Coupling N-H Deprotonation, C-H Activation, and Oxidation: Metal-Free C(sp3)-H Aminations with Unprotected Anilines

Article abstract of DOI:10.1021/jacs.7b07519

An intramolecular oxidative C(sp³)-H amination from unprotected anilines and C(sp³)-H bonds readily occurs under mild conditions using t-BuOK, molecular oxygen and N,N-dimethylformamide (DMF). Success of this process, which requires mildly acidic N-H bonds and an activated C(sp³)-H bond (BDE < 85 kcal/mol), stems from synergy between basic, radical, and oxidizing species working together to promote a coordinated sequence of deprotonation: H atom transfer and oxidation that forges a new C-N bond. This process is applicable for the synthesis of a wide variety of N-heterocycles, ranging from small molecules to extended aromatics without the need for transition metals or strong oxidants. Computational results reveal the mechanistic details and energy landscape for the sequence of individual steps that comprise this reaction cascade. The importance of base in this process stems from the much greater acidity of transition state and product for the 2c,3e C-N bond formation relative to the reactant. In this scenario, selective deprotonation provides the driving force for the process.

Full text of DOI:10.1021/jacs.7b07519

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Article
Coupling N-H deprotonation, C-H activation and oxidation:
metal-free C(sp3)-H aminations with unprotected anilines
Christopher J. Evoniuk, Gabriel dos Passos Gomes, Sean
P Hill, Fujita Satoshi, Kenneth Hanson, and Igor V. Alabugin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Oct 2017
Downloaded from http://pubs.acs.org on October 16, 2017
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Coupling N-H deprotonation, C-H activation and oxidation:
metal-free C(sp3)-H aminations with unprotected anilines
Christopher J. Evoniuk, Gabriel dos Passos Gomes, Sean P. Hill, Fujita Satoshi,¥ Kenneth
Hanson and Igor V. Alabugin*
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Florida State University, Tallahassee, Florida 32306, United States
Interdisciplinary Graduate School of Engineering Sciences, Kyushu University
¥
Supporting Information Placeholder
Abstract: An intramolecular oxidative C(sp3)ꢀH amination from unprotected anilines and C(sp3)ꢀH bonds
readily occurs under mild conditions using tꢀBuOK, molecular oxygen and N,Nꢀdimethylformamide
(DMF). Success of this process, which requires mildly acidic NꢀH bonds and an activated C(sp3)ꢀH bond
(BDE = < 85 kcal/mol), stems from synergy between basic, radical and oxidizing species working
together to promote a coordinated sequence of deprotonation; Hꢀatom transfer and oxidation that forges a
new CꢀN bond. This process is applicable for the synthesis of a wide variety of Nꢀheterocycles, ranging
from small molecules to extended aromatics without the need for transitionꢀmetals or strong oxidants.
Computational results reveal the mechanistic details and energy landscape for the sequence of individual
steps that comprise this reaction cascade. The importance of base in this process stems from the much
greater acidity of transition state and product for the 2c,3e CꢀN bond formation relative to the reactant. In
this scenario, selective deprotonation provides the driving force for the process.
Introduction: Direct construction of a CꢀN bond from a C(sp3)ꢀH bond and an NꢀH bond is a challenging
transformation in organic chemistry,1 especially, when an unprotected primary amine is used as a partner
for the notoriously unreactive CꢀH bonds.2 Even with the large amount of work conducted in this area,
only a few literature methods for C(sp3)ꢀH amination do not rely on transition metals (TMs). This is not
surprising because a typical RNH2 + R2CH2 → RN=CR2 conversion of unprotected amines3 to an imine
with the loss of two H2 molecules is thermodynamically unfavorable (∆ꢀ = +11 kcal/mol, Scheme 1,
path A). The first NꢀC bond formation in this sequence is uphill by 8 kcal/mol (Scheme 1, top left). Even
though CꢀH/NꢀH coupling becomes thermodynamically favorable when coupled with oxidation (∆ꢀ =
−47 kcal/mol, Scheme 1, path B), significant kinetic barriers for the individual steps associated with the
breaking of strong NꢀH and CꢀH bonds continue to provide challenges in the design of a practical version
of this reaction.
Scheme 1. Thermodynamics of A: dehydrogenative and B: oxidative CꢀN bond formations from CꢀH/Nꢀ
H partners
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Early advances in C(sp3)ꢀH amination chemistry go back to the HoffmanꢀLofflerꢀFreytag (HLF) reaction
that utilized homolysis of the nitrogenꢀhalogen bonds to form a nitrogen centered radical that performs
hydrogen atom transfer (HAT) to afford cyclic amination products after oxidation and proton transfer
(Scheme 2a).4 More recently, CꢀH activation was accomplished through the insertion of metal nitrenoids
into CꢀH bonds (Scheme 2b).5 The power of transition metals can be controlled and amplified by
appropriately designed directing groups (DGs) that assist with the formal metal insertion into the CꢀH
bond, that is finally oxidized by an intramolecular amino group (Scheme 2c).6
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Scheme 2. Selected approaches to CꢀH amination.
