Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis-Beirut Reaction

Article abstract of DOI:10.1021/acs.joc.7b01521

The discovery of a new variation on the Davis-Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivity - a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.

Full text of DOI:10.1021/acs.joc.7b01521

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Article
Diverting Reactive Intermediates Toward Unusual Chemistry
– Unexpected Anthranil Products from Davis–Beirut Reaction
Jie S. Zhu, Jung-Ho Son, Andrew P. Teuthorn, Makhluf J. Haddadin, Mark J. Kurth, and Dean J Tantillo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01521 • Publication Date (Web): 19 Sep 2017
Downloaded from http://pubs.acs.org on September 19, 2017
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Diverting Reactive Intermediates Toward Unusual Chemistry – Unexpected
Anthranil Products from Davis–Beirut Reaction
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¹
¹
¹
¹
Jie S. Zhu, Jung-Ho Son, Andrew P. Teuthorn, Makhluf J. Haddadin,& Mark J. Kurth, * and
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¹
Dean J. Tantillo *
¹
Department of Chemistry, University of California Davis, 1 Shields Ave., Davis, CA 95616, USA
& Department of Chemistry, American University of Beirut, Beirut, Lebanon
E-mail: djtantillo@ucdavis.edu, mjkurth@ucdavis.edu
Abstract: The discovery of a new variation on the Davis−Beirut reaction is described in which an
atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the
result of diversion of a key reactive intermediate away from its expected reactivity – a potentially
general approach to reaction design and development. Experimental and computational support
for the proposed mechanism and origins of altered reactivity are described.
Introduction
The discovery of new synthetic methodology is catalyzed in numerous ways; for example, by
challenges presented in complex natural product synthesis,1 by needs associated with drug
discovery,2 by serendipitous observation,3 and by rational development based on already existing
technology.4,5 As an example of the latter, the synthesis of key intermediates from named reactions
using modern chemistry is a cornerstone of methodology development; consider the Buchwald
modification4 of the Fischer indole synthesis6 where the key intermediate is made through N-aryl
bond formation via Pd-catalyzed cross-coupling instead of via the traditional condensation of
hydrazine with a ketone or aldehyde equivalent. However, far fewer methodology advancements
exploit alternative chemistries of highly reactive intermediates, even though such strategies
occasionally have been implemented to great effect. For example, controlling the reactivity of the
final intermediate of the Fischer indole synthesis by blocking aromatization allows the construction
of various indoline natural products in the interrupted Fischer indole synthesis.5
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Altering the course of a highly reliable reaction to access atypical structural motifs requires
careful consideration of the reaction mechanism, with the caveat that a reasonable mechanistic
model must exist. Through the aid of increasingly powerful computational methods, even highly
complex reaction mechanisms can be demystified.7 To this end, we report the discovery of a
pericyclic cascade8 route to anthranils (also known as benzo[c]isoxazoles), which was developed
by exploiting alternative reactivity of Davis–Beirut reaction intermediates.
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Originally, reactions of diethyl 1-amino-2’-nitrobenzylphosphonates with aq. NaOH in MeOH
reported by Boduszek9a and o-nitrosobenzaldehyde with benzylamine reported by Chen9b were
claimed to deliver anthranils, but our reinvestigation of those studies established that indazolones
were produced instead.10 Thus was born the Davis–Beirut reaction, which provides a robust method
for constructing 2H-indazoles from 2-nitrobenzylamines.10 It is proposed that the Davis-Beirut
reaction involves initial tautomerization of 2-nitrobenzylamine 1a by hydroxide to generate aci-nitro
intermediate 1b (Scheme 1). This intermediate is thought to undergo a rapid internal reduction-
oxidation to form nitrosophenylmethanimine 1c. Nucleophilic addition to this imine intermediate by
alcohol solvent would generate hemiaminal ether 1d, which would subsequently form a five-
membered ring via an N−N bond forming heterocyclization. The resulting ring can then be
aromatized to deliver a 2H-indazole, which can be easily transformed to an indazolone.11
Scheme 1. Davis–Beirut reaction mechanism and photochemistry of o-nitrobenzyl compounds.
O
O
N+
N+
O-
O-
Davis-Beirut
reaction
pathway
Photochemical
deprotection
pathway
RHN
OR
hn
1a
base
2a
2b
OH
N
O
N
internal
oxidation
reduction
OH
N
OH
N
O-
O-
6p
O
OR
OR
1c
RN
1b RHN
imine
2c
ring
opening
addition
+ ROH
O
N
O
O
N
N-N bond
formation
cargo
release
OH
N
N
N
R
O
OR
OR
+ ROH
OR
1d RHN
2d
This work
blocked
internal
oxidation
O
N
OH
N+
blocked
cargo
release
N
O
O–
reduction
OH
NH
NH
N
N
N
NH
highly reactive
aci-nitro intermediate
highly reactive
nitroso alcohol
never isolated anthranil from
Davis-Beirut and deprotection
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The putative mechanistic intermediates involved in the Davis–Beirut process share many
structural similarities with intermediates proposed for the photodeprotection of the o-nitrobenzyl
moiety – an established pH-sensitive photolabile protecting group for a variety of heteroatoms
(Scheme 1).12 Exposure of 2a to light causes its tautomerization to aci-nitro species 2b, which then
cyclizes to give intermediate 2c. Subsequent decomposition of this transient heterocycle gives
hemiacetal 2d and alcohol release proceeds by collapse of 2d to o-nitrosobenzaldehyde.13
As reported here, exploiting alternative reactivity of Davis–Beirut reaction intermediates led to
our discovery of a cascade8 route to anthranils. Molecules with this core framework have
pharmaceutical value14 and this heterocycle has been previously synthesized via a variety of
methods.15-19 Recently, the transformation of anthranils to other heterocycles have found use in
complex molecule synthesis.20 The utility of this heterocycle, coupled with our group’s long-
standing interest in heterocycle-to-heterocycle strategies,21 prompted us to investigate this route
to anthranils.
