol) and orthoꢀaminophenol (3
mmol). Pure material was obtained by recrystallization from hexanes/CH2Cl2, mp 104–105 oC. IR (film,
cmꢀ1) 3362 (O–H), 1588 (HC=N). 1H NMR (300 MHz, acetoneꢀd6, ppm) δ 8.82 (s, 1H), 8.70 (dd, J = 4.8,
0.8 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.91 (td, J = 7.5, 1.2 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.28 – 7.4 (m,
1H), 6.98 – 6.89 (m, 2H). 13C{1H} NMR (100.6 MHz, acetoneꢀd6, ppm) δ 159.3, 155.7, 153.7, 150.5,
137.4, 136.6, 130.1, 126.1, 122.4, 120.8, 118.2, 116.6. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C12H11N2O 198.0788; Found 198.0782.
(2E)-2-((E)-3-Phenylallylideneamino)phenol (7i) was obtained as a light yellow solid (112 mg, 25%)
according to general procedure A. 1HꢀNMR spectral data are identical to those reported in the literature.43
1H NMR (300 MHz, CDCl3, ppm) δ 8.51 (d, J = 7.7 Hz, 1H), 7.59 – 7.55 (m, 2H), 7.47 – 7.38 (m, 3H),
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7.27 – 7.16 (m, 4H), 7.01 (dd, J = 8.1, 1.1 Hz, 1H), 6.92 – 6.87 (m, 1H). 13C{1H} NMR (63 MHz, CDCl3,
ppm) δ 158.2, 152.3, 144.2, 135.6, 135.5, 129.8, 129.0, 128.9, 128.5, 127.6, 120.0, 115.5, 115.0.
(E)-2-(Benzylideneamino)-5-methylphenol (7k) was obtained as a yellow solid (413 mg, 98%)
according to general procedure B. Pure material was obtained by recrystallization from EtOH, mp 94–
96 oC. IR (film, cm−1) 3332 (O–H), 1580 (C=N). 1H NMR (300 MHz, CDCl3, ppm) δ 8.70 (s, 1H), 7.94 –
7.90 (m, 2H), 7.52 – 7.47 (m, 3H), 7.28 (br s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.86 (m, 1H), 6.75 – 6.72 (m,
1H), 2.35 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, ppm) δ 155.7, 152.3, 139.4, 136.0, 132.9, 131.4,
128.8, 128.6, 120.8, 115.5, 115.4, 21.5. HRMS (ESIꢀTOF) m/z: [M]+ Calcd for C14H13NO 211.0992;
Found 211.0984.
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(E)-2-(Benzylideneamino)-4-methylphenol (7l) was obtained as a light yellow amorphous solid (17 mg,
4%) according to general procedure B. 1HꢀNMR spectral data are identical to those reported in the
literature.44 1H NMR (300 MHz, CDCl3 ppm) δ 8.70 (s, 1H), 7.95 – 7.91 (m, 2H), 7.53 – 7.48 (m, 3H),
7.14 – 7.13 (m, 1H), 7.09 (br s, 1H), 7.05 – 7.01 (m, 1H), 6.94 – 6.91 (m, 1H), 2.34 (s, 3H). 13C{1H}
NMR (63 MHz, CDCl3, ppm) δ 156.7, 150.1, 135.9, 135.1, 131.6, 129.5, 128.8, 128.7, 116.3, 114.6, 20.8.
(E)-2-(Benzylideneamino)-5-nitrophenol (7m) was obtained as a yellow amorphous solid (353 mg,
55%) according to general procedure C. The pure product was obtained after precipitating from a mixture
of MeOH/DCM/hexanes. 1H NMR (400 MHz, acetoneꢀd6, ppm) δ 8.88 (s, 1H), 8.11 – 8.08 (m, 2H), 7.80
(dd, J = 8.7, 2.5 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.62 – 7.53 (m, 3H), 7.49 (d, J = 8.6 Hz, 1H). 13C{1H}
NMR (100.6 MHz, acetoneꢀd6, ppm) δ 163.9, 152.9, 147.7, 144.8, 136.8, 133.2, 130.5, 129.7, 119.5,
116.2, 111.3. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C13H11N2O3 243.0770; Found 243.0765.
