2-Fluoro-5-nitrophenyldiazonium: A Novel Sanger-Type Reagent for the Versatile Functionalization of Alcohols

Article abstract of DOI:10.1002/chem.202100187

As a novel Sanger-type reagent, 2-fluoro-5-nitrophenyldiazonium tetrafluoroborate enabled the versatile functionalization of primary and secondary aliphatic alcohols. Based on a mild nucleophilic aromatic substitution of the fluorine atom under unprecedented, base-free conditions, the diazonium unit on the aromatic core of the resulting aryl-alkyl ether could be employed for such diverse transformations as radical C?H activation and cyclization, as well as palladium catalyzed cross-coupling reactions.

Full text of DOI:10.1002/chem.202100187

Communication
doi.org/10.1002/chem.202100187
Chemistry—A European Journal
&
Alcohol Functionalization
2-Fluoro-5-nitrophenyldiazonium: A Novel Sanger-Type Reagent
for the Versatile Functionalization of Alcohols
Oliver Fischer and Markus R. Heinrich*[a]
fields as water analysis,[2a] photosensitization,[2b] and medicinal
Abstract: As a novel Sanger-type reagent, 2-fluoro-5-nitro-
chemistry.[2c] Given this vast potential, it was interesting to
phenyldiazonium tetrafluoroborate enabled the versatile
note that among the Sanger reagents, the free diazonium de-
functionalization of primary and secondary aliphatic alco-
rivative 3 has not yet been studied (Scheme 1D). While the in-
hols. Based on a mild nucleophilic aromatic substitution
creased reactivity of 3 compared to 1 and 2 could enable sub-
of the fluorine atom under unprecedented, base-free con-
stitutions with even weakly nucleophilic reagents like aliphatic
ditions, the diazonium unit on the aromatic core of the re-
alcohols under mild conditions, such substitution on the aro-
sulting aryl-alkyl ether could be employed for such diverse
matic core of 3 would have to proceed under acidic or at most
transformations as radical CÀH activation and cyclization,
neutral conditions due to the reactivity of the diazonium
as well as palladium catalyzed cross-coupling reactions.
unit.[3] Generally, nucleophilic aromatic substitutions on diazo-
nium salts are yet rare in literature with few synthetic applica-
tions,[4] whereas drawbacks arise from the necessity to use the
nucleophile as solvent (Scheme 1B)[4a] or the requirement to
Sanger-type reagents have a long history in organic chemis-
try,[1] and it is now 75 years ago that Frederick Sanger intro-
duced 1-fluoro-2,4-dinitrobenzene (1) for the labeling of termi-
nal amino groups in peptides (Scheme 1A).[1a] Since then, the
dinitro-benzenes 1 and 2— representing key derivatives— have
been widely used,[2] with recent applications in such diverse
protect the diazonium unit as a triazene (Scheme 1C).[4b] On
the other hand, the presence of a diazonium group on an aryl-
alkyl ether such as 4 would enable a broad range of further
functionalizations,[5,6] which cannot be achieved with the tradi-
tional dinitro substitution pattern.
Among these diazonium-based functionalizations, a particu-
larly valuable group are radical translocation reactions,[7] which
have recently been studied by Baran and co-workers,[7a] Ra-
gains and co-workers,[7b,c] and Studer and co-workers.[7d] Upon
aryl radical generation from the diazonium unit, hydrogen
atom transfer was observed from the 7-position in an alkyl
side chain, thereby enabling remote functionalization. The re-
lated aryl radical induced hydrogen atom transfer from 5-posi-
tions (1,5-HAT), which was one of our research objectives
(Scheme 1D), has earlier been investigated by Murphy et al.[7e]
as well as Curran and Xu.[7f] This approach, however, yet re-
quires multistep syntheses for the precursors, whereas the
strategy via 3 could directly provide the desired reactants 4.