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Results and Discussion
We aimed to exploit the structural similarities and different reactivities of key intermediates
found in the Davis–Beirut and o-nitrobenzyl deprotection pathways for the discovery of new
heterocyclic synthetic methods. With that objective in mind, we set out to demonstrate the base-
mediated deprotection of a 2-nitrobenzyl compound featuring a nitrogen attached to the benzylic
carbon—i.e., an interrupted Davis–Beirut process—and indole-containing substrate 3a (Scheme 2)
was selected. If realized, the based-mediated reaction of 3a would proceed via 3a.1 to form
dihyrdoanthranil intermediate 3a.2. Subsequent ring-opening of this heterocyclic intermediate
would produce nitrosoalcohol 3a.3 and, ultimately, release indole.
Indeed, when 3a was microwave heated in MeOH in the presence of KOH (5 equiv.), indole
was released via the deprotection pathway (Scheme 2). o-Nitrobenzoic acid was also isolated,
evidencing the formation of o-nitrosobenzaldehyde (® o-nitrobenzoic acid by air oxidation) over
the course of the reaction. Since the microwave cavity is dark, intermediate 3a.1 is not generated
by phototautomerization; however, the sufficiently low pKa of the benzylic hydrogens in 3a allows
base to facilitate transformation of the starting material to aci-nitro 3a.1. Formation of deprotection
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products (indole and o-nitrobenzoic acid) confirmed that base can affect the transformation outlined
in Scheme 2.
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Scheme 2. Exploring the reactivity of 3a.1.
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With this calibrating study in hand, the benzylic indole moiety was replaced with a benzylic C2
linked benzimidazole. This substrate, 4a (Scheme 3), was selected for study because it was not
expected to undergo the deprotection reaction since cargo release would involve C−C bond
cleavage and generation of a relatively high energy benzimidazolylidene. Simultaneously, the
benzimidazole nitrogen of 4a, being nucleophilic, offered the potential of intercepting the in situ
generated nitroso moiety in 4a.2 with an N−N bond forming reaction (with subsequent dehydration
and tautomerization) to generate benzoimidazocinnolinone 5.
Scheme 3. Exploring the reactivity of 4a.
When 4a was heated in MeOH with KOH, no deprotection products were found and a major
product with a m/z of 235 was isolated – the mass corresponding to the anticipated
benzoimidazocinnolinone. Surprisingly, when we attempted to confirm the structure of this product
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by X-ray crystallography, it was found instead to be anthranil 6a. Although this was a surprising
result based on our earlier work, which established that anthranils are not formed under Davis–
Beirut reaction conditions,10 serendipity, as noted by Hoye,3 can “still play a pivotal role” in science.
Through X-ray crystallography, a side-product of this base-mediated reaction of 4a was found
to be condensation-derived compound 7. As detailed in Scheme 4, we speculate that nitroso
intermediate 4a.2 undergoes base-mediated condensation with starting material 4a to give
phenylmethanimine 4a.3. Subsequent air oxidation of this intermediate, directly or perhaps via 4a.4,
delivers 7. Although this side-product can be isolated in up to 37% yield, its formation can be
minimized using the optimized reaction conditions described below.
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Scheme 4. Side-product identification and mechanism of its formation.
The reaction of benzylic heteroaromatics such as 4a to form anthranils was systematically
optimized by varying solvent, base, temperature (see Supporting Information). While generally,
both polar-protic and polar-aprotic solvents were effective for the reaction, the optimal conditions
were found to be microwave irradiation in 0.05 M DMF with 5 equiv. NaOtBu for 6 h at 125 oC. The
o
temperature needed to be ≥ 45 C and excess alkoxide was needed to achieve complete
conversion. Addition of 4Å molecular sieves improved the yield of the reaction. Substrates with
minimal ring substitution (6a-d, 6f, 6i) resulted in higher than average yields, while 6e, 6g, 6h
resulted in lower than average yields (Scheme 5).
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Scheme 5. Base mediated formation of anthranils; isolated yields.
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5
6
7
8
NO2
N
NaOtBu, DMF
4Å MS, 125 oC, 6h
R
R
O
heterocycle
6a-j
heterocycle
4a-j
9
N
N
N
N
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O
O
O
O
NH
NH
NH
NH
N
N
N
N
6a
54%
6b
52%
6c
48%
6d
50%
F
F
MeO
MeO
N
N
O
N
O
N
O
N
O
O
NH
N
NH
NH
N
NH
NH
N
N
N
N
6e
29%
6f
48%
6g
30%
6h
32%
6i
62%
N
Br
OMe
conditions: substrate (0.2 mmol), NaO Bu (1 mmol), DMF (4 mL), 4Å MS (0.2 g), 125 oC, 6h.
t
4
In addition, a diverse series of 2-nitrobenzyl compounds (Scheme 6) were prepared and
subsequently treated under base and microwave irradiation, but LCMS analysis of each crude
reaction mixture established that none of these substrates provided the targeted anthranil product.
In each case, either no reaction occurred or the reaction resulted in a complicated mixture of
products owing to the rich chemistry of nitro- and nitrosobenzenes, especially for 8a and 8b.