We have recently reported a FeCl3ꢀmediated oxidative approach to CꢀH amination with anilines
based on a sequence of electron and proton transfers.7 Although this approach is conceptually appealing,
we reasoned that if SET is coupled to anionic conditions, milder oxidants can be used. An important step
towards realizing this type of reactivity was earlier demonstrated by Sarpong and coworkers who
involved a C, N dianion into a CꢀN bond forming reaction by a mild inꢀsitu oxidation (Scheme 2d).8
A conceptually simple approach, that can couple NꢀH and CꢀH activation without the need to form a
highly reactive dianion, involves a sequence of NꢀH deprotonation and Hꢀabstraction at an activated CꢀH
bond,9 followed by an oxidation of the intermediate radical anion. The final step would convert a 2c,3e “
halfꢀbond” formed in the first two steps into a “normal” 2c,2e NꢀC bond. After the covalent CꢀN bond
is formed, the above sequence of steps can be repeated to yield a C=N unit as the product of a double Nꢀ
H/CꢀH activation (Scheme 3).
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Scheme 3. Comparison of the two approaches to making C=N moiety from the double activation of
CH2/NH2 moieties. a) Earlier reported oxidative approach: Oxidation of an aniline moiety increases CꢀH
acidity in a stereoelectronically connected ArCH2ꢀ group. Deprotonation can lead to the formation of a
benzylic radical in the close proximity to the NH2 group. Subsequent oxidation completes the first CꢀN
bond formation. b) The new radicalꢀanionic approach: NꢀH deprotonation weakens a remote CꢀH bond,
setting the stage for radical CꢀH abstraction followed by the formation of a CꢀN bond. Once the CꢀN bond
is formed, further CꢀH/NꢀH activation leads to the formation of a C=N bond bond, completing the formal
imination of a CH2 group.
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Although conceptual simplicity of this approach is appealing, finding the right combination of
oxidant, radical and base that can work together is a daunting task, especially for unprotected amine
reagents susceptible to oxidation. We report the successful C(sp3)ꢀH amination/imination cascades with
unprotected amines (Scheme 3) based on the combination of potassium tertꢀbutoxide (tꢀBuOK),
molecular oxygen and DMF. Comprehensive computational analysis reveals the unusual mechanistic
features of this tightly choreographed sequence of transformations. In the final part, we illustrate the
synthetic power of this method via preparation of new families of Nꢀheterocyclic polyaromatic πꢀ
acceptors.
Results. Following the general synthetic route outlined in the SI, we prepared a model substrate 1a (full
details in SI) that has the preꢀrequisite of a mildly acidic NꢀH bond10 and a weakened C(sp3)ꢀH
bond.11,12,13 We reacted 1a (0.01 mmol) with tꢀBuOK (3ꢀequiv) in acetonitrile (Table 1, entry 1) under air
at reflux. Under these conditions, the CꢀH amination product 2a was not observed and starting material
was reclaimed. Similarly, no reaction occurred in toluene (entry 2). However, when the reaction was
performed in DMSO, the product 2a was observed in 18% yield with low conversion of the starting
material (entry 3). Ultimately, full conversion was observed and the CH2/NH2 crossꢀcoupling product 2a
was obtained in 78% yield when DMF was used as the solvent (entry 4). These results prompted us to
carry out the remaining optimization studies in DMF. We then tested eight other bases (entries 5ꢀ12).
Only the stronger alkoxide bases provided 2a in good yields and conversion rates, with the tertꢀbutoxide
salts providing the best results (K, Na and Li). The highest yields and conversions were observed using tꢀ
BuOK as the base. We also varied the equivalents of base used in the reaction (entries 15ꢀ17) and found
the best results by using 3 equivalents.
The role of an oxidant is illustrated by the much lower reactivity under the argon atmosphere (15%
yield of 2a, entry 13). In contrast, the use of O2 as an oxidant improved conversion and yield in
comparison to the standard atmospheric conditions (entry 14). Intriguingly, higher yields were observed
at room temperature than at elevated temperatures for the model system (entries 18ꢀ20).
The optimal conditions emerged from these experiments included the use of tꢀBuOK (3 equiv.) under
an O2 atmosphere at room temperature in DMF in the presence of 4Åꢀmolecular sieves (entry 20).
Table 1. Optimization of reaction conditions.
Yields, %a
1a 2a
Entry Base
Atm Solvent Temp °C
1
2
3
tꢀBuOK
tꢀBuOK
tꢀBuOK
air
air
air
MeCN reflux
MePh 90
DMSO 90
>99 <1
>99 <1
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tꢀBuOK
Cs2CO3
Na2CO3
K2CO3
CsF
NaOMe
KOMe
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tꢀBuOLi
tꢀBuOK
tꢀBuOK
tꢀBuOK
tꢀBuOK
tꢀBuOK
tꢀBuOK
tꢀBuOK
tꢀBuOK
none
air
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DMF
DMF
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DMF
DMF
DMF
DMF
DMF
DMF
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DMF
DMF
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<1
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<1
<1
<1
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air
Ar
O2
O2
O2
O2
O2
O2
O2
O2
rt
rt
>99 <1
Reaction conditions: 1a (0.01mmol), base (3 equiv), solvent (0.5 mL) at specified temperature (rt = 23
°C) for 4 hours. aDetermined by 1H NMR using internal standard. b1 Equiv of base was used. c2 Equiv of
base was used. d4 Equiv of base was used. e4ÅꢀMolecular sieves were used in reaction.