In the present work, we show that the exceptional reactivity
of the Sanger-type reagent 3 enables a single step access to a
broad range of aryl-alkyl ethers 4 under so far unknown, base-
free conditions.[8] The diazonium and the nitro group present
in 4 can be employed for manifold further transformations in-
cluding radical translocations to allyl ethers as well as various
further intra and intermolecular CÀC bond formations.
Scheme 1. Functionalization strategies based on Sanger-type reagents bear-
ing a free or protected diazonium unit.
[a] O. Fischer, Prof. Dr. M. R. Heinrich
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry
Friedrich-Alexander-Universität Erlangen-Nürnberg
Nikolaus-Fiebiger-Str. 10, 91058 Erlangen (Germany)
E-mail: markus.heinrich@fau.de
Based on an established protocol[9] for the preparation of di-
azonium tetrafluoroborates under water-free conditions, facile
access to decagram quantities of 3 in high yield and purity
was obtained without the need for costly and time-consuming
purification methods. Subsequently, a series of experiments
was conducted to identify optimized conditions for the nucleo-
philic substitution (Scheme 2).
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202100187.
ꢀ 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution Non-Commer-
cial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for
commercial purposes.
Owing to the above-mentioned sensitivity of aromatic diazo-
nium salts to even weakly basic conditions,[5a,10] we were
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the sensitivity of the diazonium unit, the reactions were per-
formed in deuterated solvent followed by direct analysis of the
reaction mixture by 1H NMR spectroscopy using an internal
standard.
As shown by the broad range of examples, primary and sec-
ondary aliphatic alcohols with side chains bearing alkenes, al-
kynes, aromatics, alcohols, ethers, fluoro, chloro, and bromo
substituents, nitro, ester as well as urethane groups are well
tolerated. For protonated amines, a sufficiently large distance
between the positive charge and the hydroxyl group is re-
quired (compare 4r vs. 4aq), thereby showing that amino al-
cohols can be selectively functionalized at the alcohol unit,
while the otherwise more nucleophilic amine is protected by
simple protonation. An attempt with a N-Boc (tert-butyloxycar-
bonyl) protected amino alcohol led to in situ deprotection,
most probably due to the liberated hydrofluoric acid, to give
4s. To underline synthetic applicability, 4a was also synthe-
sized on gram scale (6.10 mmol, 2.13 g, 94% yield, >95%
purity). Generally, washing the diazonium intermediate 4 with
diisopropyl ether, followed by filtration or careful decantation
provided the diazonium salt in sufficiently high purity for sub-
sequent reactions in the same vessel. Concerning the stability
of the diazonium compounds, 3 and 4a could be stored in a
desiccator at room temperature for several months without
noticeable decomposition.
Scheme 2. Preparation of diazonium salt 3 and optimized conditions for nu-
cleophilic substitution.
pleased to find that the desired substitution of 3 with cyclo-
hexylmethanol (6a) to give 4a can be achieved in a neutral to
weakly acidic environment, which is undoubtedly enabled by
the exceptional reactivity of 3 at the ring position bearing the
fluorine atom.[4a]
In this context, it should be noted that diazonium tetrafluo-
roborates are known to be far less dangerous than their analo-
gous chloride or bromide salts and can be safely isolated even
at kilogram scale.[11] However, they may be explosive if they
have excessive nitrogen content.[10] To unambiguously show
that diazonium salt 3 exhibits sufficient stability, a small quanti-
ty of this compound was heated to 1008C for 30 min and the
1
resulting material was analyzed by LC/MS and H NMR spec-
troscopy. Both analytical methods did not point to major de-
composition (<10%) of the compound. During optimization,
the addition of a small amount of dry dimethylsulfoxide
(5 vol%) to dry acetonitrile turned out as beneficial to achieve
high yields of ether 4a using 2.5 equivalents of the— perspec-
tively— more readily available reactant 3.