Carbonyl-containing 8d–8f likely failed to undergo the hoped-for anthranil-forming reaction
because enolate formation probably competes with aci-nitro formation. Despite structural
similarities with 4a, the failure of 8h and 8i to give anthranil products suggests that the NH-
containing heterocyclic moiety plays a critical role in the 4 ® 6 heterocyclization reaction.
Scheme 6. Substrates which failed to give an anthranil.
NO2
X
NO2
NO2
NO2
NO2
Y
8a
8b
Y =
8c
8d
8e
8f
X = H
CN
CO2Me
CON(iPr)2
N
NH
N
O
N
NBn
NO2
CO2Ph
8g
8h
8i
In pursuit of a mechanistic scheme consistent with these experimental results, reactions of 4a
were examined using density functional theory calculations [SMD(DMF)-M06-2X/6-31+G(d,p);22
see Supporting Information for details]. Both neutral (green and blue) and anionic (red) pathways
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were examined and our results are summarized in Figure 1. The key issue here was the fact that,
experimentally, an anthranil, rather than fragmented or cinnoline products, is formed although all
three families of products arise from initial cyclization. Cyclization for the neutral system is predicted
to require a barrier of approximately 32 kca/mol (from the blue reactant to the green product; note
that the barrier for green reactant to green product is comparable to those predicted previously for
systems with alkyl or alkoxyl groups in place of the benzimidazole),23 while cyclization for the
anionic system is predicted to require a barrier of approximately 36 kcal/mol. Given the nature of
the theoretical methods used, either pathway appears to be viable, although the neutral route is
perhaps more likely. Note that the product of cyclization for the anionic system is the OH/N:–
tautomer. Proton transfer occurs during optimization when starting from NH/O:– species with NH
and O:– groups syn, while ring-opened structures are found starting from NH and O:– groups anti.
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O –
N
N
O –
– HO –
N
O
O
-8.3
OH
H
N
H
TO ANTHRANIL
PRODUCTS
H
H
N
N
N
N
N
H
N
N
-29.3
-12.6
+27.8
+19.3
-0.3
+26.9
O
N
OH
OH
FRAGMENTATION
O
N O
N
N
O –
H
O
O
O –
O
+15.2
N
N
H
H
O –
H
H
OH
H
N
N
N
N
N
N
H
N
H
N
H
H
H
N
N
N
N
[0.0]
-19.3
-30.3
– H+
+ H+
– H+ + H+
– H+ + H+
-34.7
-3.8
O –
O
O
N
O
N
OH
N
N
O –
O –
N
O
O –
OH
O –
H
+3.4
– H+
H
N
H
H
N
H
N
+35.7
+3.8
N
N
N
N
N
N
N
N
N
N
N
N
N
+8.6
[0.0]
-6.6
+2.5
-16.9
-1.6
OH
O
(highest
energy
TSS)
RING OPENING
TO FORM
BRANCHPOINT
INTERMEDIATE
INITIAL
CYCLIZATION
TO CINNOLINE
PRODUCTS
Figure 1. Reaction network examined at the SMD(DMF)-M06-2X/6-31+G(d,p) level of theory. Energies of
transition state structures are shown on arrows. Black structures represent reactants and products (not
calculated). Blue and green energies can be compared to each other; red energies cannot be compared to
these, since the red structures have one less proton than do the green and blue structures. See Supporting
Information for additional details and results on other possible pathways.
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One may question whether the initial cyclization reaction for the anionic system (Figure 2, left,
red) is a pericyclic or pseudopericyclic reaction.24 Unfortunately, the geometry of the transition state
structure (Figure 2, left) does not provide a definitive answer this question. The calculated nucleus
independent chemical shift (NICS, a measure of aromaticity)25 for the partially formed ring
(approximately -10) is indicative of aromaticity and comparable to that for the 5-membered ring in
anthranil,26 consistent with a pericyclic reaction, but non-pericyclic cyclization reactions have also
been shown to have such NICS values.27
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1.31
1.91
1.46
+35.7
1.46
2.00
1.34
1.43
1.24
1.33
2.09
1.36
1.38
1.84
1.36
1.39
O
N
1.40
O –
N
+3.8
+2.5
H
N
[0.0]
-0.3
O –
N
-6.6
O –
– HO –
OH
-8.7
N
O
H
N
N
H
N
N
N
O
N
H
O
O –
OH
-29.3
-30.3
H
H
N
N
N
N
Figure 2. Reaction coordinate diagram for the preferred pathway to anthranils. Relative energies (kcal/mol)
from the SMD(DMF)-M06-2X/6-31+G(d,p) level of theory are shown, as are selected distances (Å) for
transition state structures.
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After cyclization, ring opening from the anionic cyclized product is predicted to occur readily
(barrier of approximately 10 kcal/mol), leading to an alkoxide ion (via concerted proton transfer/ring-
opening) that could partition between fragmentation and cinnoline formation pathways. In contrast
to systems where the benzimidazole is replaced by an OR group (i.e., alcohol deprotection),13
fragmentation of the benzimidazole system seems unlikely. Direct fragmentation is associated with
a predicted barrier of approximately 24 kcal/mol, while protonation/fragmentation is associated with
a barrier of approximately 50 kcal/mol from the nitrosophenyl/benzimizaole-substituted alcohol.
Formation of cinnoline is predicted to be much more likely, with no high-energy transition state
structures involved.