Mechanistic studies. Several key experimental observations are listed below. First, deprotonation of the
ArNH2 by tꢀBuOK is confirmed by deuterium exchange in Eq. 1, with exclusive deuterium incorporation
at the nitrogen position. Second, the reaction was conducted in the dark without any deleterious effects
on the outcome (eq. 2). Third, the role of CꢀH bond strength was illustrated by the lack of reaction at the
less activated benzylic C(sp3)ꢀH bonds with the Meꢀ and Etꢀsubstituted biphenyls 1c and 1d under the
optimized conditions (eq. 3). We have also calculated the bond dissociation energies (BDEs) of the
benzylic CꢀH with similar substitution patterns to the compounds studied experimentally. The calculated
BDE threshold for Hꢀabstraction to occur under these conditions is in the vicinity of 85 kcal/mol.
Based on the recent reports of benzylic oxidations under similar conditions,14 one could suggest that the
new reaction proceeds through oxidation of C(sp3)ꢀH to form a carbonyl intermediate, followed by fast
condensation with the anilide anion driven by aromatization via the loss of H2O. To investigate the
presence of a carbonyl intermediate, we used the NHꢀMe analogue 1e to successfully interrupt the
reaction (eq. 4). The absence of oxygenꢀbearing functionalities in compound 2c where only the single Cꢀ
N bond is formed (eq. 4) provides evidence for the direct coupling of the C(sp3)ꢀH and NꢀH groups.15
Since Nꢀmethylaniline readily undergoes demethylations under baseꢀpromoted homolytic aromatic
substitution (BHAS) reactions, the latter reaction can proceed further and yield varying amount of the
fully aromatized product 2b.16 We also observed that water is detrimental for reaching the full conversion
with the more challenging substrates, as evidenced in byproduct 2d. Because two equivalents of water are
formed for each mole of product, we found that the yields can be improved by adding 4Å molecular
sieves to the reaction mixture.
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Scheme 4. Selected mechanistic experiments
The formation of a stabilized radical at the benzylic position in the presence of DMF/tꢀBuOK17
was confirmed by successful trapping of this species with TEMPO, a common trapping reagent for free
radicals (eq. 5).18
A Brꢀ containing substrate, 1f, was prepared to investigate the ability of these reagents to undergo
SET, and under our conditions, 2f was formed along with deꢀhalogenated product 2d in about a ~3:1 ratio
(eq. 6). This observation supports an electron transfer mechanism with an aromatic radical anion as an
intermediate that can either eject a halide anion or be intercepted in a different way (vide infra).17a, 19
The combination of the above observations suggests a baseꢀmediated electronꢀtransfer CꢀN coupling
as a plausible pathway for this CꢀH amination (Scheme 3, bottom).20 This pathway takes advantage of the
Nꢀanion and Cꢀradical that were supported by the above experiments. The formation of benzylic radicals
under these conditions is consistent with the detection of radical species in the reaction of DMF and
DMSO with base in the earlier EPR studies.14, 21 Furthermore, these species (likely DMF radicals) were
used for generating benzylic radicals via hydrogen atom transfer (HAT) from weakened ArꢀC(sp3)ꢀH
bonds.15,22 Recently, formation of carbamoyl radicals from tꢀBuOK in DMF under very mild conditions
was suggested as a byproduct of coupling reactions of enols with such weak oxidants as aryl iodides
through an electronꢀtransfer mediated SRN1 pathway.23 In the following part of the manuscript, we will
analyze the individual steps of this sequence of transformations first and discuss the overall energy
landscape at the end.
Computational details: Guided by these experimental results, we turned to computations for charting the
overall energy landscape and identifying the key intermediates of this chemical transformation.
Thermodynamic calculations were carried using the metaꢀhybrid (U)M06ꢀ2X functional24 and the 6ꢀ
31+G(d,p) basis set for all atoms, with an ultrafine integration grid (99,590 points). A brokenꢀspin
approach was applied when necessary. The implicit SMD25 solvation model was used to simulate the
effects of N,Nꢀdimethylꢀformamide (DMF) throughout the calculated structures. Grimme’s D3 version
(zero damping) for empirical dispersion26 was also included. Unless otherwise noted, all results presented
are at the (SMD=DMF)/(U)M06ꢀ2X(D3)/6ꢀ31+G(d,p)/int=ufine level of theory. We opted for the hybrid
PBE0 functional27 to describe HOMOꢀLUMO gaps of the larger systems. Frequency calculations were
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carried for all structures to confirm them as either a minimum or a TS. We used the Nucleus Independent
Chemical Shift (NICS)28 scans29 to evaluate local aromaticity in the polyaromatic systems. All
calculations were performed with the Gaussian 09 software package.30 Threeꢀdimensional structures and
orbital plots were produced with CYLView 1.0.1,31 IQmol 2.8.032 and Chemcraft 1.8.33
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Deprotonation/H-atom transfer: Calculations support that the tertꢀbutoxide anion is sufficiently basic to
deprotonate ArNH2 and generate anilide anion in a downhill process (∆ꢀ = −9 kcal/mol). Although the tꢀ
BuO anion is predicted to be sufficiently basic to remove the proton from the benzylic Ar2CH2 group,
formation of the Nꢀcentered anion is calculated to be more exergonic because of the greater acidity of the
NꢀH bond, (9 kcal vs. 3 kcal, Scheme 5).
