Di- and Trifluorinated 2-Azidobenzimidazole Derivatives: Synthesis, Photooxygenation, and 19F NMR Prediction

Article abstract of DOI:10.1002/ejoc.202100603

The photoreactivity of a series of hitherto unknown, multiply fluorinated 2-azidobenzimidazole derivatives was investigated. The synthesis of the starting material includes regioselective p-defluorination of nitrobenzene derivatives employing Ogoshi's conditions. If the 6-position was unsubstituted, irradiation in the presence of N-protected amino acids at 300 nm (Rayonet) led to the formation of arylesters by oxygenation of the 6-position in good to excellent yields and perfect regioselectivity. We did not observe any displacement of fluoride. If the 6-position itself was fluorinated, alternative positions of the benzene portion were attacked. Mechanistically, the reaction proceeds through ring opening of the singlet nitrene to the cyanodiimine or via the iminobenzimidazolium ion. The availability of a set of fluorinated photo-adducts prompted the quantum chemical calculation of their ¹⁹F NMR chemical shifts. Even with the most suitable method investigated (ωB97XD/TApr-cc-pVDZ), deviations of up to 5 ppm from the experimental values were observed, underlining the importance of experimental measurements.

Full text of DOI:10.1002/ejoc.202100603

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Di- and trifluorinated 2-azidobenzimidazole derivatives: synthesis,
photooxygenation, and 19F NMR prediction
Authors: Nils Eckhard Kanitz, Marvin Fresia, Peter G Jones, and
Thomas Lindel
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100603
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01/2020

10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
Di- and trifluorinated 2-azidobenzimidazole derivatives:
synthesis, photooxygenation, and 19F NMR prediction
Nils E. Kanitz[a], Marvin Fresia[a], Peter G. Jones[b], and Thomas Lindel[a],*
Dedicated to the memory of Professor Ludger Ernst
Abstract. The photoreactivity of a series of hitherto unknown, multiply
fluorinated 2-azidobenzimidazole derivatives was investigated. The
synthesis of the starting material includes regioselective p-
defluorination of nitrobenzene derivatives employing Ogoshi's
conditions. If the 6-position was unsubstituted, irradiation in the
presence of N-protected amino acids at 300 nm (Rayonet) led to the
formation of arylesters by oxygenation of the 6-position in good to
excellent yields and perfect regioselectivity. We did not observe any
displacement of fluoride. If the 6-position itself was fluorinated,
alternative positions of the benzene portion were attacked.
Mechanistically, the reaction proceeds via ring opening of the singlet
nitrene to the cyanodiimine or via the iminobenzimidazolium ion. The
availability of a set of fluorinated photoadducts prompted the quantum
chemical calculation of their 19F NMR chemical shifts. Even with the
most suitable method investigated (ωB97XD/TApr-cc-pVDZ),
deviations of up to 5 ppm from the experimental values were observed,
underlining the importance of experimental measurements.
substituent could be used to distinguish between carboxylates as
a group, chloride, bromide, and hydrogen placed in the reactive
6-position.
N
N
N
N
300 nm (Rayonet)
HOAc, –N2
NH2
N3
6
AcO
1
2
Scheme 1. Regioselective photo 6-acetoxylation of 2-azido-1-
methylbenzimidazole
In this paper, we analyze the photoreactivity of all six difluorinated
2-azidobenzimidazole derivatives, and of the 4,5,7-trifluoro
compound. Fluorinated 2-azidobenzimidazoles have not been
described previously. It was to be seen, whether C6 would remain
the single favored position of nucleophilic attack, with the fluorine
substituents remaining in place. The study would give us the
opportunity to validate the predictability of the 19F NMR shifts of
these heterocycles by quantum chemical calculation. Perhaps the
combination of several 19F NMR chemical shifts would allow to
distinguish even between similar amino acid nucleophiles. Finally,
the outcome of the title reaction was unclear, if the reactive 6-
position was blocked by a fluoro substituent.