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At this point we were faced with the task of rationalizing why cinnolines are not observed. The
first pathway to anthranil products—proton transfer immediately following initial cyclization, then
hydroxide ion loss (not shown)—that we examined was predicted to involve a transition state
structure (for hydroxide loss) that was much higher in energy than any transition state structures
en route to these heterocycles. After exploring many alternative mechanisms (see Supporting
Information for details), we arrived at the “to anthranil products” pathway in Figure 1 and shown in
Figure 2: tautomerization after ring-opening (which could be stepwise or a concerted [1,5]
sigmatropic shift) à concerted proton transfer/electrocyclization à hydroxide loss. The highest
energy transition state structure in this cascade, after initial cyclization and ring-opening, is
predicted to be approximately 4 kcal/mol lower in energy than that for formation of cinnolines.
Thus, we arrive at a complex network of reactions, but one that is consistent with our
experimental observations: predominant formation of anthranil rather than cinnolines or
fragmentation products. Note that removing intermolecular hydrogen-bonds involving the
benzimidazole NH (modeled by replacing the NH with NCH3) leads to an increase in the relative
energy of the transition state structure for ring closure en route to anthranil (by approximately 4
kcal/mol) and this is consistent with the lack of anthranil formation observed with an N-alkylated
reactant (8i). Several alternative mechanistic pathways were examined, but none were found to be
more favorable than those described above (see Supporting Information for details).
Conclusion
In summary, we described a pericyclic cascade route to anthranils. This work provides an
example of reaction development via diversion of an expected reactive intermediate toward
previously unexpected chemistry—here an intermediate proposed to play a key role in both the
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Davis–Beirut reaction and the photodeprotection of the o-nitrobenzyl protecting group was
exploited. With sufficient mechanistic understanding, this scenario could be implemented as a
strategy for designing new routes to valuable products with useful functions and, in so doing, create
new opportunities for discovery.
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Experimental Section
General procedures. All chemicals were purchased from standard commercial suppliers and used
without further purification. Anhydrous solvents were dispensed from a solvent purification system
utilizing two dry neutral alumina or prepared using dry molecular sieves. Analytical TLC was
performed using pre-coated plates (silica gel 60 F254) and visualized with UV light or I2 chamber.
Flash chromatography in glass columns was performed using 60 Ǻ 230-400 mesh silica gel (Fisher).
1H NMR spectra and proton decoupled 13C NMR spectra were obtained on a 400 MHz Bruker, 600
MHz Varian, or 800 MHz Bruker NMR spectrometer. 1H and 13C chemical shifts (δ) are reported in
parts per million (ppm) relative to residual solvent peaks. Multiplicities are given as: s (singlet), d
(doublet), t (triplet), q (quartet), and m (multiplet). Coupling constants (J) are given in Hz. For HRMS
analysis, samples were analyzed by flow-injection analysis into a Thermo Fisher Scientific LTQ
Orbitrap (San Jose, CA) operated in the centroided mode. Samples were injected into a mixture of
50% MeOH/H2O and 0.1% formic acid at a flow of 0.2 mL/min. Source parameters were 5.5 kV
spray voltage, capillary temperature of 275 °C, and sheath gas setting of 20. Spectral data were
acquired at a resolution setting of 100,000 fwhm with the lockmass feature, which typically results
in a mass accuracy.
Ethyl 2-nitrobenzeneacetimidate hydrochloride (S1). A stoppered three-neck round bottom
flask was charged with a stir bar, 2-(2-nitrophenyl)acetonitrile (2.66 g, 20 mmol), and toluene (20
mL). Ethanol (1.76 mL) was added to the flask stirred at room temperature for 3 minutes. HCl gas
(generated by addition of HCl to H2SO4) was then vigorously bubbled through the reaction mixture
for 20 minutes. This solution was stirred at room temperature overnight, poured into 350 mL of
Et2O, and placed in the freezer for 3 h. The solids were collected by vacuum filtration and washed
2 times with Et2O (20 mL) to afford the product as a white solid (3.73 g, 93.3%) and used directly
in the next step.
Ethyl 2-(4,5-dimethoxy-2-nitrophenyl)acetimidate hydrochloride (S2). A stoppered three-neck
round bottom flask was charged with a stir bar, 2-(4,5-dimethoxy-2-nitrophenyl)acetonitrile (2.00 g,
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9.0 mmol), and toluene (20 mL). Ethanol (6 mL) was added to the flask stirred at room temperature
for 3 minutes. HCl gas (generated by addition of H2SO4 to HCl) was then vigorously bubbled
through the reaction mixture for 20 minutes. This solution was stirred at room temperature
overnight, poured into 350 mL of Et2O, and placed in the freezer for 3 h. The solids were collected
by vacuum filtration and washed 2 times with Et2O (20 mL) to afford the product as a white solid
(2.00 g, 72.9%) and used directly in the next step.
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1-Benzyl-2-(2-nitrobenzyl)-1H-benzo[d]imidazole (8i). A 20 mL Biotage microwave vial was
charged with a stir bar, S1 (0.500 g, 2.05 mmol), and methanol (10 mL). N1-benzylbenzene-1,2-
diamine (0.452 g, 2.28 mmol) was added to the flask and the reaction vial was sealed. The mixture
was heated in the microwave at 60 oC for 6 h. The solvent was removed under reduced pressure
and the crude product was purified by flash column chromatography using a mixture of ethyl
acetate/hexanes to afford the product as a tan solid (0.456 g, 64.8%); mp 128−130 °C. 1H NMR
(400 MHz, Chloroform-d) δ 8.05 (d, J = 8.1, 1H), 7.82 – 7.71 (m, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.43
(t, J = 7.8 Hz, 1H), 7.35 – 7.26 (m, 7H), 7.05 (dd, J = 7.0, 2.5 Hz, 2H), 5.40 (s, 2H), 4.58 (s, 2H).
