Base-Promoted Aerobic Oxidation/Homolytic Aromatic Substitution Cascade toward the Synthesis of Phenanthridines

Article abstract of DOI:10.1002/adsc.201900995

The current protocol represents a transition metal-free synthesis of polysubstituted phenanthridines from abundant starting materials like benzhydrol and 2-iodoaniline derivatives. The reaction involves sequential oxidation of alcohol and direct condensation reaction with the amine resulting in a C?N bond formation followed by a radical C?C coupling in a cascade sequence. The used base potassium tert-butoxide plays a dual role in dehydrogenation and homolytic aromatic substitution reaction. Using this methodology, twenty substituted phenanthridine derivatives were synthesized with up to 85% isolated yield. (Figure presented.).

Full text of DOI:10.1002/adsc.201900995

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DOI: 10.1002/adsc.201900995
Very Important Publication
Base-Promoted Aerobic Oxidation/Homolytic Aromatic
Substitution Cascade toward the Synthesis of Phenanthridines
Debabrata Maiti,a Atreyee Halder,a and Suman De Sarkara,*
a
Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur – 741246, West
Bengal, India
E-mail: sds@iiserkol.ac.in
Manuscript received: August 9, 2019; Revised manuscript received: September 6, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900995
lowed by a homolytic aromatic substitution.[6] Another
popular approach is the photolysis or oxidant-induced
Abstract: The current protocol represents a transi-
tion metal-free synthesis of polysubstituted phenan-
cyclization of oxime, imine or nitrile derivatives via
thridines from abundant starting materials like
the formation of iminyl radical.[7] Cascade annulation
benzhydrol and 2-iodoaniline derivatives. The reac-
of nitriles with biphenyls containing diazo or hyper-
tion involves sequential oxidation of alcohol and
valent iodine is also reported.[8] All these methods
direct condensation reaction with the amine result-
(Scheme 1a), although widely studied, suffer from the
ing in a CÀ N bond formation followed by a radical
limited scope and practicality due to the elaborated
synthesis of starting biphenyl derivatives.
CÀ C coupling in a cascade sequence. The used base
potassium tert-butoxide plays a dual role in dehy-
Apart from biphenyl starting materials, transition
drogenation and homolytic aromatic substitution
metal-catalyzed intermolecular annulation between
reaction. Using this methodology, twenty substituted
aryl iodides and imine derivatives was reported for the
phenanthridine derivatives were synthesized with up
synthesis of phenanthridines.[9] Recently, a one-pot
to 85% isolated yield.
sequential cross-dehydrogenative-coupling and cycli-
zation method was developed using a palladium
Keywords: Phenanthridine; Radical; Aerobic oxida-
catalyst and strong oxidant.[10] However, transition
tion; Homogeneous catalysis; Aromatic substitution
metal-free protocols for the synthesis of phenanthri-
Phenanthridines represent a vastly valuable class of N-
heteroaryl core structures for organic synthesis, owing
to the widespread occurrence in natural alkaloids and
biologically active pharmaceuticals, having antitumor,
antibacterial, antituberculosis activities.[1] A well-
known phenanthridine, ethidium, and its derivatives
Figure 1. Examples of bioactive phenanthridine derivatives.
are effective DNA intercalating reagents and have
found application as a fluorescent tag.[2] Additionally,
the physical properties of various functional materials
were found to be improved by introducing phenanthri- dines from readily available materials are less explored
dine derivatives.[3] Thus, the usefulness of this struc- and are on high demand.
tural motif has been realized by synthetic organic
chemists and attention has been paid for the develop- promoted cross-coupling of an activated CÀ H bond
In 2008, Itami and co-workers reported KOtBu
ment of new synthetic methodologies (Figure 1).[4]
and haloarenes under microwave irradiation.[11] Combi-
Classical synthesis of phenanthridines involves the nation of base and different organocatalysts[12] have
dehydrative cyclization of N-acyl-2-biphenylamine been employed to promote the cross-coupling product
derivatives under harsh conditions.[5] A modern ap- of aryl halide with unactivated arenes via base-
proach includes the generation of biphenyl imidoyl promoted homolytic aromatic substitution (BHAS).[13]
radical intermediates from 2-isocyanobiphenyls fol- In 2011, Bin Li first synthesized phenanthridines from
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Scheme 1. Methods for the Synthesis of Phenanthridines.
imine substrate using Pd-catalyzed intramolecular CÀ H pling. Moreover, aromatic substitution reactions in-
activation/CÀ C cross-coupling,[14] subsequently Kwong volving radical intermediates often require large excess
group reported a transition-metal-free procedure.[15] of another coupling partner for successful
However, the requirement of the prefunctionalized heterocoupling.[13d] From a sustainability point of view,
starting materials limits the practical application of we intended to address this issue and use the equimolar
these methods.
amounts of both reagents.