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Scheme 5. NꢀH bonds are prone to selective deprotonation whereas CꢀH bonds are prone to selective
Hꢀatom transfer.
On the other hand, the bisꢀbenzylic CꢀH bond is more reactive towards homolytic cleavage than the
aniline NꢀH bonds (the BDEs of 84 and 94 kcal/mol, respectively). The difference in the CꢀH and NꢀH
BDEs suggest that Hꢀatom abstraction should proceed at the benzylic position and form a Cꢀcentered
radical. Interestingly, the benzylic CꢀH BDE in the Nꢀdeprotonated species is slightly increased (85.5
kcal/mol). The lack of BDE lowering suggests that, in the twisted reactant, communication between the
negative charge and the spin is unimportant and these two centers remain effectively distonic.9
Alternatively, the Nꢀanion can be oxidized into an Nꢀcentered radical that can abstract the benzylic CꢀH
intramolecularly.
Scheme 6. Two approaches to benzylic CꢀH activation. Energies in kcal/mol.
We have considered molecular oxygen, superoxide, tꢀBuO radical and C(O)NMe2 radical derived
from DMF as the key species that can serve as radicals and/or oxidizing agents (Scheme 7). Although
molecular oxygen is the primary reactant, it cannot serve directly as efficient radical CꢀH activator.
Calculations suggest that Hꢀatom abstraction becomes exergonic only with the more reactive tꢀBuO and
C(O)NMe2 radicals (Scheme 6).
Given the reaction conditions, we suggest that C(O)NMe2 radical derived from DMF is the key
species that can perform Hꢀabstraction at the ArꢀCH2ꢀR position which produces radical anion in an
exergonic step. Hence, the overall success of transformation would depend on finding a way for making
these high energy reactive intermediates under the reaction conditions.
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The role of DMF radical: In this section, we discuss a difficult part of this cascade – the role of
potassium tertꢀbutoxide, DMF and oxygen in the formation of radicals needed to perform the CꢀH
activation step of the cascade. The difficulty begins with the deprotonation of DMF by tertꢀbutoxide.
DMF is 9.5 pKa units less acidic than tꢀBuOH in water (pKa (DMF in H2O) = 26.5,34 pKa (tꢀBuOH in
H2O) = 17). Hence, deprotonation of DMF by tꢀBuOK is thermodynamically uphill. DMF deprotonation
reported by Reeves and coꢀworkers used stronger bases than tꢀBuOK (t-BuLi or lithium diisopropylamide
(LDA)).35 Although we could not find the pKa of DMF in DMF or DMSO in the literature (pKa (tꢀBuOH
in DMSO) = 29.4), according to our calculations, deprotonation of DMF by tꢀBuO anion is ~11 kcal/mol
endergonic in DMF. Even though thermodynamics of this process are unfavorable, a small amount of
DMF anion is still formed at the equilibrium. Indeed, 1H and 13C experiments conducted by Drapeau and
coꢀworkers verified the fast exchange of the formamide proton in a wet solution of DMFꢀd7 with tꢀ
BuOK.23
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Scheme 7. DMF cannot oxidize DMF anion, whereas oxygen does so favorably. Energies in kcal/mol.
Drapeau and coꢀworkers have shown computationally that the cation provides stabilization to the
DMF anion formed following deprotonation.23 They found that in the case of Li+, too much stabilization
can be detrimental to the reaction cascade, essentially creating a potential energy well that the
intermediates could not escape. Whereas the stabilization provided by K+ was sufficient to establish
reasonable reaction barriers for their reaction. Recent computational analysis by Houk and coꢀworkers in
a tꢀBuOKꢀmediated dehydrogenative CꢀH silylation reaction showcased the benefit of K+ over Na+ in key
steps of their mechanism.36 We have briefly explored the effects of cation on the anionic pathways
outlined in this work and found that they do not change the main trends for most of the steps (see SI for
additional details). Considering the above, we have only introduced K+ and DMF in our computational
model for the “problematic” DMF radical formation step (vide infra).