13C NMR (101 MHz, Chloroform-d) δ 151.9, 148.6, 142.6, 135.7, 135.6, 133.6, 132.3, 131.5, 129.0,
128.2, 127.9, 126.3, 125.3, 122.8, 122.2, 119.8, 109.6, 47.2, 31.7. HRMS (ESI-Orbitrap) m/z: [M +
H]+ Calcd for C21H18N3O2: 344.1394; Found: 344.1389.
2-(2-Nitrobenzyl)-1H-benzo[d]imidazole (4a). A 50 mL round bottom flask was charged with a
stir bar, S1 (1.30 g, 5.33 mmol), and methanol (30 mL). 1,2-Phenylenediamine (0.640 g, 5.92 mmol)
was added to the flask and the reaction mixture was heated on the oil bath at 60 oC for 6 h. After
cooling to room temperature, the solids were collected by vacuum filtration and washed with cold
methanol to afford the product as a tan solid (1.25 g, 92.7%); mp 241−243°C. 1H NMR (400 MHz,
Chloroform-d) δ 8.01 (d, J = 8.2, 1H), 7.69 (dd, J = 7.6, 1.4 Hz, 1H), 7.60 (td, J = 7.6, 1.4 Hz, 1H),
7.56 (broad, 1H), 7.44 (td, J = 7.9, 7.5, 1.5 Hz, 1H), 7.25 – 7.22 (m, 2H), 6.72 (d, J = 1.4 Hz, 1H),
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4.54 (s, 2H). C NMR (101 MHz, DMSO-d6) δ 152.2, 148.8, 133.7, 133.1, 131.9, 128.4, 124.8,
121.3, 118.4, 110.9, 32.5. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C14H12N3O2: 254.0924;
Found: 254.0913.
7-Methyl-2-(2-nitrobenzyl)-1H-benzo[d]imidazole (4b). A 20 mL Biotage microwave vial was
charged with a stir bar, S1 (0.600 g, 2.46 mmol), and methanol (15 mL). 3-Methylbenzene-1,2-
diamine (0.333 g, 2.73 mmol) was added to the flask and the reaction vial was sealed. The mixture
was heated in the microwave at 60 oC for 6 h. The solvent was removed under reduced pressure
and the crude product was purified by flash column chromatography using a mixture of ethyl
acetate/hexanes to afford the product as a white solid (0.456 g, 62.4%); mp 201−203°C. 1H NMR
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(400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.58 (t, J =
7.3 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 4.55 (s, 2H),
2.45 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 149.3, 134.1, 133.3, 132.4, 128.8, 125.2, 32.8, 17.2.
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C15H14N3O2: 268.1086; Found: 268.1070.
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5,6-Difluoro-2-(2-nitrobenzyl)-1H-benzo[d]imidazole (4c). A 20 mL Biotage microwave vial was
charged with a stir bar, S1 (0.500 g, 2.05 mmol), and methanol (15 mL). 4,5-Difluorobenzene-1,2-
diamine (0.328 g, 2.28 mmol) was added to the flask and the reaction vial was sealed. The mixture
was heated in the microwave at 60 oC for 6 h. The solvent was removed under reduced pressure
and the crude product was purified by flash column chromatography using a mixture of ethyl
acetate/hexanes to afford the product as a brown solid (0.151 g, 25.5%); mp 178−180°C. 1H NMR
(400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.07 (dd, J = 8.1, 1.3 Hz, 1H), 7.73 (td, J = 7.6, 1.4 Hz, 1H),
7.65 – 7.55 (m, 2H), 7.51 (dd, J = 10.9, 7.5 Hz, 2H), 4.54 (s, 2H). 13C NMR (101 MHz, DMSO-d6)
δ 154.4, 148.7, 147.6, 145.2, 133.8, 133.2, 131.6, 128.5, 124.9, 32.5. HRMS (ESI-Orbitrap) m/z:
[M + H]+ Calcd for C14H10F2N3O2: 290.0741; Found: 290.0736.
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2-(2-Nitrobenzyl)-1H-naphtho[2,3-d]imidazole (4d). A 20 mL Biotage microwave vial was
charged with a stir bar, S1 (0.492 g, 2.02 mmol), and methanol (15 mL). Naphthalene-2,3-diamine
(0.354 g, 2.24 mmol) was added to the flask and the reaction vial was sealed. The mixture was
heated in the microwave at 60 oC for 6 h. The solvent was removed under reduced pressure, the
solids were collected by vacuum filtration and washed with cold dichloromethane to afford the
product as a light brown solid (0.472 g, 69.4%); mp 190−192°C. 1H NMR (400 MHz, Chloroform-d)
δ 8.04 (dd, J = 8.3, 1.3 Hz, 1H), 8.02 – 7.91 (m, 4H), 7.73 (dd, J = 7.8, 1.5 Hz, 1H), 7.62 (td, J =
7.5, 1.3 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.42 (dd, J = 6.4, 3.2 Hz, 2H), 4.61 (s, 2H). 13C NMR (101
MHz, DMSO-d6) δ 157.5, 149.3, 134.3, 133.8, 131.8, 130.1, 129.1, 128.2, 125.4, 123.8, 33.3.
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C18H14N3O2: 304.1086; Found: 304.1075.