With optimized conditions available, an evaluation of scope
and limitations was carried out. Selected results from a large
series of experiments conducted on 0.1 mmol scale are sum-
marized in Scheme 3 (see also Supporting Information). Due to
Limitations of the reaction scope, which also give insights
into the characteristics of the novel Sanger type reagent, are
as follows. While steric demand in the b-positions of secondary
alcohols 6 is largely acceptable (e.g., 4al), tertiary alcohols
such as tert-butanol do not undergo the substitution reaction
with 3. This is also true for deactivated, less nucleophilic alco-
hols such as 2,2,2-trifluoroethanol. Allylic alcohols and activat-
ed benzylic alcohols (e.g., benzhydrol, furfuryl alcohol), in con-
Scheme 3. Scope of primary and secondary alcohols suitable for nucleophilic substitution of 3. Yields determined using dimethyl sulfone as internal standard.
[a] Reaction performed at 08C. [b] N-Boc protected amino alcohol used as reactant 6s. [c] 1 equiv. of 3 used. [d] CDCl3 added to the reaction.
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Chemistry—A European Journal
trast, provided complex product mixtures, thereby pointing to
the leaving group properties of the diazonium-substituted 4-
nitrophenolate.
A control experiment with the n-butyl substituted aryl ether
(4, R1 =R2 =H, R3 =Et, Scheme 4) revealed that, if no particular
position in the alkyl chain is activated by alkyl substitution,
then hydrogen atom transfer will preferably occur from the b
(1,5-HAT) and to a lesser extent from the a position (1,4-HAT)
with a ratio of 2.2:1 (28 and 13% yield). The fact that 1,5-hy-
drogen atom transfer step is reasonably fast, can be estimated
from an experiment in which the cyclohexylmethyl substituted
ether 4a (Scheme 3) was treated with three equivalents of
iodide instead of TEMPO. Although trapping of aryl radicals by
iodide is known to proceed with high rate constants around
1010 sÀ1,[5a] only 27% of the Sandmeyer product (the aryl
iodide) were obtained, whereas 37% of the reaction products
could be directly related to hydrogen atom transfer (see the
Supporting Information for details).
Regarding phenols, which are reliable substrates for diaryl
ether synthesis when combined with the classical Sanger re-
agents 1 and 2 (Scheme 1),[2a,12] such starting materials either
led to no reaction with 3 (if acceptor-substituted; e.g., 4-nitro-
phenol) or to complex product mixtures (if donor-substituted;
e.g., 4-methoxyphenol). The latter case can be rationalized by
competing azo coupling between 3 and the phenol, as well as
aryl radical formation due to the reductive properties of the
phenol.
While primary and secondary aliphatic amines mainly
showed triazene formation resulting from nucleophilic attack
on the diazonium unit,[13] the outcomes with anilines depend
(as those for phenols) on the actual substitution pattern.
Donor-substituted anilines (e.g., N,N-diethyl-1,4-phenylenedi-
amine) again act as reductants and partners for azo coupling
to yield complex mixtures. Interestingly, acceptor-substituted
anilines provided benzotriazoles via substitution of the fluorine
atom and cyclization involving the diazonium unit (see
Scheme 1C and the Supporting Information).[4b]
As outlined in Scheme 4, the sequence combining nucleo-
philic aromatic substitution of diazonium salt 3 with radical
translocation is a so far unique strategy to convert aliphatic al-
cohols 6 into activated allylic ethers 7 in only two reaction
steps. Perspectively, the corresponding alcohols may be ob-
tained under mild conditions and with high yields via metha-
nolytical cleavage of the 4-nitrophenyl unit as described by Ta-
kahashi and Ogasawara.[14] Compounds structurally related to 7
have further been reported to be useful for numerous applica-
tions, including allylic alkylation,[15] Claisen rearrangement,[16]
and carbonyl olefination.[17] As illustrative examples, the previ-
ously prepared allylic ethers 7a and 7aj were further convert-
ed under Tsuji–Trost conditions[18] to transform 8a and 8b into
the highly functionalized 1,3-diketones 9a and 9aj in yields of
62 and 88%, respectively (Scheme 5).