Once the DMF anion is formed, our computations suggest that its oxidation with oxygen is close to
thermoneutral. Inclusion of potassium counterion in the computational model makes this electron transfer
slightly exergonic. Hence, the overall combination of deprotonation and oxidation is ~10 kcal/mol uphill
and, thus, should be capable of producing only very small concentrations of DMF radicals at the
equilibrium.37 However, this situation is not uncommon in autooxidation processes (for example, the
notorious reaction of THF with oxygen) and can still lead to efficient transformations. In other words, as
long as steps propagating the cascade are fast and efficient, the endergonicity of the initiation step simply
corresponds to ~ 10 kcal/mol penalty needed for reaching the rateꢀlimiting transition state for the overall
cascade. On the other hand, oxidation of a DMF anion by another molecule of DMF with the formation
of a DMF radical and a DMF radical anion, suggested earlier in the literature,17b,c is highly energetically
unfavorable.
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2c, 3e C-N bond formation/oxidation: Once the C, N radical anion is formed, its cyclization is
exergonic due to the formation of a 2c, 3e bond at the shorter N···C distances. The importance of the
negative charge at this step is illustrated by the comparison of the evolution of 2c,3e interaction in the
neutral amine and the deprotonated analogue. In the neutral system, the CꢀN bond formation is ~20
kcal/mol uphill whereas it becomes >10 kcal/mol exergonic in the anionic case! One can suggest that
destabilization of nonꢀbonding electrons in the lone pair by the negative charge can serve as a source of
increased reactivity. Furthermore, presence of the π ꢀsystem in the cyclized product allows an additional
way to stabilize the additional electron by “ejecting”38 it from the threeꢀelectron CꢀN “halfꢀbond”
into the π*ꢀorbital. In other words, presence of an orthogonal πꢀsystem facilitates the CꢀN bond formation
by preventing the extra electron from going to the very high energy ꢁꢂ∗ꢃꢄ orbital (Scheme 8). Instead,
such electronꢀtransfer between the σꢀ and πꢀsystems leads to formation of a normal 2c,2e NꢀC bond and
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a delocalized πꢀanion with a low activation barrier of ~8.9 kcal/mol in an overall downhill process (~ꢀ12
kcal/mol).
Scheme 8. Effect of deprotonation on kinetic and thermodynamics of 2c,3e bond formation
Scheme 8 further illustrates that the advantage of radical anionic process over its neutral counterpart
is in the much greater acidity of the cyclic TS for the 2c,3e CꢀN bond formation in comparison to the
acyclic reactant state. Reaction acceleration by deprotonation may be a powerful general concept for the
control of chemical reactivity (see SI for details on the influence of K+ on this step).39 . The presence of
K+ increases the activation barrier for the cyclization step by ~4 kcal/mol, resulting in an unproductive
effect on the overall reaction.
Importantly, the cyclic anionꢀradical readily transfers an electron to molecular oxygen with the
formation of superoxide anion in a highly exergonic step (∆ꢀ = −31 kcal/mol) that finishes the first CꢀN
bond formation. In this scenario, the CꢀH/NꢀH activation is accomplished via NꢀH deprotonation, CꢀH
radical abstraction and an electron transfer. Although electron transfer from the cyclic radical anion to
the DMF radical is also potentially viable. It should be noted that oxygen should be more abundant under
the reaction conditions where it can serve as a stoichiometric oxidant.
In addition to "ejection" of electron via oxidation or MO crossing, the negative charge of radicalꢀ
anion can also lead to anion elimination40 as shown by facile loss of methoxide from the MeO substituted
cyclized radical anion (Scheme 9).
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Scheme 9. Elimination of MeOꢀanion from a cyclic radicalꢀanion. Energies in kcal/mol.
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nd Cycle (for the C=N bond formation): Formation of the C=N bond can be initiated via two different
pathways. In the first of them, deprotonation of the NꢀH bond or fast HAT to an external radical, such as
the DMFꢀradical (Scheme 10). The subsequent highly exergonic HAT transfer is assisted via weakening
of the CꢀH bond by the adjacent Nꢀcentered anion41 and strong stabilization of the formed radical via
conjugation. In the radical anion, the CꢀH bond is so weak that even superoxide is capable of abstracting
it in an exergonic fashion. Subsequent aromatization is promoted by oxidation to deliver the final product
in a favorable step (∆ꢀ = −16.6 kcal/mol).
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Scheme 10. Activation of the nonꢀaromatic product of the first stage of the cascade
Alternatively, the benzylic CꢀH bond can be abstracted by a radical. This step can be fast and highly
exergonic if DMF radical is used to perform HAT, to generate a relatively unreactive benzylic radical.
However, it is reasonable to suggest that deprotonation of NꢀH is more likely given the concentration of tꢀ
BuO anion in the system when compared to the concentration of other radicals.
The overall cascade with the most relevant thermodynamic values is summarized in Scheme 11. The
key CꢀN bond formation proceeds as a sequence of three mildlyꢀexergonic steps that is made irreversible
by a highly exergonic electron transfer from the C,N radicalꢀanion to oxygen.
tBuO H
DMF
H
H
NH
Ph
N
N
H
HN
H
H = -11.0
G = -8.9
tBuO
Ph
Ph
DMF
H = -11.8
G = -10.8
Ph
H = -9.0
G = -8.9
O2
O2,
r.t.