6-Bromo-2-(2-nitrobenzyl)-1H-benzo[d]imidazole (4e). A 50 mL round bottom flask was
charged with a stir bar, S1 (0.260 g, 1.07 mmol), and methanol (30 mL). 4-Bromobenzene-1,2-
diamine (0.200 g, 1.08 mmol) was added to the flask and the reaction mixture was refluxed on the
oil bath for 6 h. The solvent was removed under reduced pressure and the crude product was
purified by flash column chromatography using a mixture of ethyl acetate/hexanes to afford the
product as a brown oil (0.090 g, 25.0%). 1H NMR (800 MHz, Acetone-d6) δ 8.09 (dd, J = 8.2, 1.3
Hz, 1H), 7.73 (td, J = 7.6, 1.4 Hz, 1H), 7.68 – 7.66 (m, 1H), 7.64 (ddd, J = 7.7, 1.5, 0.6 Hz, 1H),
7.60 (ddd, J = 8.2, 7.4, 1.5 Hz, 1H), 7.44 (dd, J = 8.5, 0.6 Hz, 1H), 7.29 (dd, J = 8.5, 1.9 Hz, 1H),
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4.65 (s, 2H).. 13C NMR (201 MHz, Acetone-d6) δ 153.5, 149.3, 131.8, 128.5, 124.9, 124.6, 114.0,
32.7. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C14H11BrN3O2: 332.0035; Found: 332.0046.
6-Methoxy-2-(2-nitrobenzyl)-1H-benzo[d]imidazole (4f). A 50 mL round bottom flask was
charged with a stir bar, S1 (0.491 g, 2.01 mmol), and methanol (30 mL). 4-Methoxybenzene-1,2-
diamine (0.275 g, 1.99 mmol) was added to the flask and the reaction mixture was refluxed on the
oil bath for 4 h. The solvent was removed under reduced pressure and the crude product was
purified by flash column chromatography using a mixture of ethyl acetate/hexanes to afford the
product as a light brown solid (0.290 g, 51.0%); mp decomp. 1H NMR (400 MHz, Chloroform-d) δ
7.98 (dd, J = 8.2, 1.3 Hz, 1H), 7.61 (dd, J = 7.8, 1.4 Hz, 1H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.46 –
7.38 (m, 2H), 7.00 (s, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 4.50 (s, 2H), 3.83 (s, 3H). 13C NMR (101
MHz, Chloroform-d) δ 156.4, 151.1, 148.6, 134.0, 133.1, 131.9, 128.4, 125.1, 112.0, 55.8, 33.1.
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C15H14N3O3: 284.1035; Found: 284.1038.
5,6-Dimethyl-2-(2-nitrobenzyl)-1H-benzo[d]imidazole (4g). A 50 mL round bottom flask was
charged with a stir bar, S1 (0.490 g, 2.00 mmol), and methanol (30 mL). 4-Bromobenzene-1,2-
diamine (0.270 g, 1.98 mmol) was added to the flask and the reaction mixture was refluxed on the
oil bath for 6 h. The solvent was removed under reduced pressure and the crude product was
purified by flash column chromatography using a mixture of ethyl acetate/hexanes to afford the
product as a light brown solid (0.230 g, 41.0%); mp 272−274°C. 1H NMR (400 MHz, Acetone-d6) δ
8.05 (dd, J = 8.1, 1.4 Hz, 1H), 7.69 (td, J = 7.5, 1.4 Hz, 1H), 7.62 – 7.52 (m, 2H), 7.25 (s, 2H), 4.59
(s, 2H), 2.31 (s, 6H). 13C NMR (201 MHz, Acetone-d6) δ 150.8, 150.8, 149.3, 133.4, 132.8, 132.4,
132.3, 130.1, 128.2, 124.7, 32.5, 19.4. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C16H16N3O2:
282.1243; Found: 282.1254.
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2-(4,5-Dimethoxy-2-nitrobenzyl)-1H-benzo[d]imidazole (4h). A 20 mL Biotage microwave vial
was charged with a stir bar, S2 (0.304 g, 1.00 mmol), and methanol (10 mL). 1,2-Phenylenediamine
(0.119 g, 1.10 mmol) was added to the flask and the reaction vial was sealed. The mixture was
heated on the oil bath at 80 oC for 6 h. The solvent vessel was placed in the freezer overnight and
the solids were collected by vacuum filtration to afford the product as an orange crystal (0.202 g,
64.4%); mp 224−226°C. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.71 (s, 1H), 7.47 – 7.38
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(m, 2H), 7.27 (s, 1H), 7.10 (dd, J = 6.0, 3.2 Hz, 2H), 4.56 (s, 2H), 3.90 (s, 6H), 3.89 (s, 6H). C
NMR (101 MHz, DMSO-d6) δ 153.5, 153.2, 148.0, 141.2, 127.3, 115.9, 108.8, 56.7, 56.5, 33.7.
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C16H16N3O4: 314.1141; Found: 314.1130.
5-(2-Nitrobenzyl)-1H-tetrazole (4i). A 20 mL Biotage microwave vial was charged with a stir bar,
2-(2-nitrophenyl)acetonitrile (0.324 g, 2.00 mmol), NH4Cl (0.214 g, 4.00 mmol) and DMF (10 mL).
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Sodium azide (0.390 g, 6.00 mmol) was added to the flask and the reaction vial was sealed. The
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mixture was heated on the oil bath at 150 C for 12 h. The solvent was removed under reduced
pressure and the crude product was purified by flash column chromatography using a mixture of
ethyl acetate/hexanes to afford the product as a light orange solid (0.0937 g, 22.8%); mp
142−144°C. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J = 8.4, 1.3 Hz, 1H), 7.77 (td, J = 7.6, 1.3
Hz, 1H), 7.67 – 7.57 (m, 2H), 4.61 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 148.9, 134.6, 133.7,
130.8, 129.6, 125.6, 27.9. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C8H8N5O2: 206.0678;
Found: 206.0667.