Introduction
Research on marine natural products containing 2-
aminoimidazole moieties led us to the discovery of the photo-
induced, regioselective oxygenation of 2-azidobenzimidazole
1
]
derivatives in the 6-position (Scheme 1).[
For instance,
irradiation of 2-azido-1-methylbenzimidazole (1) in the presence
of acetic acid at 300 nm (Rayonet apparatus) afforded 6-acetoxy-
2-aminobenzimidazole derivative 2 in high yield. We could show
that N-protected amino acids and certain peptides reacted
chemoselectively with their carboxy termini, even in the presence
of water.[2] In a pilot study, we extended our reaction to 4-, 5-, and
7-monofluoro derivatives of 2-azidobenzimidazole.[3] We hoped to
be able to conclude on the structure of adducts and other
irradiation products by 19F NMR spectroscopy even in complex
mixtures. Encouragingly, the 19F NMR signal of the fluorine
Synthesis of the fluorinated 2-azidobenzimidazoles
For accessing the hitherto unknown fluorinated 2-
azidobenzimidazoles, we followed two routes. The 4,7-difluoro,
5,7-difluoro, and 4,5,7-trifluoro derivatives 3, 4, and 5,
respectively, were assembled via N-methylated nitroanilines
(Scheme 2).
Monodefluorination
of
1,2,3,5-tetrafluoro-4-
nitrobenzene (3) and of pentafluoronitrobenzene (5) occurred
regioselectively in the p-position to the nitro group on treatment
with
Ph3SiH/cat.
TBAT
(tetrabutylammonium
difluorotriphenylsilicate, Ogoshi's conditions, Scheme 2).[
4
]
Gratifyingly, the hitherto unknown non-symmetrical 1,2,4-trifluoro-
3-nitrobenzene obtained from 3 reacted with methylamine
regioselectively at C2, affording the difluorinated N-
methylnitroaniline 7 (5JFF 6 Hz).
[a]
M. Sc. N. E. Kanitz, M. Sc. M. Fresia, Prof. Dr. T. Lindel
Institute of Organic Chemistry
Technical University Braunschweig
Hagenring 30, 38106 Braunschweig, Germany
E-mail: th.lindel@tu-braunschweig.de
Homepage: www.oc.tu-bs.de/lindel
The trifluorinated analog 8 was obtained accordingly. Differing
from
3 and 5, 2,4-difluoro-N-methyl-6-nitroaniline (6) was
obtained from the corresponding nitroaniline (4) with Me2SO4
under alkaline phase transfer conditions (89%). The fluorinated
N-methylnitroaniline derivatives 6, 7, and 8 were converted to the
corresponding benzimidazoles (9, 10, 11) by reductive (Fe)
condensation with formic acid.[5] Azidation of 9, 10 and 11 was
performed with TosN3 after 2-lithiation and sodium pyrophosphate
[b]
Prof. Dr. P. G. Jones
Institute of Inorganic and Analytical Chemistry
Technical University Braunschweig
Hagenring 30, 38106 Braunschweig, Germany
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
work-up.[6] We obtained azidobenzimidazoles 12, 13, and 14 that
Scheme 3. Synthesis of 4,5- and 4,6-difluoro derivatives of 2-
azidobenzimidazole,
X-ray
analysis
of
22
(TBABr:
could be stored for months at 4 °C without decomposition.
tetrabutylammonium bromide)
F
1) Ph3SiH (1.1 eq.), TBAT
(5 mol%), PhMe, rt, 1 d
X
F
NO2
F
The synthesis of 2-azido-4,5-difluoro- (22) and 2-azido-4,6-
difluoro-1-methylbenzimidazole (23) started from the
2) NH2Me (1.1 eq.),
THF, 0 °C to rt, 2 h
Y
F
regioisomeric difluorinated nitroaniline derivatives 15 and 16 that
were converted to the corresponding benzimidazoles (17, 18,
Scheme 3). Methylation of 4,5-difluorobenzimidazole (17)[ 7 ]
afforded two separable regioisomers (19, 21), of which 19 (69%,
NOESY correlation between N-CH3 and 7-H) was converted to
4,5-difluorinated azidobenzimidazole 19. We obtained an X-ray
analysis of azido compound 22 that proved the regiochemical
outcome of the preceding methylation.[8] The 6,7-difluoro analog
was obtained in an analogous manner from side product 21. The
synthesis of the 5,6-difluorinated derivative started from 4,5-
difluorobenzene-1,2-diamine (see the SI).