(E)-Methyl 4-(3,5-dichlorobenzylideneamino)-3-hydroxybenzoate (7n) was obtained as a yellow solid
(486 mg, 75%) according to general procedure A. Pure material was obtained by recrystallization from
EtOH, mp 207 – 208 oC. IR (film, cm−1) 3394 (O–H), 1714 (C=O), 1562 (C=N). 1H NMR (300 MHz,
DMSO, ppm) δ 8.73 (s, 1H), 8.09 (d, J = 2.1 Hz, 2H), 7.79 (t, J = 2.0 Hz, 1H), 7.47 (s, 1H), 7.46 (dd, J =
6.0, 1.9 Hz, 1H), 7.29 – 7.26 (m, 1H), 3.83 (s, 3H). 13C{1H} NMR (63 MHz, DMSO, ppm) δ 165.9,
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158.9, 151.0, 141.5, 139.3, 134.6, 130.7, 128.7, 127.4, 120.6, 119.7, 116.8, 52.1. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C15H12Cl2NO3 324.0194; Found 324.0190.
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(E)-2-((4-Bromobenzylidene)amino)-4-nitrophenol (7o) was obtained as a yellow amorphous solid
(238 mg, 37%) according to general procedure C. Pure product was obtained after precipitating from a
mixture of MeOH/DCM. 1H NMR (400 MHz, CDCl3, ppm) δ 8.69 (s, 1H), 7.86 – 7.81 (m, 4H), 7.67 (d, J
= 8.4 Hz, 2H), 7.34 (d, J = 8.7 Hz, 1H), 7.17 (s, 1H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 160.4,
152.2, 147.7, 141.2, 134.0, 132.6, 130.8, 128.0, 116.6, 116.1, 110.8. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C13H10BrN2O3 320.9875; Found 320.9867.
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(E)-4-Nitro-2-((3,4,5-trimethoxybenzylidene)amino)phenol (7p) was obtained as a yellow solid (215
mg, 72%) according to general procedure C from 2ꢀaminoꢀ4ꢀnitrophenol (0.9 mmol) and 3,4,5ꢀ
trimethoxybenzaldehyde (0.9 mmol). Pure material was obtained by recrystallization from CH2Cl2, mp
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187–188 oC. IR (film, cm−1) 3349 (O–H), 1581 (C=N), 1462 (NO2). H NMR (400 MHz, CDCl3, ppm) δ
8.70 (s, 1H), 8.22 (d, J = 2.6 Hz, 1H), 8.14 (dd, J = 9.0, 2.6 Hz, 1H), 7.19 (s, 2H), 7.10 (d, J = 8.9 Hz,
1H), 3.97 (s, 6H), 3.96 (s, 3H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 160.4, 157.7, 153.8, 142.5,
141.4, 135.9, 130.3, 124.5, 115.1, 112.3, 106.6, 61.2, 56.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H17N2O6 333.1087; Found 333.1091.
3-(3-Amino-4-hydroxyphenyl)propanoic acid (14). To a solution of 3ꢀ(4ꢀhydroxyꢀ3ꢀ
nitrophenyl)propanoic acid (815 mg, 3.86 mmol) in abs. EtOH (50 mL) was added 10% Pd–C (402 mg,
10 mol %). and H2 gas was passed through the resulting suspension at room temperature for 2 hours.
Progress of the hydrogenation was followed by UPLCꢀMS analysis. Once the reaction is completed, it
was filtered through a plug of Celite. The filtrate was concentrated to obtain the product as pale green
foam (636 mg, 91%) that was used in the next step without additional purification. IR (film, cmꢀ1) 3370,
3335 (N–H), 2934 (O–H). 1H NMR (400 MHz, CD3OD, ppm) δ 6.64 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 8.0
Hz, 1H), 6.47 (dd, J = 8.0, 2.2 Hz, 1H), 2.74 (t, J = 7.8 Hz, 2H), 2.50 (t, J = 7.8 Hz, 1H). 13C{1H} NMR
(100.6 MHz, CD3OD, ppm) δ 177.6, 145.0, 135.4, 133.8, 120.2, 117.7, 115.6, 37.6, 31.7. HRMS(ESIꢀ
TOF) m/z: [M+H]+ Calcd for C9H12NO3 182.0817; Found 182.0817.