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General Procedure for Synthesis of Anthranil. A 2-5 mL Biotage microwave vial was
charged with a stir rod, 2-(2-nitrobenzyl)-1H-benzo[d]imidazole derivative (0.2 mmol), 4Å molecular
sieves (0.2 g), and sodium tert-butoxide (1 mmol, 5 equiv.), and DMF (4 mL; 0.05 M). The mixture
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was heated under microwave irradiation at 125 C for 6 hours. The reaction was cooled room
temperature and 1 M HCl (100 mL) was added and the solution was extracted 3 times with ethyl
acetate (50 mL). The organic layers were combined and removed under reduced pressure. The
crude reaction mixture was purified by flash column chromatography using mixtures of ethyl
acetate/hexanes.
General remarks: The use of 1 M HCl significantly simplifies the purification process by
removing the unwanted dimer and its decomposition products.
3-(1H-benzo[d]imidazol-2-yl)benzo[c]isoxazole (6a). Synthesized according to the general
procedure and isolated as an orange solid (0.0255 g, 54.3%); mp 246−248°C. 1H NMR (400 MHz,
DMSO-d6) δ 13.78 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 9.0 Hz, 2H), 7.63 (broad, 1H), 7.54
(dd, J = 9.0, 6.3 Hz, 1H), 7.39 – 7.26 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 157.6, 156.3, 144.4,
141.2, 132.7, 126.7, 124.9, 123.4, 121.8, 120.4, 116.5, 115.2, 112.7. HRMS (ESI-Orbitrap) m/z: [M
+ H]+ Calcd for C14H10N3O: 236.0824; Found: 236.0811.
3-(7-Methyl-1H-benzo[d]imidazol-2-yl)benzo[c]isoxazole (6b). Synthesized according to the
general procedure and isolated as a light yellow solid (0.0260 g, 52.2%); mp 240−242°C. 1H NMR
(400 MHz, DMSO-d6) δ 13.75 – 13.66 (m, 1H), 8.33 – 8.26 (m, 1H), 7.74 – 7.77 (m, 1H), 7.68 –
7.61 (m, 1H), 7.55 – 7.49(m, 1H), 7.46 – 7.40 (m, 1H), 7.33 – 7.18 (m, 2H), 7.15 – 7.07 (m, 1H),
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2.68 – 2.58 (d, 3H). C NMR (101 MHz, DMSO-d6) δ 157.6, 156.5, 144.2, 143.9, 141.2, 140.4,
134.6, 134.5, 132.6, 130.0, 126.5, 126.5, 125.2, 124.8, 123.4, 123.3, 122.9, 122.0, 121.9, 117.7,
116.5, 116.3, 115.1, 110.0, 17.5, 16.9. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C15H12N3O:
250.0980; Found: 250.0975.
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3-(5,6-Difluoro-1H-benzo[d]imidazol-2-yl)benzo[c]isoxazole (6c). Synthesized according to the
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general procedure and isolated as a brown solid (0.0262 g, 48.3%); mp decomp. H NMR (400
MHz, DMSO-d6) δ 14.05 (s, 1H), 8.21 (dt, J = 8.9, 1.0 Hz, 1H), 7.89 (broad, 1H), 7.75 (d, J = 9.1,
1H), 7.63 (broad, 1H), 7.53 (ddd, J = 9.1, 6.4, 1.0 Hz, 1H), 7.29 (dd, J = 8.9, 6.4 Hz, 1H). 13C NMR
(101 MHz, DMSO-d6) δ 170.3, 157.1, 155.2, 142.5, 132.2, 126.4, 121.0, 116.0, 114.8, 59.7, 20.7,
14.1. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C14H8F2N3O: 272.0635; Found: 272.0625.
3-(1H-naphtho[2,3-d]imidazol-2-yl)benzo[c]isoxazole (6d). Synthesized according to the
general procedure and isolated as a yellow solid (0.0283 g, 49.6%); mp 230−232°C. 1H NMR (400
MHz, DMSO-d6) δ 13.80 (s, 1H), 8.41 (s, 1H), 8.39 – 8.32 (m, 1H), 8.18 – 8.01 (m, 3H), 7.81 (d, J
= 9.1 Hz, 1H), 7.62 – 7.53 (m, 1H), 7.40 – 7.48 (m, 2H), 7.37 (dd, J = 8.8, 6.3 Hz, 1H). 13C NMR
(101 MHz, DMSO-d6) δ 157.2, 155.5, 144.5, 144.0, 134.7, 132.3, 131.1, 130.2, 128.3, 127.5, 126.8,
124.5, 123.6, 121.3, 116.8, 116.7, 115.0, 107.6. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C18H12N3O: 286.0980; Found: 286.0970.
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3-(6-Bromo-1H-benzo[d]imidazol-2-yl)benzo[c]isoxazole (6e). Synthesized according to the
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general procedure and isolated as a yellow powder (0.0181 g, 28.9%); mp 245−247°C. H NMR
(400 MHz, DMSO-d6) δ 13.99 (s, 1H), 8.28 – 8.21 (m, 1H), 8.00 (broad, 1H), 7.83 – 7.72 (m, 2H),
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7.59 – 7.51 (m, 1H), 7.48 (s, 1H), 7.36 – 7.28 (m, 1H). C NMR (101 MHz, DMSO-d6) δ 157.6,
155.8, 132.7, 127.6, 126.9, 126.4, 122.6, 122.1, 121.6, 116.7, 115.3, 114.4, 79.6. HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C14H9BrN3O: 313.9929; Found: 313.9917.