F
X
NO2
NH
3
5
: X=H
: X=F
Me2SO4 (5 eq.), 2 M aq.
NaOH, TBABr (1 mol%),
PhMe, rt, 2 d
6: X=F, Y=H (quant. from 4)
: X=H, Y=F (69% from
8: X=Y=F (65% from 5)
NO2
NH2
F
7
3
)
Fe (10 eq.),
F
NH4Cl (10 eq.),
iPrOH/HCOOH
(1:1), rf, 3 h
4
Y
4
Y
i) n-BuLi (1.1 eq.),
Irradiation experiments
X
X
N
N
Et2O, –78 °C, 30 min
N
N
5
N3
The irradiation experiments were performed on a preparative
scale in a Rayonet reactor (300 nm) at 10 mM concentration in a
borosilicate flask in DCM. As reaction partners, we chose HOAc,
ii) TosN3 (1.1 eq.),
78 °C to rt, 2 h
iii) Na4P2O7ꞏ10 H2O,
rt, 12 h
7
F
F
12: X=F, Y=H (73%)
: X=H, Y=F (81%)
: X=Y=F (82%)
9: X=F, Y=H (90%)
: X=H, Y=F (88%)
: X=Y=F (86%)
13
14
10
11
pivalic acid, and Boc-protected glycine,
L-alanine, L-valine, L-tert.-
leucine, and -phenylalanine. As observed for the non-fluorinated
L
Scheme 2. Route to 4,7-difluoro, 5,7-difluoro, and 4,5,7-trifluoro
derivatives of 2-azidobenzimidazole via N-methylnitroanilines
(TBABr: tetrabutylammonium bromide, TBAT: tetrabutylammonium
difluorotriphenylsilicate)
analog,[3,4] about 2 h were needed for the complete decomposition
of 2-azido-4,5-difluoro-1-methylbenzimidazole (22) in DCM/HOAc
(8:1). After rapid formation of about 40% of product, the reaction
rate dropped. A similar observation as for 22 was made on
irradiation of 2-azido-1,3-thiazole and of 2-azidobenzothiazole.[9]
Fe (10 eq.),
i) NaH (1.1 eq.),
THF, 0 °C to rt
ii) CH3I (1.1 eq.),
0 °C to rt
NH4Cl (10 eq.),
i-PrOH/HCOOH
(1:1), 85 °C
F2, F3
O
Y
X
NO2
NH2
Y
X
N
N
N
R1 OH
O
NH2
N
H
R1
O
R1 = Me, t-Bu
F
F
F2, F3
17: X=F, Y=H (89%)
18
15: X=F, Y=H
: X=H, Y=F (79%)
N
N
16
24-31
: X=H, Y=F
N3
300 nm (Rayonet), DCM
O
6
H
(i) n-BuLi (1.1 eq.), Et2O, –78°C
(ii) TosN3 (1.1 eq.),
Y
Y
X
N
N
N
N
BocHN
F2, F3
78 °C to rt
12, 13, 14, 22
N3
OH
N
R2
X
O
NH2
(iii) Na4P2O7ꞏ10 H2O, rt
F
F
BocHN
N
R2 = H, Me, t-Bu, Bn
O
19: X=F, Y=H (64%)
20
22: X=F, Y=H (81%)
23
R2
: X=H, Y=F (61%)
: X=H, Y=F (73%)
32-47
+
(X=F, Y=H)
Scheme 4. Irradiation of 6-unsubstituted difluoro and trifluoro 2-
azidobenzimidazole derivatives 12, 13, 14, 22 in the presence of
carboxylic acids (for structures and yields, see Figure 1)
N
N
F
F
21
22
(20%)
[1]
[2]
A. Sudakow, P. G. Jones, T. Lindel, Eur. J. Org. Chem. 2012,
681–684.