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(E)-3-(3-((4-Bromobenzylidene)amino)-4-hydroxyphenyl)propanoic acid (7q) was obtained as a
brown amorphous solid (106 mg, 25%) according to general procedure C from 3ꢀ(3ꢀaminoꢀ4ꢀ
hydroxyphenyl)propanoic acid (14; see above) (1.2 mmol) and 4ꢀbromobenzaldehyde (1.5 mmol);
product 7q was used in the next step without additional purification because of its instability. IR (film,
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cm−1) 3409 (O–H), 1699 (C=O), 1586 (C=N). H NMR (300 MHz, CD3OD, ppm) δ 8.67 (s, 1H), 7.92 –
7.89 (m, 2H), 7.65 – 7.63 (m, 2H), 7.13 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.2, 1.9 Hz, 1H), 6.81 (d, J =
8.2 Hz, 1H), 2.86 (t, J = 7.7 Hz, 2H), 2.52 (t, J = 7.7 Hz, 2H). 13C{1H} NMR (100.6 MHz, CD3OD, ppm)
δ 176.9, 159.2, 151.2, 138.3, 136.9, 133.9, 133.0, 131.5, 129.1, 126.6, 119.1, 116.7, 37.1, 31.4. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C16H15BrNO3 348.0235; Found 348.0237
General Procedure D for the Synthesis of Substituted Benzoxazoles from Imines. A solution of
electrochemically prepared I(III) oxidant 2 (67 mM in HFIP) was added under argon to a solution of
imine (0.3 mmol) in HFIP (0.5 mL). The resulting solution was stirred at room temperature until complete
conversion of 7 (usually 10 min) and the progress of the reaction was monitored by GCꢀMS and 1H NMR.
Diethylether (50 mL) was then added and the resulting suspension was kept at +4 °C for 15 minutes. The
formed precipitate (iodoarene 1) was removed by filtration and washed with Et2O. Drying under air
allowed for 92ꢀ94% recovery of mediator 1. The combined filtrates were concentrated under reduced
pressure and the residue was purified by column chromatography on silica gel to yield the corresponding
substituted benzoxazole.
General Procedure E for One-pot Two-step Synthesis of Substituted Benzoxazoles from the
Aldehyde and Aniline. A light brown solution of orthoꢀaminophenol (0.4 mmol, 1 equiv) and aldehyde
(0.48 mmol, 1.2 equiv) in CHCl3 (2 mL; for benzoxazole 8j) or in HFIP (2mL; for benzoxazole 8b) was
stirred at room temperature for 6 hours. Then freshly prepared I(III) reagent 2 (67 mM solution in HFIP)
was added under argon atmosphere and stirring at room temperature was continued for 30 minutes.
Addition of diethylether (50 mL) afforded a suspension that was cooled at +4 °C for 15 minutes. The
formed sandꢀcolored precipitate (iodoarene 1) was removed by filtration. The filter cake was washed with
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Et2O and dried under air. The filtrate was concentrated and the residue was purified by column
chromatography on silica gel to yield the corresponding benzoxazole.
