Arylhydrazine trapping of benzynes: Mechanistic insights and a route to azoarenes

Article abstract of DOI:10.1021/acs.orglett.1c00897

Arylhydrazines (ArNαHNβH2) are ambident nucleophiles. We describe here their reactivity with benzynes generated in situ by thermal cyclization of several multiynes. Products arising from attack of both the alpha- and beta-nitrogen atoms are observed. These competitive modes of reaction were explored by DFT calculations. Substituent effects on the site-selectivity for several substituted phenylhydrazines were explored. Interestingly, the hydrazo products from beta-attack (ArNHNHAr') can be oxidized, sometimes in situ by oxygen alone, to give structurally complex, unsymmetrical azoarenes (ArN=NAr'). Toluenesulfonohydrazide and benzohydrazide analogues were each demonstrated to undergo similar transformations, including oxidation to the corresponding benzyne-trapped azo compounds.

Full text of DOI:10.1021/acs.orglett.1c00897

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Letter
Arylhydrazine Trapping of Benzynes: Mechanistic Insights and a
Route to Azoarenes
Dorian S. Sneddon and Thomas R. Hoye*
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ABSTRACT: Arylhydrazines (ArNαHNβH2) are ambident nucleophiles. We describe here their
reactivity with benzynes generated in situ by thermal cyclization of several multiynes. Products
arising from attack of both the alpha- and beta-nitrogen atoms are observed. These competitive
modes of reaction were explored by DFT calculations. Substituent effects on the site-selectivity
for several substituted phenylhydrazines were explored. Interestingly, the hydrazo products from
beta-attack (ArNHNHAr′) can be oxidized, sometimes in situ by oxygen alone, to give
structurally complex, unsymmetrical azoarenes (ArNNAr′). Toluenesulfonohydrazide and
benzohydrazide analogues were each demonstrated to undergo similar transformations,
including oxidation to the corresponding benzyne-trapped azo compounds.
zoarenes (ArNNAr′) are notable for their light-driven
cis/trans isomerization and, thereby, their potential to
6a, the azoarene 7a, the 1,1-diarylhydrazine 8a, and, to a
small extent, the aniline derivative 9a.6 The relative amounts
of these products depended upon the amount of oxygen
present in the reaction vessel. That is, under aerobic
conditions, none of the hydrazo product 6a was observed.
Under an atmosphere of nitrogen, this compound was clearly
evident in the NMR spectrum of the crude product mixture,
and although it could be isolated, its further conversion to
the oxidized azoarene 7a occurred both upon routine
handling as well as while kept in solution in an NMR
sample tube over time. Notice that the ratio of the total
amount of 6a and 7a to that of 8a was ca. 1.5 in both
experiments. This, in turn, implies that the nucleophilic
addition of 2a to the benzyne is competitive at the α- vs β-
nitrogen atoms.
The competition between the two nitrogen atoms is
surprising given that the reaction of 2a with dimethyl
acetylenedicarboxylate (DMAD) is reported to occur
exclusively at the β-nitrogen atom (NH2).7−9 This is in line
with the notion that the phenyl substituent would reduce the
nucleophilicity of the α-nitrogen atom for both steric and
electronic reasons. Therefore, we decided to explore whether
DFT calculations would shed any light on this curious
outcome of a preference for attack by Nα. In particular, we
A
act as photoswitches. In this capacity, they have been
employed in biological probes, molecular machines, drug
delivery systems, optical devices, and data storage.1 Currently
(and classically), most azoarenes are constructed by way of
the addition reaction of phenoxides to aryl diazonium ions
(Figure 1a).2 This reaction, however, has limitations in terms
of its substrate scope and efficiency. Alternatively, the Mills
reaction involves condensation of anilines with aryl nitroso
compounds and allows for the synthesis of structurally more
complex azoarenes (Figure 1b).3−5 A limitation in that
method is that the attacking aniline typically needs to be
electron rich and efficiencies can suffer due to side reactions
including overoxidation of the requisite nitroso compound.