In our ongoing research program towards the
We commenced our study by reacting benzhydrol
sustainable synthesis of heteroaryl compounds,[16] we (1a) and 2-iodoaniline (2a) in the presence of base
envisioned base-promoted aerial oxidation[17] followed KO Bu and tetramethylethyldiamine (L1) at 140 C
t
°
by homolytic aromatic substitution cascade for the (Table 1). To our delight, the desired 6-phenylphenan-
synthesis of phenanthridine derivatives (Scheme 1b). thridine (3aa) was formed in 47% yield (entry 1).
This transition metal-free approach would allow the However, other additives like diol L2 and bipyridine
direct use of alcohols[18] and 2-iodoaniline derivatives. L3 were found to be completely inefficient. More rigid
However, we realized the major challenge of control- 1,10-phenanthroline (L4) showed the best result and
ling the reaction on the desired sequence of ketone 3aa was detected in 86% by NMR and in 82% isolated
generation followed by imine formation and then the yield.
annulation via a radical intermediate. Alteration in this
The necessary synergistic effect of base and ligand
°
order will result in copious undesired biproducts. For at 140 C was confirmed as the reaction was found to
example, base-promoted homolytic cleavage of CÀ I be inefficient in the absence of either of these (entry 5
bond in 2-iodoaniline before imine formation will and 6). In view of the functional group tolerability,
cause a serious problem of unselective radical cou- ligand-free approach at further higher temperature was
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Table 1. Optimization of the reaction conditions[a].
Entry
L (mol%)
solvent
Base
Yield[b]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
–
L4
L4
L4
L4
L4
L4
L4
L4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-dioxane
HOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
–
47
0
Trace
86 (82)[c]
18
0
53
0
58
0
22
67
63
NaOtBu
K3PO4
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
9
10
11[d]
12[e]
13[f]
Toluene
Toluene
Toluene
[a] Reaction conditions: 1a (0.12 mmol), 2a (0.10 mmol), ligand (20 mol%), base (2 equiv.), solvent (0.4 mL), 20 h under air.
[b] NMR yield.
[c] Isolated yield.
[d] Under Ar atmosphere.
[e]
°
At 120 C.
[f] For 12 h.
not performed.[19] Another butoxide base showed lines were tested, in all cases reaction underwent
substantial conversion, however weak base like K3PO4 smoothly and delivered phenanthridine 3ai–3al in
was not suitable, which signified that stronger base good yields.
was necessary for the effective deprotonation of
Same reaction condition was further applied for
alcohol in the dehydrogenative process. Few other different derivatives of benzhydrol 1b–i with 2-iodo-
solvents were tested (entry 9 and 10), but toluene was aniline (2a). Fluoren-9-ol was transferred to the
the optimal choice for the reaction. As expected, the desired product 3ba in 67% yield. Electron-rich
reaction is far less effective under inert atmosphere symmetric benzhydrol derivatives (1c and 1d) partici-
indicating aerial oxygen as the terminal oxidant. pated in CÀ N and CÀ C coupling reactions efficiently.
Furthermore, lowering the reaction temperature and However, in the case of bistolyl (3da) the formation of
time had a negative impact and comparatively lower two regioisomers was observed.[14,15b] Unsymmetrical
yields were obtained (entry 12 and 13).
para-substituted benzhydrols (1e and 1f) delivered the
Once the optimal reaction condition was estab- products 3ea and 3fa respectively, as a regioisomeric
lished, we evaluated the scope of substituted 2-iodoani- mixture from the coupling with both rings. In this case,
lines 2 with benzhydrol 1a as a model substrate. the radical aromatic substitution occurred with a slight
Electron-rich iodoanilines bearing different alkyl preference for the unsubstituted phenyl unit. Regiose-
groups on the para-position reacted efficiently, leading lectivity largely improved in the case of
to the corresponding phenanthridines (3ab–ad) in phenylÀ pyridinyl substituted alcohol 1g and the for-
good yields. Electron withdrawing groups (À CN, À F) mation of the corresponding product 3ga was observed
were also tolerated well, affording moderate to good as a single regioisomer. However, when the optimal
yields (3ae and 3af). The reaction of meta-substituted condition was applied to meta- and ortho-substituted
2-iodoanilines furnished 3ag and 3ah in excellent unsymmetrical benzhydrols (1h and 1i), all possible
yields. Furthermore, differently substituted biarylani- regioisomers were observed.
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Table 2. Substrate Scope Using Substituted Iodoanilines.[a,b]
[a] Reaction conditions: 1a (0.3 mmol), 2a–l (0.25 mmol), 1,10-phenanthroline (20 mol%), KOtBu (0.5 mmol), in toluene (1 mL),
20 h under air.
[b] Isolated yield.