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2-Phenylbenzo[d]oxazole (8a) was obtained as a white solid (51 mg, 87%) according to general
procedure D. The crude product was purified by column chromatography on silica gel using gradient
elution from 0% EtOAc in heptane to 9% EtOAc in heptane. Analytical TLC on silica gel, 1:9
EtOAc/heptane, Rf = 0.4. Pure material was obtained by recrystallization from heptane, mp 105.5 – 106.5
oC. 1HꢀNMR spectral data are identical to those reported in the literature.37 1H NMR (300 MHz, CDCl3,
ppm) δ 8.31 – 8.25 (m, 2H), 7.82 – 7.77 (m, 1H), 7.62 – 7.58 (m, 1H), 7.57 – 7.52 (m, 3H), 7.40 – 7.34
(m, 2H). 13C{1H} NMR (75 MHz, CDCl3, ppm) δ 163.0, 150.7, 142.1, 131.5, 128.9, 127.6, 127.1, 125.1,
124.5, 120.0, 110.5. GCꢀMS (EI) m/z: [M]+ found for C13H9NO 195.38.
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2-(4-Bromophenyl)benzo[d]oxazole (8b) was obtained as a white solid (71 mg, 87%) according to
general procedure D. The crude product was purified by column chromatography on silica gel using
gradient elution from 0% EtOAc in heptane to 9% EtOAc in heptane. Analytical TLC on silica gel, 1:9
EtOAc/heptane, Rf = 0.45. Pure material was obtained by recrystallization from heptane, mp 158.5 –
159.5 oC. 1HꢀNMR spectral data are identical to those reported in literature.37 1H NMR (300 MHz, CDCl3,
ppm) δ 8.14 – 8.10 (m, 2H), 7.80 – 7.74 (m, 1H), 7.69 – 7.64 (m, 2H), 7.61 – 7.55 (m, 1H), 7.40 – 7.34
(m, 2H). 13C{1H} NMR (63 MHz, CDCl3, ppm) δ 162.1, 150.7, 142.0, 132.2, 129.0, 126.2, 126.1, 125.4,
124.8, 120.1, 110.6. GCꢀMS (EI) m/z: [M]+ found for C13H8BrNO 273.44.
Use of general procedure E afforded benzoxazole 8b in 81% yield (66 mg).
2-(2-Nitrophenyl)benzo[d]oxazole (8c) was obtained as pale yellow solid (64 mg, 89%) according to
general procedure D. The crude product was purified by column chromatography on silica gel using
gradient elution from 0% EtOAc in heptane to 33% EtOAc in heptane. Analytical TLC on silica gel, 1:9
EtOAc/heptane, Rf = 0.1. Pure material was obtained by recrystallization from heptane, mp 104.5 – 105.5
oC. 1HꢀNMR spectral data are identical to those reported in literature.45 1H NMR (300 MHz, CDCl3, ppm)
δ 8.17 – 8.14 (m, 1H), 7.92 – 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.85 – 7.79 (m, 1H), 7.78 – 7.67 (m, 2H),
7.62 – 7.55 (m, 1H), 7.45 – 7.37 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, ppm) δ 158.8, 151.0, 141.5,
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132.3, 131.8, 131.4, 126.0, 124.9, 124.2, 121.5, 120.7, 110.9. GCꢀMS (EI) m/z: [M]+ found for
C13H8N2O3 240.38.
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2-Mesitylbenzo[d]oxazole (8d) was obtained as a yellow thick oil (56 mg, 79%) according to general
procedure D. The crude product was purified by column chromatography on silica gel using gradient
elution from 3% EtOAc in hexanes to 15% EtOAC in hexanes. Analytical TLC on silica gel, 1:10
EtOAc/hexanes, Rf = 0.48. 1HꢀNMR spectral data are identical to those reported in literature.37 1H NMR
(400 MHz, CDCl3, ppm) δ 7.86 – 7.79 (m, 1H), 7.62 – 7.56 (m, 1H), 7.41–7.35 (m, 2H), 6.98 (s, 2H),
2.36 (s, 3H), 2.29 (s, 6H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 163.4, 150.8, 141.7, 140.4, 138.6,
128.8, 125.1, 125.0, 124.3, 120.3, 110.7, 21.4, 20.5. UPLCꢀMS (ESI) m/z: [M+H]+ found for C16H16NO
238.29.