A. Sudakow, U. Papke, T. Lindel, Chem. Eur. J. 2014, 20,
10223–10226.
N. E. Kanitz, T. Lindel, Z. Naturforsch. 2016, 71b, 1287–1300.
K. Kikushima, M. Grellier, M. Ohashi, S. Ogoshi, Angew.
Chem. Int. Ed. 2017, 56, 16191–16196.
E. J. Hanan, B. K. Chan, A. A. Estrada, D. G. Shore, J. P.
Lyssikatos, Synlett 2010, 2759–2764.
[6]
[7]
[8]
P. Zanirato, S. Cerini, Org. Biomol. Chem. 2005, 3, 1508–
1513.
H. M. Alkahtani, A. Y. Abbas, S. Wang, Bioorg. Med. Chem
Lett. 2012, 22, 1317–1321.
CCDC-2048726 contains the supplementary crystallographic
data for compound 22, which can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam. ac.uk/data_request/cif (12, Union Road,
Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or
deposit@ccdc.cam.ac.uk).
[3]
[4]
[5]
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10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
[9]
M. D'Auria, R. Racioppi, L. Viggiani, P. Zanirato, Eur. J. Org.
Chem. 2009, 932–937.
F
F
F
F
F
F
F
F
F
F
N
N
N
N
N
N
N
N
N
O
O
O
O
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
N
O
AcO
O
O
O
t-Bu
Bn
44 (63%)
24 (89%)
36 (80%)
40 (74%)
32 (62%)
F
F
F
F
F
N
N
N
N
N
N
N
N
N
O
O
O
O
NH2
NH2
NH2
NH2
BocHN
BocHN
BocHN
N
O
AcO
O
O
O
F
(63%)
F
F
(48%)
F
(65%)
t-Bu
F
(70%)
Bn
45
25
37
41
(81%)
33
F
F
F
F
F
N
N
N
N
N
N
N
N
N
N
O
O
O
O
NH2
NH2
NH2
NH2
BocHN
BocHN
BocHN
O
AcO
O
O
O
F
F
F
F
F
t-Bu
Bn
46 (63%)
26 (76%)
38 (71%)
42 (58%)
34 (59%)
F
F
F
F
F
F
F
F
F
F
N
N
N
N
N
N
N
N
N
O
O
O
O
NH2
NH2
NH2
NH2
BocHN
BocHN
BocHN
N
O
AcO
O
O
O
F
(79%)
F
27
F
(73%)
F
(55%)
t-Bu
F
(69%)
Bn
47
39
43
(91%)
35
Figure 1. Photoadducts obtained by irradiation of difluoro and trifluoro 2-azidobenzimidazoles 12, 13, 14, and 22 in the presence of carboxylic
acids. Conditions: carboxylic acid (HOAc: neat; amino acids: 4 eq.), 300 nm (Rayonet), 10 mM in DCM, 2 h.
If the 6-position was unsubstituted, regioselective 6-oxygenation
took place in yields between 48% and 91% (Scheme 4, Figure 1).
We did not observe substitution of any of the fluoro substituents
by carboxylate. We synthesized amino acid aryl esters (24–47)
from five carboxylic acids and four fluorinated 2-
azidobenzimidazole derivatives (4,5-difluoro, 4,7-difluoro, 5,7-
difluoro, 4,5,7-trifluoro). With the exception of the irradiation
experiments in pure acetic acid, we observed formation of the
reduced side product 2-amino-1-methylbenzimidazole that was
very difficult to remove by column chromatography. For
satisfactory yields, it proved to be necessary to use at least four
equivalents of carboxylic acid. This became clear on irradiation of
2-azido-1-methyl-5-fluorobenzimidazole[3] in the presence of
varying concentrations of Boc-tert.-Leu (4, 3, 2, 1 eq.), affording
isolated yields of 89%, 69%, 43%, and 29% of aryl ester,
respectively. Irradiation in the presence of ammonium chloride
provided the 6-chlorinated 2-aminobenzimidazole derivatives
(see the SI).