DMF,
tBuOK
H = -32.0
G = -30.5
SET
O2
O2
DMF
tBuO
H
N
SET
O2
N
H
N
N
Ph
Ph
Ph
Ph
tBuO H
H = -9.7
G = -11.0
DMF
H
H = -35.7
G = -35.4
H = -17.3
G = -16.6
Scheme 11. The thermodynamic landscape for the double CꢀH/NꢀH amination cascade
An important feature of this transformation is the “build up” of reductive potential;42 the
intermediate anions and radicals are weaker reductants in comparison to the radicalꢀanions. Keeping the
reductive potential low at the beginning prevents premature involvement of oxygen until we build a
radicalꢀanion that is easy to oxidize. This oxidation can either directly provide the product (from the
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cyclic radicalꢀanion) or lead to an open polar C,N diradicaloid species (from the acyclic radicalꢀanion)
that converge without barrier to the cyclic product in silico.43,44
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Scheme 12. Free energies, in kcal/mol, for electron transfer to molecular oxygen illustrate the “build up”
of reductive potential along the path of the reaction.
Reaction Scope: Benzylic C(sp3)ꢀH bonds activated by a single πꢀsystem were insufficiently reactive
under the reaction conditions (equation 3 in mechanistic studies above). In contrast, doubly benzylic or
“benzꢀallylic” CH2 groups are readily involved in the CꢀN bond formation, suggesting the key role of
radical Hꢀatom abstraction for the reaction success.
Electronꢀwithdrawing (e.g., ꢀCF3, ꢀCN, ꢀCO2Et, etc.) and moderately electronꢀdonating groups (ꢀ
CH3) were well tolerated. As an aside, an aqueous workup should be avoided with base sensitive
functional groups to prevent hydrolysis (as evidenced by the conversion of ꢀCN → ꢀCO2H, product 2q →
2r). On the other hand, strongly donating functional groups required longer reaction times and,
occasionally, elevated temperature. Certain halogen substituents (ꢀF, ꢀCl, ꢀCF3) are also compatible with
the reaction conditions. However, as mentioned earlier, the Brꢀsubstituted substrate 1f underwent
reductive debromination to a small degree, an observation that further supports an electron transfer
mechanism. Additional substitution (ꢀCH3, ꢀPh) at the αꢀposition of alkene reactants has no deleterious
effect on the yields of the corresponding products (2m and 2n). Substrates containing heterocyclic units,
both on the aniline ring and at the C(sp3)ꢀH terminus (2w, 2x, 2y), readily participate in the double Cꢀ
H/NꢀH activation as well.
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Scheme 13. Substrate scope for multiple successful approaches to prepare a diverse library of Nꢀ
heterocycles. Unless otherwise stated, yields are of the isolated product. aYield determined by 1HNMR.
The addition of a heteroatomic functionality to the benzylic/allylic group also weakens the C(sp3)ꢀH bond
and allows for CꢀN bond formation to occur. In the latter case, fragmentation of the benzyl/allyl
heteroatom group takes place, which is in agreement with the proposed radicalꢀanionic mechanism.45 The
second combination of cyclization and fragmentation expands the utility of this method to the preparation
of unsubstituted Nꢀheterocycles.
Extended N-heteroaromatics: The key step to assemble our C(sp3)ꢀH amination precursors is a Suzuki
coupling of a diꢀborylated aromatic moiety with an appropriate oꢀaminoaryl halide or the reverse
approach that utilizes an aromatic dihalide and an oꢀamino boronic ester. The building blocks for the key
step are available from dimethyl aromatics via a sequence of benzylic bromination followed by Friedelꢀ
Crafts alkylation using benzene and pꢀxylene as the aromatic nucleophile to prepare Core1 and Core4
respectively (Scheme 13). Additionally, 1,4ꢀdimethoxybenzene and pꢀxylene were used as the aromatic
nucleophiles prior to a Miyaura borylation to provide Core2 and Core3, respectively (Scheme 13).
Synthesis of diꢀborylated dihydroanthracene core, Core5 (Scheme 13), was accomplished using
innovative chemistry recently reported by Zhang and coꢀworkers.46 The synthetic pathway is scalable
with Core2 and Core5 being prepared on a gram scale (Core2 = 1.3 g, Core5 = 3 g, Scheme 13).
Expansion of this protocol to the preparation of extended aromatics demonstrates the farꢀreaching
applications of this synthetic methodology. We prepared a variety of extended Nꢀheterocyclic compounds
by developing a modular simple synthesis that starts from the easily modified cores. Depending on
whether the CH2 groups are located at the opposite or adjacent positions of the preꢀexisting cycles, the
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ring annulation via bisꢀcascades can either diverge from or converge to the core of the structure. These
cascades provide distinctly different heterocycles and illustrate the flexibility of our synthetic
methodology.