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2-(4-Methoxyphenyl)benzo[d]oxazole (8e) was obtained as light brown solid (51 mg, 75%) according to
general procedure D. The crude product was purified by column chromatography on silica gel using
gradient elution from 0% EtOAc in heptane to 33% EtOAc in heptane. Analytical TLC on silica gel, 1:9
EtOAc/heptane, Rf = 0.2. Pure material was obtained by recrystallization from heptane, mp 99–100 oC.
1HꢀNMR spectral data are identical to those reported in literature.37 1H NMR (300 MHz, CDCl3, ppm) δ
8.23 – 8.18 (m, 2H), 7.78 – 7.72 (m, 1H), 7.59 – 7.53 (m, 1H), 7.37 – 7.29 (m, 2H), 7.06 – 7.01 (m, 2H),
3.90 (s, 3H). 13C{1H} NMR (63 MHz, CDCl3, ppm) δ 163.2, 162.3, 150.7, 142.3, 129.4, 124.6, 124.4,
119.7, 119.6, 114.3, 110.4, 55.4. GCꢀMS (EI) m/z: [M]+ found for C14H11NO2 225.44.
2-(2-(Allyloxy)phenyl)benzo[d]oxazole (8f) was obtained as a light orange amorphous solid (33 mg,
46%) according to general procedure D. The crude product was purified by column chromatography on
silica gel using gradient elution from 3% EtOAc in hexanes to 10% EtOAc in hexanes. Analytical TLC on
silica gel, 1:4 EtOAc/hexanes, Rf = 0.55. 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (dd, J = 7.7, 1.8 Hz,
1H), 7.83 – 7.79 (m, 1H), 7.61 – 7.57 (m, 1H), 7.48 – 7.44 (m,1H), 7.40 – 7.30 (m, 2H), 7.11 – 7.03 (m,
2H), 6.15 – 6.06 (m, 1H), 5.64 (dq, J = 17.3, 1.8 Hz, 1H), 5.33 (dq, J = 10.7, 1.6 Hz, 1H), 4.75 (dt, J =
4.7, 1.8 Hz, 2H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 162.1, 157.6, 150.7, 142.1, 132.9, 132.7,
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131.6, 125.0, 124.4, 121.1, 120.2, 117.4, 116.9, 113.8, 110.6, 69.7. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C16H14NO2 252.1025; Found 252.1029.
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general procedure D. The crude product was purified by column chromatography on silica gel using
isocratic elution with 2% EtOAc in hexanes. Analytical TLC on silica gel, 1:10 EtOAc/hexanes, Rf =
0.58. 1H NMR (400 MHz, CDCl3, ppm) δ 8.18 – 8.15 (m, 1H), 7.83 – 7.79 (m, 1H), 7.62 – 7.58 (m, 1H),
7.49 – 7.45 (m, 1H), 7.41 – 7.35 (m, 4H), 6.14 – 6.04 (m, 1H), 5.11 – 5.04 (m, 2H), 4.05 (d, J = 6.6 Hz,
1H). 13C{1H} NMR (100.6 MHz, CDCl3, ppm) δ 163.1, 150.5, 142.2, 140.8, 137.3, 131.2, 131.1, 130.4,
126.6, 126.2, 125.2, 124.5, 120.3, 116.0, 110.6, 38.6. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H14NO 236.1075; Found 236.1074.
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2-(Pyridin-2-yl)benzo[d]oxazole (8h) was obtained as an offꢀwhite solid (56 mg, 95%) according to
general procedure D. The crude product was purified by column chromatography on silica gel using
gradient elution from 0% EtOAc in heptane to 33% EtOAc in heptane. Analytical TLC on silica gel, 1:4
EtOAc/ heptane, Rf=0.15. Pure material was obtained by recrystallization from heptane, mp 100.5 – 101.5
oC. 1HꢀNMR spectral data are identical to those reported in the literature.46 1H NMR (300 MHz, CDCl3,
ppm) δ 9.41 (br s, 1H), 8.71 (d, J = 4.3 Hz, 1H), 8.54 – 8.51 (m, 1H), 7.80 – 7.77 (m, 1H), 7.61 – 7.56
(m, 1H), 7.48 (dd, J = 7.8, 5.0 Hz, 1H), 7.42 – 7.35 (m, 2H). 13C{1H} NMR (63 MHz, CDCl3, ppm) δ
160.3, 151.2, 150.7, 147.9, 141.5, 135.3, 125.8, 125.0, 123.9, 123.8, 120.3, 110.8. GCꢀMS (EI) m/z: [M]+
found for C12H8N2O 196.41.