6-fluoro derivative 50 in equal amounts (25–30%) as major
products. Quantum chemical calculation (ωB97XD/TApr-cc-
pVDZ, vide infra) predicts the 19F NMR chemical shift of 50 (exp
‒
140.7, calc ‒140.5). The 4,6- and 6,7-difluorinated 2-
azidobenzimidazole derivatives 23 and 51 (obtained from 21)
reacted in a cleaner manner to the regioisomeric diacetoxy
monofluoro compounds 52 (75%) and 53 (67%), respectively,
which could be isolated and purified. According to NMR analysis,
the single aromatic hydrogen 5-H of both 52 and 53 is placed para
to C7a and vicinal to the fluoro substituent. Positioning of the
fluorine atoms at C6 (53) and C4 (52), respectively, was possible
based on the analysis of all JCF coupling constants, after having
4
identified the acetoxylated carbon atoms based on weak JHC
-
correlations shown by the acetyl methyl groups (53: JC7a-F < 2 Hz;
52: JC7a-F 17.6 Hz). In the case of 53, the 19F NMR chemical shift
was accurately predicted (exp ‒140.9, calc ‒140.0). For the 4-
fluorinated product 52 the deviation was greater (exp ‒134.7, calc
‒127.9), as we had already observed for the 4,7-difluorinated
compounds (Scheme 6).
6-Fluorinated 2-azidobenzimidazoles
In a second series of experiments, we irradiated our 6-fluorinated
2-azidobenzimidazole derivatives in acetic acid (Scheme 5).
Monofluorinated compound 48[3] afforded a mixture containing
6,7-diacetoxylated 2-aminobenzimidazole 49 and the 5-acetoxy-
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10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
exp. –140.9
calc. –140.0
F
F
F
OAc
X
N
N
N
– 15.4 kcalmol-1
F
F
N
N
N
N
X=F, Y=H
CN
NH2
N3
N
6,7-difluoro
N
F
OAc
54
55
Y
48
: X=Y=H
51: X=F, Y=H
: X=H, Y=F
+ H+
53
Nu
6
HOAc, 2 h
Rayonet(300 nm)
Nu
6
+ H+
23
F
F
F
A
B
N
H
N
N
+ 21.0 kcalmol-1
OAc
NH
X=H, Y=F
AcO
N
N
CN
N
NH2
4,6-difluoro
F
exp. –134.7
calc. –127.9
56
57
F
17.7 Hz
X=Y=H
6-fluoro
52 (75%)
Scheme 6. Energy differences calculated for singlet nitrene 54 and
diazaxylylene 55 and for their protonated forms 56 and 57 (B3LYP/6-
31G*, gas phase)
exp. –140.7
calc. –140.5
OAc
N
When reacting the 6-fluorinated 2-azidobenzimidazoles (23, 48,
51), re-formation of the aromate in the second step is excluded.
As for nitrene 54 (Scheme 6), ring opening to the N-
cyanodiazaxylylene or protonation to the closed iminium ion may
occur after loss of dinitrogen. Scheme 7 outlines a possible
mechanism for the case of coarctate ring opening of the singlet
nitrene.
F
AcO
N
N
+
NH2
NH2
N
AcO
(1:1, not sep,
main products)
49
50
Scheme 5. Irradiation of 2-azidobenzimidazole derivatives 23, 48, 51
with a blocked, fluorinated 6-position. Experimental and calculated
19F NMR chemical shifts (ωB97XD/TApr-cc-pVDZ) are given.