3-(6-Methoxy-1H-benzo[d]imidazol-2-yl)benzo[c]isoxazole (6f). Synthesized according to the
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general procedure and isolated as a dark yellow solid (0.0254 g, 47.9%); mp decomp. H NMR
(400 MHz, DMSO-d6) δ 13.69 – 13.58 (m, 1H), 8.29 – 8.21 (m, 1H), 7.77 – 7.69 (m, 2H), 7.56 –
7.47 (m, 1H), 7.31 – 7.23 (m, 1H), 7.07 – 6.90 (m, 2H), 3.86 – 3.82 (m, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 157.9, 157.5, 156.4, 145.3, 140.3, 139.0, 135.8, 132.6, 126.3, 121.9, 121.0, 115.9,
115.0, 113.9, 113.0, 101.8, 94.7, 56.0. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C15H12N3O2:
266.0930; Found: 266.0915.
3-(5,6-Dimethyl-1H-benzo[d]imidazol-2-yl)benzo[c]isoxazole (6g). Synthesized according to
the general procedure and isolated as a yellow powder (0.0160 g, 30.4%); mp 268−270°C. 1H NMR
(400 MHz, DMSO-d6) δ 13.81 (s, 1H), 8.42 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.16 – 8.03 (m, 3H),
7.81 (d, J = 9.1 Hz, 1H), 7.58 (dd, J = 9.1, 6.3 Hz, 1H), 7.43 (d, J = 6.0 Hz, 2H), 7.37 (dd, J = 8.8,
6.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 157.5, 156.6, 140.3, 132.6, 126.3, 121.9, 116.1,
115.1, 20.6. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C16H14N3O: 264.1137; Found: 264.1122.
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3-(1H-benzo[d]imidazol-2-yl)-5,6-dimethoxybenzo[c]isoxazole (6h). Synthesized according to
the general procedure and isolated as a yellow powder (0.0191 g, 32.4%); mp decomp. 1H NMR
(400 MHz, DMSO-d6) δ 13.56 (s, 1H), 7.71 (broad, 2H), 7.34 (s, 1H), 7.32 (broad, 2H), 7.04 (s, 1H),
3.95 (s, 3H), 3.93 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ 155.9, 155.8, 153.0, 151.5, 141.7, 112.8,
95.7, 91.7, 79.6, 56.6, 56.4. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C16H14N3O3: 296.1035;
Found: 296.1030.
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3-(1H-tetrazol-5-yl)benzo[c]isoxazole (6i). Synthesized according to the general procedure and
isolated as a yellow solid (0.0232 g, 62.0%); mp 142−144°C. 1H NMR (400 MHz, DMSO-d6) δ 8.16
(dd, J = 8.8, 1.1 Hz, 1H), 7.60 (d, J = 9.1 Hz, 1H), 7.42 (ddd, J = 9.1, 6.3, 1.1 Hz, 1H), 7.11 (dd, J
= 8.8, 6.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 157.0, 153.2, 132.0, 124.2, 122.8, 114.6,
114.5. HRMS (ESI-Orbitrap) m/z: [M - H]- Calcd for C8H4N5O: 186.0421; Found: 186.0423.
(E)-(2-(((1H-benzo[d]imidazol-2-yl)(2-nitrophenyl)methylene)amino)phenyl)(1H-
benzo[d]imidazol-2-yl)methanone (7). A 2-5 mL Biotage microwave vial was charged with a stir rod,
4a (0.0506 g, 0.2 mmol), and potassium hydroxide (0.056 g, 1 mmol), and methanol (4 mL) and
o
water (0.4 mL). The mixture was heated under microwave irradiation at 60 C for 6 hours. The
reaction was cooled room temperature and water (100 mL) was added and the solution was
extracted 3 times with ethyl acetate (50 mL). The organic layers were combined and removed under
reduced pressure. The crude reaction mixture was purified by flash column chromatography using
mixtures of ethyl acetate/hexanes to afford the product as a yellow solid (0.0182 g, 18.7%); mp
decomp. 1H NMR (400 MHz, DMSO-d6) δ 13.77 (broad, 2H), 8.29 (d, J = 1.1 Hz, 1H), 8.26 (d, J =
1.1 Hz, 1H), 7.98 (td, J = 7.5, 1.1 Hz, 2H), 7.92 – 7.84 (m, 4H), 7.70 (broad, 1H), 7.68 (broad, 1H),
7.62 (broad, 1H), 7.60 (broad, 1H), 7.41 (broad, 2H), 7.29 (broad, 2H). 13C NMR (101 MHz, DMSO-
d6) δ 184.8, 147.7, 147.4, 142.9, 134.8, 134.6, 133.7, 132.1, 129.9, 126.2, 124.2, 123.4, 121.3,
113.0. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C28H19N6O3: 487.1519; Found: 487.1490.
Acknowledgements
The authors dedicate this work in memory of Roland J. Kurth, a wonderful and gracious mentor.
JSZ thanks Prof. David E. Olson (UC Davis) for helpful discussions. DJT gratefully acknowledges
support from the US National Science Foundation (XSEDE program). MJK gratefully acknowledges
support from the National Institutes of Health (DK072517) and the UC Davis Tara K. Telford CF
Fund (fellowship to JSZ).
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Supporting information. Computational details, reaction mechanisms, NMR spectra, and X-ray
crystallography data (PDF).
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