(E)-2-Styrylbenzo[d]oxazole (8i) was obtained as a pale yellow solid (52 mg, 78%) according to general
procedure D. The crude product was purified by column chromatography on silica gel using gradient
elution from 0% EtOAc in heptane to 9% EtOAc in heptane. Analytical TLC on silica gel, 1:9 EtOAc/
heptane, Rf = 0.23. Pure material was obtained by recrystallization from heptane, mp 83.5 – 84.5 oC. 1Hꢀ
NMR spectral data are identical to those reported in the literature.47 1H NMR (300 MHz, CDCl3, ppm) δ
7.81 (d, J = 16.4 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.63 – 7.59 (m, 2H), 7.57 – 7.51 (m, 1H), 7.47 – 7.39 (m,
3H), 7.38 – 7.32 (m, 2H), 7.10 (d, J = 16.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, ppm) δ 162.8,
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150.4, 142.2, 139.5, 135.1, 129.8, 129.0, 127.6, 125.2, 124.5, 119.9, 113.9, 110.3. GCꢀMS (EI) m/z: [M]+
found for C15H11NO 221.45.
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2-Tert-butylbenzo[d]oxazole (8j) was obtained as an offꢀwhite amorphous solid (52 mg, 74%) according
to general procedure E. The crude product was purified by column chromatography on silica gel using
gradient elution from 0% EtOAc in heptane to 33% EtOAc in heptane. Analytical TLC on silica gel, 1:9
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EtOAc/heptane, Rf = 0.33. 1HꢀNMR spectral data are identical to those reported in the literature.39 1
H
NMR (300 MHz, CDCl3, ppm) δ 7.73 – 7.68 (m, 1H), 7.50 – 7.46 (m, 1H), 7.32 – 7.26 (m, 2H), 1.50 (s,
9H). 13C{1H} NMR (63 MHz, CDCl3, ppm) δ 173.5, 150.8, 141.2, 124.3, 123.9, 119.7, 110.3, 34.1, 28.4.
GCꢀMS (EI) m/z: [M]+ found for C11H13NO 175.32.
6-Methyl-2-phenylbenzo[d]oxazole (8k) was obtained as an offꢀwhite solid (47 mg, 75%) according to
general procedure D. The crude product was purified by column chromatography on silica gel using
gradient elution from 0% EtOAc in heptane to 10% EtOAc in heptane. Analytical TLC on silica gel, 1:9
EtOAc/heptane, Rf = 0.35. Pure material was obtained by recrystallization from heptane, mp 92 – 93 oC.
1HꢀNMR spectral data are identical to those reported in the literature.48 1H NMR (300 MHz, CDCl3, ppm)
δ 8.27 – 8.23 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.55 – 7.50 (m, 3H), 7.39 (dt, J = 1.6, 0.6 Hz, 1H), 7.19 –
7.16 (m, 1H), 2.52 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, ppm) δ 162.5, 151.0, 139.9, 135.5, 131.2,
128.8, 127.4, 127.3, 125.8, 119.3, 110.7, 21.8. GCꢀMS (EI) m/z: [M]+ found for C14H11NO 209.43.
5-Methyl-2-phenylbenzo[d]oxazole (8l) was obtained as an offꢀwhite amorphous solid (54 mg, 86%)
according to general procedure D. The crude product was purified by column chromatography on silica
gel using gradient elution from 0% EtOAc in heptane to 10% EtOAc in heptane. Analytical TLC on silica
gel, 1:9 EtOAc/heptane, Rf = 0.36. 1HꢀNMR spectral data are identical to those reported in the literature.37
1H NMR (300 MHz, CDCl3, ppm) δ 8.29 – 8.24 (m, 2H), 7.57(dt, J = 1.7, 0.8 Hz, 1H), 7.56 – 7.51 (m,
3H), 7.48 – 7.45 (d, J = 7.9 Hz, 1H), 7.19 – 7.15 (m, 1H), 2.50 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3,
ppm) δ 163.1, 149.0, 142.3, 134.4, 131.4, 128.9, 127.5, 127.33, 126.2, 119.9, 109.9, 21.5. GCꢀMS (EI)
m/z: [M]+ found for C14H11NO 209.44.