Based on the straightforward accessibility of aryl-alkyl ethers
4 from various primary and secondary alcohols 6, we then
turned to the first field of application. To evaluate the feasibili-
ty of radical translocation reactions, nine aryl-alkyl ethers
(4a,b,f,q,z and 4aj–am) were prepared on a 0.5 mmol scale,
purified by washing with diisopropyl ether, and subsequently
submitted to a reaction with (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO) (1.0 equiv.) to induce aryl radical generation.
Via hydrogen atom transfer a new double bond is introduced
in the side chain (Scheme 4). Within the optimization of the
radical translocation step, it turned out that the conditions
originally reported by Baran and co-workers[7a] cannot be di-
rectly applied, but that a parallel addition of aryl-alkyl ether 4
and TEMPO to the reaction mixture is necessary to reach
useful yields for the alkenes 7 (see the Supporting Information
for details and mechanism). Notably, this transformation is the
first example of an olefination by CÀH activation to yield acti-
vated aryl-allyl ethers.
Scheme 5. Tsuji–Trost reactions using activated allylic ethers 7a and 7aj.
Remarkably, Tsuji–Trost reactions have so far not been con-
ducted with 4-nitrophenol as a leaving group. As a second
field of application, and again exploiting the presence of the
diazonium unit in the aryl-alkyl ethers 4, we turned to radical
reactions proceeding under carbon–carbon bond formation
(Scheme 6). Within this study, the tricylic dibenzoxepanes 10n
and 10p as well the spirocyclic derivate 11 l became accessible
in only two steps from the alcohols 6n, 6p, and 6l. As shown,
the novel type of Pschorr cyclization[19] to the spirocyclic dihy-
drobenzofuran 11 l requires a shorter chain length (n=0) and
an additional nitro group (R2 =4-NO2) in the aryl-alkyl ether
4l.[20]
The further synthetic options arising from the presence of
the nitro substituent on the aromatic core of the diazonium
salt were exemplified by three transformations using dibenzox-
epane 10n as starting material (Scheme 6). In palladium-cata-
Scheme 4. Two-step synthesis of activated allylic alcohols 7 from 3 and 6 in-
volving a radical translocation reaction.
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Chemistry—A European Journal
synthetic options are nicely complemented by additional func-
tionalization via the nitro aromatic group, which overall ren-
ders the novel Sanger-type reagent 3 a broadly applicable tool
in organic synthesis.
Acknowledgements
O.F. thanks the GRK1910 and the Graduate School Molecular
Science for support of this work. O.F. thanks Lamis Herrera for
experimental assistance in the laboratory. Open access funding
enabled and organized by Projekt DEAL.
Scheme 6. Aryl-alkyl ethers 4 in Pschorr cyclizations and further transforma-
tions of the nitro group.
Conflict of interest
The authors declare no conflict of interest.
lyzed reactions employing BrettPhos as key ligand,[21] reduction
to 12n, aryl–aryl coupling to 13n as well as amination to give
14n were achieved in good to high yields. As a result, the
overall strategy gives facile access to the diverse dibenzoxe-
panes requiring only 2 to 3 reaction steps, which is an ideal
starting point for the elucidation of structure–activity relation-
ships. Known applications of dibenzoxepanes comprise differ-
ent fields of medicinal chemistry,[22a,b,c] natural product synthe-
sis,[22d,e] and mechanistic studies,[22f,g] whereas the reported syn-
thetic studies further underline the general interest in this
compound class.[22h,i] This is also the case for the spirocyclic
compound 11 l, which constitutes the key structural element
of several natural products of the kadsuralignan and interiorin
type, which are known for their antioxidant and anti-HIV prop-
erties.[23]
Keywords: CÀC bond formation · CÀH activation · diazonium ·
nucleophilic aromatic substitution · Sanger reagent
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Manuscript received: January 18, 2021
Accepted manuscript online: January 22, 2021
Version of record online: February 24, 2021
Chem. Eur. J. 2021, 27, 5417 –5421
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