To gain mechanistic understanding into the process, as a substrate instead of benzhydrol, providing the
several experiments were performed (Scheme 2). The phenanthridine product in 81% yield (Scheme 2c),
reaction was completely shut down when a stoichio- which proved that the oxidation of the alcohol is the
metric amount of TEMPO was added, concluding that initial step. To find the rate-determining step, 1a and
this transformation might involve a radical pathway. 1a–d1 were reacted with 2b separately under the
The necessity of the halogen functionality for the standard condition for 6 h, which revealed a kinetic
homolytic aromatic substitution was confirmed as p- isotope effect (KIE) KH/KD =1.86 (Scheme 2d). In
toluidine (2b’) forms imine 4ab’ (16%) and N- another experiment, 1a–d5 was reacted with 2b, which
alkylated amine 4ab’’ (29%) by subsequent MPV type did not show any KIE and displayed an equal
reduction (Scheme 2b).[17d] For 2-iodoaniline sub- preference for the radical aromatic substitution in the
strates, this reductive alkylation reaction was not deuterated and non-deuterated phenyl rings (Sche-
observed, most likely because of the faster follow-up me 2e). This indicates the rate-determining step does
SET process (Scheme 3). Only the formation of not involve the aryl CÀ H bond cleavage, thus the
benzophenone was observed by base mediated aerial oxidation step should be the rate-determining step.
oxidation of benzhydrol in absence of the iodoaniline
(See SI). Generation of H2O2 as byproduct was also reports,
Based on the mechanistic studies and literature
probable mechanism is depicted in
a
proved by treating the crude reaction mixture with KI Scheme 3. The reaction initiates by the interaction
À
and noticing the formation of I3 spectrophotometri- between the ligand phenanthroline (Phen) and KOtBu
cally (See SI). Furthermore, benzophenone was used to generate the radical anion 5 via an inner-sphere
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Table 3. Substrate Scope Using Substituted Benzhydrols.[a,b]
[a] Reaction conditions: 1b–i (0.3 mmol), 2a (0.25 mmol), 1,10-phenanthroline (20 mol%), KOtBu (0.5 mmol), in toluene (1 mL),
20 h under air.
[b] Isolated yield.
electron transfer process.[20] This radical anion 5 acts as process until the formation of imine. Such electronic
an organic super-electron donor. Alternatively, in situ differences between aniline and imine are responsible
formed dimeric heterocyclic structures as electron to prevent other possible side reactions that could
donors, as suggested by Murphy, cannot be ruled occur from uncontrolled radical processes. The frag-
out.[21] On the other hand, base-catalyzed aerial mentation of iodide from 8 followed by 6-endo-trig
oxidation of benzhydrol generates benzophenone 6 radical annulation gives 10. Finally, radical chain
with the formation of peroxide anion.[17e] Condensation propagation regenerates radical anion 8 from another
of 6 with 2-iodoaniline forms imine 7. An outer-sphere molecule of imine 7 and the aromatization of 10
single electron transfer, initiated from the reaction delivers phenanthridine 3. Alternatively, kinetically
between the iodine-containing imine 7 and 5, provides more favorable 5-exo-trig cyclization from 9 produces
the radical anion species 8. Presumably, the starting the spirocyclohexadienyl 11 which upon ring expan-
electron-rich 2-iodoaniline does not undergo the SET
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Scheme 2. Mechanistic studies.
sion and follow-up chain transfer reaction forms other challenging reactivity control by tuning the electronic
regioisomer of 3.[22]
nature of different reaction intermediates.
Herein, we report a transition metal-free aerobic
oxidation of alcohol and direct condensation reaction
with amine to form a CÀ N bond followed by a CÀ C
Experimental Section
coupling in a cascade sequence to achieve the targeted General Procedure for the Synthesis of Phenanthri-
phenanthridine. The used base KOtBu displayed a dines 3
twofold activity in oxidation and homolytic aromatic
Benzhydrol
1
(0.30 mmol, 1.2 equiv.), 2-iodoaniline
2
substitution reaction via a controlled radical pathway.
This protocol demonstrates synthetic advantages in
terms of cheap starting materials like alcohols over
corresponding carbonyl compounds and also shows the
(0.25 mmol, 1.0 equiv.) 1,10-phenanthroline (9 mg, 20 mol%)
and KOtBu (0.50 mmol, 2.0 equiv.) were placed in a pre-dried
standard glass reaction tube. Toluene (1 ml) was added and the
°
sealed reaction tube was heated at 140 C in an oil bath for 20 h.
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Scheme 3. Proposed mechanism.
At ambient temperature EtOAc (20 ml) was added, washed with
brine (12 ml), dried over Na2SO4, concentrated under vacuum,
and purified by silica gel column chromatography to deliver
phenanthridine 3.
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Generous support by the CSIR [Fellowship to DM], SERB,
DST, India [ECR/2016/000225 to SDS] and IISER Kolkata
[Fellowship to AH and infrastructure] is gratefully acknowl-
edged.
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Base-Promoted Aerobic Oxidation/Homolytic Aromatic Sub-
stitution Cascade toward the Synthesis of Phenanthridines
Adv. Synth. Catal. 2019, 361, 1–9
D. Maiti, A. Halder, S. De Sarkar*