Gratifyingly, the bisꢀcascade reaction only required slight modification to the earlier optimized
conditions and applied to assemble extended Nꢀheterocyclic aromatics in a short synthetic pathway from
commercially available anilines in moderate to good yields (Scheme 13). The diverging bisꢀsubstrates
only required a slight modification to the equivalents of tꢀBuOK used in the reaction (6 equivalents
instead of 3). On the other hand, the converging bisꢀsubstrates not only required 6 equivalents of tꢀBuOK,
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o
but also required elevated temperatures (120 C instead of room temperature). Interestingly, when a bisꢀ
diverging substrate where R = Br was placed under the elevated temperatures, full cleavage of the Br
substituent occurred to provide 3f. In accordance with our earlier result in mechanistic studies, this
finding further corroborates the formation of radical anion. With this short list of modifications, we
successfully prepared new extended Nꢀheteroaromatics with varying functionality.
Synthesis of diverging expanded core:
Synthesis of diverging core:
Br
Br
Bpin
Bpin
Br
Br
Ar
Ar
a, b
c
a, b
Ar
Ar
A1
Br
Core4
Br
Br
A3
Br
Br
Synthesis of converging core:
Bis-boronic ester:
Bpin
Ph
OMe
Ar =
d, e
Ph
MeO
Br
Core1
Core3
Core2
Bpin
Core5
B1
Assembly of substrates:
Converging:
Diverging
Diverging
from the core:
expanded:
R
R
H2N
Ar
H2N
NH2
R
KOt-Bu, DMF,
O2, rt or 120°C
f
Core1-5
NH2
Ar
NH2
X
X = B(OH)2, Br, I
NH2
H2N
R = H, CH3, CF3, Cl, Br
R
R
Diverging:
CF3
Cl
N
N
N
O
O
N
O
N
Diverging
expanded:
N
N
N
N
O
F3C
Cl
N
3a, 77a
3b, 73a
3c, 72a
3d, 86a
3e, 44a
Converging:
F3C
N
N
N
N
N
N
N
N
CF3
3f, 68a, 71b
3g, 65a
3h, 59a
3i, 45a, 60c
Scheme 14. Alternative approaches that allow assembly of three different heterocycle families; and list of
extended polyaromatics available through the double CH2/NH2 coupling reactions. Synthesis of
precursors and substrates for the cyclization of bisꢀstructures; 3aꢀi. a) NBS, BPO, C6H6, reflux b) AlCl3,
●
PhNO2, ArꢀH, 110°C c) Pd(dppf)Cl2 CH2Cl2, B2pin2, KOAc, DMSO d) Na, tꢀBuOH, THF, rt e)
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[Ir(COD)OMe2], TMPhen (3,4,7,8ꢀtetramethylphenanthroline), B2pin2, THF, 85°C. f) Pd(PPh3)4,
K2CO3; PhMe, EtOH, H2O (5:2:1) reflux.
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9
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
3a
3a
3e
3e
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280 320 360 400 440 480 520
Wavelength (nm)
280 320 360 400 440 480 520
Wavelength (nm)
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
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0.0
1.0
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0.2
0.0
3f
3f
3i
3i
300 350 400 450 500 550 600 650
Wavelength (nm)
300 350 400 450 500 550 600 650
Wavelength (nm)
Figure 1. Absorption and emission spectra for structures 3a, 3e, 3f and 3i. Please see Supporting
Information for full experimental details.
Table 2. Photophysical Data for Compounds 3a-i
E0,0
(eV)
em (nm)b
τ (ns)c
Φd
e
Compd.
λ
abs (nm)
λ
305, 408
290, 404
299, 400
307, 401
313, 413
296, 437
301, 442
295, 435
270, 479
418
418
406
406
418
475
485
473
489
2.9
5.1
1.7
1.1
4.1
2.3
2.5
2.2
2.7
0.13
0.04
0.28
0.08
0.07
0.49
0.57
0.81
0.39
3.00
3.04
3.06
3.05
2.97
2.81
2.74
2.80
2.50
3a
3b
3c
3d
3e
3f
3g
3h
3i
aUV and visible region peak values. b,cExcitation at 360 nm. dCalculated relative to DPA in
47 e
chloroform at room temperature (Φ = 1.00).
absorption and emission spectra.
E
0,0
calculated from crossover wavelength of
Photophysical properties:
We investigated the electronic structure of all of the extended Nꢀheterocycles by UVꢀVis absorption and
fluorescence spectroscopy (Figure 1, Table 2). The divergent and convergent series of extended Nꢀ
heterocycles, 3a-3i, have two distinct absorption bands in the UV/Vis spectra; one (λmax) around 300 nm
and another past 400 nm.
The lowest energy transition for 3a, 3b, 3c, 3d and 3e, corresponds to a weak absorbance above 400 nm
and is apparently partially forbidden. The difference between normal and extended cores for the diverging
series does not lead to a large change in the absorbance energy (418 vs. 418 nm for 3a vs. 3e). The weak
response to the increase in the size of the core may originate from the distorted geometry of 3e, which
corresponds to a fused bisꢀ[4]helicene and, thus, is bent from planarity.48 On the other hand, the
converging series (3f, 3g, 3h and 3i) show strong hyperchromism for the absorbance above 400 nm. The
absorbance for the lowest transition is presumably due to the differences in planarity and conjugation of
the chromophoric units for each respective series and the transition probability of their dipole moment.