X
coarctate
ring opening
AcO
N
F
N
N
6
H
48: X=H, Y=H
51: X=F, Y=H
HOAc, hꞏ
A
Reaction mechanism
23
– N2
: X=H, Y=F
Y
It can be assumed that irradiation causes the azido group to lose
dinitrogen forming a singlet nitrene. Five-membered heterocycles
carrying a singlet nitrene functionality in vicinity of the heteroatom
can undergo coarctate ring opening to conjugated 6
systems.[10,11] Gadosy and McClelland have shown that irradiation
of 2-azido-1-methylimidazole affords a mixture of an iminium ion
and an N-cyanodiimine in competing processes.[ 12 ] Similar
behavior was observed by Wilson, Platz, et al. for 8-
azidoadenosine derivatives.[13,14] For the 4,7-difluorinated singlet
nitrene 54, we performed orienting quantum chemical calculations
(B3LYP/6-31G*, gas phase) to estimate on the behavior of the
nitrene. The non-protonated neutral singlet nitrene 54 would
undergo almost barrier-free ring opening to the (1E,6Z)-
diazaxylylene 55, which is more stable than 54 by about
15 kcalꞏmol-1. However, protonation of the singlet nitrene at the
exocyclic nitrogen would change the picture and prevent ring
opening. The closed 2-iminoimidazolium ion 56 was calculated to
be by 21 kcalꞏmol-1 more stable than the opened protonated
(1E,6Z)-diazaxylylene 57 and could also participate in the
mechanism. The pKa value of 57 should be similar enough to
those of the carboxylic acid reaction partners. In either case,
attack of a nucleophile at C6 would be preferred (Scheme 7).
HOAc  attack at C6
attack at C7
X=H, Y=H
X=F, Y=H
X=H, Y=F
attack at C5
X
AcO
N
AcO
F
NH2
N
6
X=H, Y=H:
[3,3]
acetate
Y
migration
B
X OAc
F
NH
N
AcO
F
NH
7
5
H
N
N
H
AcO
N
H
H
OAc
Y
C
D
X=H, Y=H, F:
–HF
X=F, Y=H:
[3,3], –HF
acetate
migration
–HOAc
4,6-difluoro
6-monofluoro
6,7-difluoro
6-monofluoro
59
60 50
,
58
, respectively
Scheme 7. Possible mechanism of the formation of products 50, 58,
59, and 60 in the case of coarctate ring opening.
Nucleophilic attack of acetate at the -position of the ,-
unsaturated iminium moiety of intermediate A should still occur,
followed by nitrogen protonation affording intermediate B.
Depending on substituents X and Y, a second acetate could
attack at C5, C7, or both (X=Y=H), leading to the fluorinated
diacetoxy intermediates C or D, respectively. A 6,7-difluorinated
intermediate C could undergo [3,3] sigmatropic acetate migration
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10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
to 59, followed by loss of HF, affording the product. If intermediate
C is 4,6-difluorinated or 6-monofluorinated, loss of HF would
happen directly without prior acetate migration to product 60 and
50, respectively. Intermediate D would lose HOAc to form 58.
chemical shift differences are observed within the series of 4,7-
and 5,7-difluorinated photo adducts. In both cases, the 19F NMR
chemical shifts of the aryl esters can clearly be distinguished from
those of the azido compound, which are shifted by about 15–
20 ppm to lower field.
The thermodynamically more stable triplet nitrenes appear to play
an increasing role, if sterically hindered nucleophiles are
employed, giving the system time to undergo ISC. Differing from
the neutral singlet nitrene, the triplet nitrene prefers the intact
benzimidazole core. With pivalic acid as nucleophile, we obtained
the 6-unsubstituted amine 62 as major side product (17%,
Scheme 8). As a second byproduct, we isolated the non-
symmetrical orange-colored diazo compound 64 (7%), which
must have been formed by coupling of triplet nitrenes 61 and 63.