To our knowledge, nucleophilic addition of an arylhy-
drazine to a benzyne species has never been reported. Herein,
we demonstrate one-pot formation of azoarenes 4 via
reaction of benzynes generated by the hexadehydro-Diels−
Alder (HDDA) reaction (1 to 1*) with arylhydrazines 2 to
produce intermediate hydrazoarenes 3 (Figure 1c). These are
readily and conveniently oxidized with MnO2 (or, even, via
autoxidation). Via this strategy, both electron-donating and,
especially, electron-withdrawing substituents on the hydrazine
are tolerated and significant structural complexity is
introduced into the products in a single step via the trapping
of 1*. The results described here constitute a complementary
strategy for the construction of complex azoarenes.
Received: March 15, 2021
Published: April 19, 2021
Our initial experiment involved heating of the triyne
HDDA substrate 5 in chloroform at 90 °C in the presence of
1 equiv of phenylhydrazine 2a (Figure 2). The characterized
products were the 1,2-diarylhydrazine (hydrazo compound)
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© 2021 American Chemical Society
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attacks by 2a onto I are both the rate- and product-
determining steps for the two overall reactions. The final
conversions of IIIβ/α to products IVβ/α would most likely
be mediated by an external proton shuttle such as
PhNHNH2.
We also briefly explored by DFT the two modes of
competitive reaction between PhNHNH2 (2a) and DMAD
(see the Supporting Information for details). While a full
exploration of the potential surface for this process is
complex, one potentially significant difference between the
transition structures for the DMAD vs benzyne reactions is
the distance between the attacking nitrogen atom and the
electrophilic sp-hybridized carbon atom. In TS-I → IIβ and
TS-I → IIα, that distance is 3.0 and 3.7 Å, respectively. In
contrast, for the analogous TSs for the addition to DMAD,
the TSs have a much smaller separation of the reacting
centers (2.0 Å for both Nβ−C and Nα−C). This reflects a
reaction surface with a much later transition state, consistent
with the considerably higher exergonicity for addition of 2a
to benzyne I vs DMAD (ΔΔG° ∼ 20 kcal mol−1) for the first
elementary step of formation of the zwitterions IIβ/α vs that
of the DMAD analogues. The much longer N−C distances in
the reactions with benzyne via TS-I → IIβ/α significantly
minimize the role of steric interaction in approach of the
nucleophile to benzyne.
We next examined the effect of substituents on the
arylhydrazine (Table 1). The presence of electron-with-
drawing groups on the phenyl ring significantly enhanced the
preference for attack by Nβ; none of the products from
reaction at Nα were seen (entries b−e). In the case of the p-
nitrophenyl analogue, the diarylhydrazine precursor of 7b was
isolable, although it too was seen to air oxidize slowly, for
example, in an NMR sample solution. MnO2 was used to
fully convert the crude product to the azo adduct. Likewise,
the crude material from trapping with 2-hydrazinopyridine 2e
was also proactively oxidized with MnO2 to ensure full
conversion to 7e. Entries f and g show results using
phenylhydrazine derivatives similar in electronic character to
that of 2a itself. And, similarly, comparable amounts of
products from both Nβ and Nα attack were isolated. Results
using p-methoxyphenylhydrazine are conspicuously absent
from Table 1. This substance is known to be very challenging
to prepare and handle because of its sensitivity to
autoxidation.10 The o-methoxy analogue 2h was free-based
immediately prior to use; the azo derivative 7h was isolated
in low yield. Analysis of the NMR spectrum of the crude
Figure 1. Complementarity of this de novo construction of one
arene of an azoarene (panel c) with the most common, classical
methods for their conjunctive synthesis (panels a and b).
computed the energetics for reaction of o-benzyne I with 2a
(Figure 3). The overall free energy of reaction leading to IVβ
vs IVα (the analogues of 6a and 8a, respectively) is, as
expected, largely exergonic, the former more so because of
the greater resonance delocalization into each of the two
phenyl rings.