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All of the extended Nꢀheterocycles are fluorescent with emission above 400 nm. The observed trends
follow a pattern similar to the absorption data, with the spectra for the convergent cores being
bathochromically shifted about 60 nm relative to the divergent series. The quantum yields for the
divergent series (3aꢀ3e) are rather low (Φ = 4ꢀ13%, Table 2), with the exception of 3c (Φ = 28%).
Conversely, the quantum yields for the convergent series (3fꢀ3i) are dramatically improved (Φ = 39ꢀ81%,
Table 2).
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The role of N-atoms in electronic properties of polyaromatics: The new synthetic sequences outlined
in this work provided concise routes to the Nꢀheterocyclic analogues of benzo[k]tetraphene,
dibenzo[c,l]chrysene, and dibenzo[fg,qr]pentacene. The parent hydrocarbons have been reported in the
past.49 However, the literature reports lack complete sets of photophysical data. Due to scarcity of
experimental information, we have calculated the frontier MOs and analyzed the effect of Nꢀheteroatom
incorporation on these orbitals.
Scheme 15. Comparison of structures and frontier MOs for the Nꢀderivatives prepared in this work
with their hydrocarbon parents. HOMO and LUMO energies, at the PBE0(D3)/6ꢀ31+G(d,p) level of
theory, are in eV.
Comparison of the HOMO and LUMO nodal structures for the Nꢀheterocycles and their hydrocarbon
parents illustrate that orbital symmetry is quite robust and not influenced strongly by the introduction of
two nitrogen atoms. Only two of the six pairs of FMOs (the HOMOs of phenanthridino[10,9ꢀk]
phenanthridine and dibenzo[c,l]chrysene) are significantly different (Scheme 15). This observation is
consistent with the general features observed in the electronic absorption spectra for the new heterocycles.
In agreement with the experimental data, TDꢀDFT analysis of the lowest energy excitations for the Nꢀ
containing systems found that the first excited states for the “diverging” systems correspond to weakly
allowed states with multiple contributors, of which the HOMOꢀLUMO transition is the major one. For the
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convergent ring system, the lowest excited state has a much larger oxidation state and corresponds almost
entirely to a HOMOꢀLUMO transition.
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G
F
E
C
A
B
G
F
E
C
B
A
Scheme 16. Selected changes in local aromaticity revealed by the NICSꢀxy scans
The local aromaticity analysis via NICSꢀxy scans is able to detect noticeable differences in the
electronic structures of these three pairs of carbo/heterocycles. For example, the two Nꢀcontaining rings
of quinolino[4,3ꢀj] phenanthridine are less aromatic than the analogous rings of benzo[k]tetraphene
(Scheme 16).50
Conclusions
In summary, we have developed a direct method for converting C(sp3)ꢀH and NꢀH bonds into CꢀN
bonds in the presence of base, molecular oxygen and DMF. Each reaction component plays a separate
role in the synergistic effort which involves a coordinated sequence of deprotonation, Hꢀatom transfer and
electron transfer for each CꢀN bond formation. tꢀButoxide base plays two roles: a) it deprotonates
nitrogen and b) provides sufficient concentration of deprotonated DMF that can be converted into a DMF
radical. The role of DMF radical is in selective activation of the CꢀH bond partner in CꢀN bond formation
via HAT that forms a Cꢀcentered radical. The CꢀN bond is formed initially as a 2c,3e interaction between
the Nꢀanion and Cꢀradical, a process that is assisted by state crossing “ejecting” the extra electron into
an orthogonal πꢀsystem and forging a “normal” 2c,2e CꢀN bond. This process of 2c,3e bond formation
becomes much faster and more favorable thermodynamically when aniline is deprotonated, indicating that
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both the TS and the product of the “neutral” version of this process are considerably more acidic than
the starting benzylic radical (Scheme 8). Oxidation of the cyclic radicalꢀanion intermediate by molecular
oxygen finishes the sequence of deprotonation, HAT and oxidation that are necessary for the success of
this deceivingly simple transformation. The process opens a quick access to the previously unknown
classes of extended Nꢀheterocycles.
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ASSOCIATED CONTENT
Supporting Information
1
Full experimental details, H NMR, 13C NMR, HRꢀMS and NMR spectra for all newly reported
compounds. UVꢀVis and emission spectra along all photophysical data are available for extended Nꢀ
heteroaromatics, and computational details for all calculated structures. The Supporting Information is
available free of charge on the ACS Publications website at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*alabugin@chem.fsu.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The fundamental and synthetic aspects of this study were supported by donors of the ACS Petroleum
Research Fund (PRF#57377ꢀND4) and by the National Science Foundation (CHEꢀ1465142). We
appreciate the allocation of computational resources from FSU RCC and the NSF XSEDE (TGꢀ
CHE160006). F.S. is grateful for support from An Educational and Research Promotion (Overseas
Scientific Activity) Program 2016 for Doctor Course Students, Interdisciplinary Graduate School of
Engineering Sciences, Kyushu University and Prof. M. Shindo.
TOC Graphic:
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