Possibly, triplet nitrene 61 oxidizes the main reaction product 6-
pivaloyl-2-amino-1-methylbenzimidazole (28) to triplet nitrene 63
and is itself reduced to amine 62. In a second pathway to amine
62, triplet nitrene 61 could oxidize pivalate to the carboxyl radical,
which subsequently would undergo decarboxylation, followed by
oxidation of the radical to the cation.[15] The solvent DCM is inert.
When 22 was irradiated in CD2Cl2 in the presence of pivalic acid
(4 eq.), no incorporation of deuterium occurred, excluding the
solvent as the source of hydrogen.
–(159.00.4)
–(157.70.9)
F
R
O
O
R
N
N
N
N
O
NH2
O
NH2
F
F
F
F
–(156.81.0)
–(155.80.2)
exp. –(162.91.1)
calc. –(162.70.5)
–(136.60.1)
–(132.60.2)
–(155.01.3)
–(152.9 0.3)
–(158.30.4)
–(158.40.1)

F
F
O
R
R
O
N
N
O
NH2
N
O
NH2
N
F
F
–(161.40.5)
–(161.20.1)
–(139.01.5)
–(134.20.4)
–(162.10.2)
–(160.60.7)
Figure 2. Averaged experimental (above) and calculated (below,
ωB97XD/TApr-cc-pVDZ) 19F NMR chemical shifts of acyloxy
photoarylation products 24-47
O
F
Having a set of fluorinated 2-aminobenzimidazole derivatives in
hand, we performed quantum chemical calculations of the
19F NMR chemical shifts for all of our 6-acyloxylated compounds.
We compared the experimental 19F NMR chemical shifts of 4-F
and 7-F of the 4,7-difluorinated 6-acetoxy compound 25 with the
calculated values obtained with the functional/basis set
combinations B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p),
ωB97XD/TApr-cc-pVDZ, and ωB97XD/TApr-cc-pVTZ (see the
SI). The smallest deviation was found for ωB97XD/TApr-cc-pVDZ
(calc-exp 3.2 ppm (4-F) and 0.0 ppm (7-F)), which was used for
all further calculations. The B3LYP/6-311+G(d,p) calculation,
which had shown good accuracy for trifluoromethyldiazirines,[16]
showed higher deviations (calc-exp –7.8 ppm (4-F) and –3.6 ppm
(7-F)). The highest averaged deviations between calculated and
experimental values were observed for 5-F of the 5,7-difluorinated
(calc-exp +4.8 ppm) and 4-F of the 4,7-difluorinated (calc-exp
+4.0 ppm) adducts. The highest accuracy was obtained for the
4,5-difluorinated series (averaged calc-exp +0.2 ppm (5-F) and
+1.0 ppm (4-F)). The 19F NMR chemical shifts of the 4,5,7-
trifluorinated adducts were so similar, that the quantum chemical
calculation would not have allowed assignments of the shifts. The
quantum chemical method we chose showed a performance
comparable to the (GIAO)/B3LYP/6-311++G(d,p) calculations by
Alkorta et al. for 4,5,6,7-tetrafluoro-1-methylbenzimidazole.[17]
F
OH
F
F
N
N
N
N
NH2
N
, – CO2
–
61 (triplet)
62 (17%)
F
F
N
N
NH2
28 (67%)
62
–
F
PivO
F
F
N
F
N
N
N
N
N
N
61
(triplet)
N
N
F
PivO
PivO
F
64 (7%)
63 (triplet)
Scheme 8. Possible formation of 2-aminobenzimidazole 62 and of
diazo compound 64 from triplet nitrene 61 on reaction with pivalic acid
Predictability of the 19F NMR chemical shifts
Figure 2 summarizes the averaged 19F NMR chemical shifts
observed for all difluorinated and trifluorinated adducts obtained
from the 6-unsubstituted 2-azidobenzimidazole derivatives. For
the 4,5-difluorinated adducts, we observed strong H,13C HMBC
1
correlations between 7-H and C5, which allowed the assignment
of all 13C NMR signals. Subsequent assignment of the fluorine
atoms exploited the coupling constants of the 13C satellite signals
in the 19F NMR spectrum. Similarly, the 5,7-difluorinated adducts
were assigned. In the H NMR spectra of the 4,7-adducts, 5-H
appeared as doublet of doublets (10 and 5 Hz), assigning the 3JHF
Conclusion
In summary, multiply fluorinated 2-azidobenzimidazoles have
been synthesized for the first time and investigated regarding their
preparative photochemistry. Their short syntheses pass via N-
methylated nitroanilines, obtained via regioselective p-
defluorination, or N-methylation of fluorinated benzimidazoles.