The transition structures associated with attack by Nβ (TS-
I → IIβ) vs Nα (TS-I → IIα), leading to the zwitterions IIβ
or IIα, respectively, are quite similar in energy, consistent
with the experimental observation of comparable amounts of
products arising from these two processes. The nearly
barrierless exergonic events that convert IIβ/α to IIIβ/α
(simple proton transfers) indicate that the initial α- vs β-
a
Figure 2. Product distribution from reaction of the benzyne derived from heating triyne 5 in the presence of phenylhydrazine 2a. Isolated
yield.
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Figure 3. DFT calculations for reaction of o-benzyne I with phenylhydrazine 2a. [SMD(CHCl3)/M11/6-31+G(d,p)].
reaction mixture suggested the presence of a significant
amount of 8h, but that material also degraded upon
attempted purification.11
diarylhydrazine product 16. Trace amounts of a compound
deemed to be the corresponding azoarene were detected by
GC-MS analysis of the crude product mixture. This high
selectivity for attack by Nα in 2 suggests that hydrogen
bonding by fluoride ion to the more acidic PhNH
preferentially activates Nα for addition compared to the
additive-free reaction conditions of the thermal HDDA
variant.
We have described here the first examples of nucleophilic
trapping of benzynes by arylhydrazines. Either of the nitrogen
atoms is capable of adding to produce either 1,2- or 1,1-
diarylhydrazine compounds via attack by either the β- vs α-
nitrogen atoms, respectively. The ratio of these competitive
processes is influenced by the electronic character of the aryl
substituent in the hydrazine. DFT calculations suggest that
the greater proportion of addition through the α-nitrogen
compared to reactions with simple electron-deficient alkynes
supports the idea that the addition to (the highly electro-
philic) benzyne proceeds via a transition state lying much
earlier on the reaction coordinate. In many instances, the 1,2-
diarylhydrazines were observed to undergo air oxidation to
the corresponding azo analogues. This process could be
readily forced to completion by exposing the crude reaction
products to MnO2 prior to purification; the 1,1-isomer was
not oxidized. The benzo- and sulfonohydrazide analogues 13a
and 13b were shown to add to an HDDA-benzyne exclusively
through the unsubstituted, more nucleophilic nitrogen atom.
The initial adducts could again be oxidized to the
Several experiments were then performed to address several
complementary aspects of this chemistry (Figure 4).
Unsurprisingly, the iodophenyl derivative 7f smoothly
underwent cross-coupling to the biaryl derivative 10. We
then showed that the linker unique to triyne 5 was not a
requirement for the reaction. That is, the tetraynes 11a and
11b were each trapped by the nitrophenylhydrazine 2b to
give, following oxidation, the azo compounds 12a and 12b
(Figure 4b).6 We also showed that hydrazides 13a and 13b,
each perforce having a quite different level of nucleophilicity
of its two nitrogen atoms, react smoothly with the benzyne
produced by heating triyne 5. Direct oxidation by addition of
MnO2 produced the azo derivatives 14a and 14b,
respectively. It is notable that, while the former appeared
to be quite stable, the arylazosulfone analogue was observed
to photobleach rather easily upon handling under the
ambient laboratory conditions. This presumably reflects the
reported photoinitiated homolytic fragmentation of com-
pounds containing an ArNNSO2R moiety.12
Finally, because we were unable to identify reports of any
reactions of hydrazines with arynes generated by conventional
methods (i.e., non-HDDA), we briefly explored the reaction
of the Kobayashi benzyne from precursor 1513,14 with three
phenylhydrazine derivatives (Figure 5). In each instance, by
far, the major product, following isolation, was the 1,1-
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Table 1. Azoarenes 7 (and 1,1-Diarylhydrazines 8, Where
Observed) Formed from Reactions of the HDDA-Benzyne
from Triyne 5 in the Presence of Arylhydrazines 2,
Followed by Oxidation (in Air or with MnO2)
Figure 4. (a) The azo functionality is compatible with a Pd0-
catalyzed (Suzuki) cross-coupling reaction. (b) The nature of the
HDDA-benzyne is not limited to that derived from 5. (c) Benzo-
and sulfonohydrazides undergo analogous transformations.