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6-Nitro-2-phenylbenzo[d]oxazole (8m) was obtained as a light yellow amorphous solid (44 mg, 61%)
according to general procedure D. The crude product was purified by column chromatography on silica
gel using gradient elution from 0% EtOAc in heptane to 33% EtOAc in heptane; analytical TLC on silica
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gel, 1:9 EtOAc/heptane, Rf = 0.19. 1HꢀNMR spectral data are identical to those reported in literature.48 1
NMR (300 MHz, (CD3)2O, ppm) δ 8.62 (dd, J = 2.2, 0.5 Hz, 1H), 8.37 (dd, J = 8.8, 2.2 Hz, 1H), 8.34 –
H
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8.31 (m, 2H), 7.98 (dd, J = 8.8, 0.5 Hz, 1H), 7.72 – 7.64 (m, 3H). 13C{1H} NMR (63 MHz, CDCl3, ppm)
δ 167.4, 149.9, 147.4, 145.1, 132.9, 129.2, 128.3, 126.0, 120.9, 119.8, 107.2. GCꢀMS (EI) m/z: [M]+
found for C13H8N2O 240.43.
Methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (8n) was obtained as a white solid (87
mg, 90%) according to general procedure D. The crude product was purified by column chromatography
on silica gel using gradient elution from 0% EtOAc in heptane to 10% EtOAc in heptane. Analytical TLC
on silica gel, 1:9 EtOAc/heptane, Rf = 0.35. Pure material was obtained by recrystallization from heptane,
mp 171.5 – 172.5 oC. IR (film, cmꢀ1) 1725 (C=O). 1H NMR (250 MHz, CDCl3, ppm) δ 8.27 (dd, J = 1.6,
0.6 Hz, 1H), 8.15 (d, J = 1.9 Hz, 2H), 8.12 (dd, J = 8.4, 1.6 Hz, 1H), 7.80 (dd, J = 8.5, 9.6 Hz, 1H), 7.54
(t, J = 1.9 Hz, 1H), 3.98 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, ppm) δ 166.4, 162.8, 150.5, 145.5,
135.9, 131.9, 129.3, 127.9, 126.7, 126.1, 120.0, 113.5, 52.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C15H10Cl2NO3 322.0037; Found 322.0035.
2-(4-Bromophenyl)-5-nitrobenzo[d]oxazole (8o) was obtained as a sandꢀcolored solid (62 mg, 69%)
according to general procedure D. The crude product was purified by column chromatography on silica
gel using gradient elution from 3% EtOAc in hexanes to 10% EtOAc in hexanes. Analytical TLC on silica
gel, 1:10 EtOAc/hexanes, Rf = 0.44. Pure material was obtained by recrystallization from
hexanes/CH2Cl2, mp 176ꢀ177 oC. 1HꢀNMR spectral data are identical to those reported in the literature.49
1H NMR (400 MHz, CDCl3, ppm) δ 8.48 (dd, J = 2.2, 0.5 Hz, 1H), 8.32 (dd, J = 8.7, 2.2 Hz, 1H), 8.15 –
8.12 (m, 2H), 7.84 (dd, J = 8.7, 0.5 Hz, 1H), 7.72 – 7.69 (m, 2H). 13C{1H} NMR (100.6 MHz, CDCl3,
ppm) δ 166.6, 150.1, 147.4, 145.4, 132.7, 129.7, 128.0, 125.0, 121.1, 120.1, 107.4. HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C13H8BrN2O3 318.9718; Found 318.9715.
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