Irradiation of the 6-unsubstituted 2-azidobenzimidazoles in the
presence of carboxylic acids including a series of amino acids
regioselectively afforded the 6-acyloxy products in good to
excellent yield without displacement of any of the other fluorine
1
4
and JHF couplings, respectively. Assignment of the trifluoro
adducts exploited the fact that the 3JFF coupling constant is largest,
4
5
followed by JFF and JFF. As we had observed for the
corresponding monofluorinated 2-amino-6-acyloxybenzimidazole
derivatives,[3] there is only small 19F NMR dispersion among
entries of the same fluorination series. The largest 19F NMR
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10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
substituents. If the 6-position was blocked by a fluorine
substituent, the outcome was less predictable with acetoxy
groups being also incorporated at the neighboring positions. The
19F NMR chemical shift differences between photoadducts
obtained from different carboxylates are surprisingly small. The
19F NMR chemical shifts of the arylesters can easily be
distinguished from those of the unreacted azido compound.
Quantum chemical calculations showed deviations of the
calculated and experimental 19F NMR chemical shifts of the
irradiation products as high as 5 ppm. Thus, it was necessary to
synthesize all compounds in order to obtain the true values. In
principle, 2-azidobenzimidazole-type compounds could also
become useful for photoaffinity labelling (PAL), a technique that
covalently attaches ligands to their putative biological targets by
irradiation, mainly by exploiting diazirine, benzophenone, and
phenyl azide chemistry.[18] For diazirine moieties we had found
low chemoselectivity, even when reacted with phenol or small
peptides.[19] Ideally, fluoro substituents would serve as probes in
19F NMR experiments. 19F NMR is background free in biological
systems and 19F NMR chemical shifts are sensitive to their
Supporting Information
The Supporting Information contains all relevant experimental
procedures, characterization data, X-ray data, results of quantum
chemical calculations, and NMR spectra.
AUTHOR INFORMATION
Corresponding Author
* E-mail: th.lindel@tu-bs.de
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
ACKNOWLEDGMENT
20
]
biomolecular environment.[
In upcoming research, the
decomposition rates of the azido groups will have to be addressed.
We thank TU Braunschweig for financial support.
Keywords: azido compounds, heterocycles, nitrenes,
photochemistry, quantum chemical calculation
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10.1002/ejoc.202100603
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Heterocycles
N. E. Kanitz, M. Fresia, P. G. Jones, T.
Lindel*
Page No. – Page No.
Di-
and
trifluorinated
2-
azidobenzimidazole
derivatives:
synthesis, photooxygenation, and 19F
NMR prediction
Photofunctionalization of amino acids with fluorinated azidobenzimidazoles: Irradiation in the presence of N-protected amino
acids at 300 nm (Rayonet) affords fluorinated arylesters by oxygenation of the 6-position in good to excellent yields and perfect
regioselectivity. Even with the most suitable method investigated (ωB97XD/TApr-cc-pVDZ), deviations of up to 5 ppm from the
experimental values were observed, underlining the importance of experimental measurements.
–133.7
–(155.01.3)
O
F
F
O
R
N
N
N
R
OH
O
N3
NH2
N
h
F
F
regioselective
–118.4
–(139.01.5)
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