Figure 5. Reactions of o-benzyne with arylhydrazines 2a,b,g gave 1-
phenyl-1-arylhydrazines 16a,b,g.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00897.
A .zip file containing the XYZ coordinates (.xyz files) of
each computed structure (ZIP)
a
This example was also performed on a 1 mmol scale, and 7b was
b
isolated in 74% yield. Evidence for this compound was seen in the
NMR spectrum of the crude product mixture, but it proved to be too
labile for isolation.
A PDF containing (i) preparative details for all new
compounds, (ii) spectroscopic characterization data
1
(including copies of both H and 13C NMR spectra)
for all new compounds, and (iii) a description of DFT
computational methods and the geometries and
energies of each species shown in the manuscript
(PDF)
corresponding azo compounds, now bearing an electron-
withdrawing group. Several arylhydrazines were used to trap
o-benzyne itself to produce the 1-phenyl-1-arylhydrazine
isomer highly selectively. This method of construction of
azoarenes complements known, classical approaches and is
capable of providing structurally complex azo compounds.
FAIR data, including the primary NMR FID files, for
compounds 2d, 2g, 6a, 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h,
8a, 8f, 8g, 9a, 9h, 10, 12a, 12b, 14a, 14b, 16a, 16b,
and 16g (ZIP)
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(8) Heindel, N. D.; Kennewell, P. D. Imine-enamine tautomers
from hydrazine and aryl hydrazine additions to acetylenedicarbox-
ylate. J. Org. Chem. 1970, 35, 80−83.
AUTHOR INFORMATION
■
Corresponding Author
(9) Sucrow, W. Reactions of acetylenes with hydrazines. Org. Prep.
Proced. Int. 1982, 14, 91−155.
Thomas R. Hoye − Department of Chemistry, University of
Minnesota, Minneapolis, Minnesota 55455, United States;
orcid.org/0000-0001-9318-1477; Email: hoye@
umn.edu
(10) Frahn, J. L.; Illman, R. J. The preparation of 4-
methoxyphenylhyd-razine and some other arylhydrazines. Aust. J.
Chem. 1974, 27, 1361−1365.
(11) Hong, S.-S.; Bavadekar, S. A.; Lee, S.-I.; Patil, P. N.;
Lalchandani, S. G.; Feller, D. R.; Miller, D. D. Biosteric
phentolamine analogs as potent α-adrenergic antagonists. Bioorg.
Med. Chem. Lett. 2005, 15, 4691−4695.
Author
Dorian S. Sneddon − Department of Chemistry, University
of Minnesota, Minneapolis, Minnesota 55455, United States
(12) Dossena, A.; Sampaolesi, S.; Palmieri, A.; Protti, S.; Fagnoni,
M. Visible light promoted metal- and photocatalyst-free synthesis of
allylarenes. J. Org. Chem. 2017, 82, 10687−10692.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00897
(13) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-induced
1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under
mild conditions. Chem. Lett. 1983, 12, 1211−1214.
(14) Shi, J.; Li, L.; Li, Y. o-Silylaryl triflates: A journey of
Kobayashi aryne precursors. Chem. Rev. 2021, 121 (7), 3892−4044.
Author Contributions
D.S.S. performed all of the experimental work; both authors
interpreted the data and co-wrote the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported through the National Institutes
of General Medical Sciences of the U.S. Department of
Health and Human Services (R35 GM127097). Support for
some of the instrumentation came from an NIH Shared
Instrumentation Grant (S10OD011952, NMR) and an NIH
Cancer Center Support Grant (CA-77598, MS). DFT
calculations were performed with resources provided by the
Minnesota Supercomputing Institute.
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