Triarylmethanes and their Medium-Ring Analogues by Unactivated Truce–Smiles Rearrangement of Benzanilides

Article abstract of DOI:10.1002/anie.202102192

Intramolecular nucleophilic aromatic substitution (Truce–Smiles rearrangement) of the anions of 2-benzyl benzanilides leads to triarylmethanes in an operationally simple manner. The reaction succeeds even without electronic activation of the ring that pla

Full text of DOI:10.1002/anie.202102192

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11272–11277
International Edition:
German Edition:
doi.org/10.1002/anie.202102192
doi.org/10.1002/ange.202102192
Synthetic Methods Very Important Paper
Triarylmethanes and their Medium-Ring Analogues by Unactivated
Truce–Smiles Rearrangement of Benzanilides
Roman Abrams, Mehul H. Jesani, Alex Browning, and Jonathan Clayden*
Abstract: Intramolecular nucleophilic aromatic substitution
(
Truce–Smiles rearrangement) of the anions of 2-benzyl
benzanilides leads to triarylmethanes in an operationally
simple manner. The reaction succeeds even without electronic
activation of the ring that plays the role of electrophile in the
SNAr reaction, being accelerated instead by the preferred
conformation imposed by the tertiary amide tether. The amide
substituent of the product may be removed or transformed into
alternative functional groups. A ring-expanding variant (n to
n + 4) of the reaction provided a route to doubly benzo-fused
medium ring lactams of 10 or 11 members. Hammett analysis
returned a 1 value consistent with the operation of a partially
concerted reaction mechanism.
T
riarylmethanes are privileged molecular structures finding
[1–8]
application in numerous aspects of chemical science.
The
[1]
triarylmethane scaffold occurs in natural products, medic-
inal agents, building blocks in materials chemistry, and
ligand scaffolds. Additionally, triarylmethanes are com-
monly used as dyes and fluorescent probes, culminating in
their recent use as red light-absorbing photoredox catalysts
and red light-fluorescing OLEDs.
[
2]
[3]
[
4]
[
5]
[6]
[7]
[
8]
Owing to the diverse utility of triarylmethanes, various
synthetic methods have been developed for their prepara-
Scheme 1. a–d) Previous approaches to triarylmethanes. e) This work:
synthesis of triarylmethanes by conformationally accelerated intramo-
[
9]
tion. Common approaches include Lewis and Brønsted acid-
lecular S Ar (Truce–Smiles) rearrangement. LA: Lewis acid, BA:
N
[
10]
mediated Friedel–Crafts alkylations, and transition metal-
Brønsted acid, TM: transition metal.
3
2
catalysed C(sp )ꢀC(sp ) Suzuki or Kumada cross-couplings
[
11]
(
Scheme 1a). They may also be made by the CꢀH arylation
SNAr reactions are far from a mechanistic rarity, paving the
way for their broader application in synthesis as they provide
of diarylmethanes that results from deprotonative transition
metal-catalysed cross-coupling processes (Scheme 1b), or
by Lewis or Brønsted acid-promoted arylations of quinone
[12]
[15]
a transition metal-free route to arylation reactions. SNAr
reactions of diarylmethane carbanions conceptually offer
a simple method for triarylmethane construction, but reports
are surprisingly sparse and restricted to highly activated nitro-
[
13]
methides (Scheme 1c).
Nucleophilic aromatic substitution (S Ar) reactions have
N
[
19]
been used as a valuable way of making Arꢀheteroatom and
ArꢀC bonds, but as a reaction class they have recently
undergone an academic resurgence, as a result of several
containing aryl electrophiles (Scheme 1d).
Here we describe a much more general and operationally
simple approach to triarylmethanes by the use of a conforma-
related discoveries in the field of concerted S Ar mecha-
tionally enhanced intramolecular S Ar reaction, or Truce–
Smiles rearrangement (Scheme 1e). Classical Truce–Smiles
rearrangements proceed by 1,4- or 1,5-N or O to C intra-
N
N
[
14–18]
[14]
nisms.
Jacobsen and co-workers showed that concerted
[
*] Dr. R. Abrams, M. H. Jesani, A. Browning, Prof. J. Clayden
School of Chemistry, University of Bristol
Cantock’s Close, Bristol BS8 1TS (UK)
molecular S Ar of electron-deficient aryl rings, but in our
N
conformationally accelerated variant, much greater substrate
generality is possible because no electronic activation is
E-mail: j.clayden@bristol.ac.uk
[20,21]
required.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102192.
N-Methylated benzanilides such as 1 prefer to adopt
E conformations in which the N-aryl ring lies trans to the
[22]
carbonyl group, and with the amide carbonyl group twisted
ꢀ
2021 The Authors. Angewandte Chemie International Edition
[
23]
more or less perpendicular to the benzamide ring. This
conformational bias can be used to promote intramolecular
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
SNAr for unactivated and even moderately electron-rich aryl
rings, by pre-organisation of the nucleophilic and electrophilic
1
1272
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[
18]
components for reaction. With the aim of exploiting such
a reaction for the synthesis of triarylmethanes, 2-benzylbenz-
amide 1 was treated with base with the aim of generating
a nucleophilic benzylic anion (Table 1).
Table 1: Optimisation studies.
[
a]
[b]
[c]
Entry
Base (equiv)
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
NaHMDS (2.0)
NaHMDS (2.0)
NaHMDS (2.0)
LiHMDS (2.0)
KHMDS (2.0)
KHMDS (1.1)
KHMDS (2.0)
20
60
16
16
1
1
1
<5
49
73
62
81 (67)
70
Scheme 2. Scope of migrating aryl group (green aryl group) for the
Truce–Smiles rearrangement. Reactions were carried out on
a 0.20 mmol scale. Yields of product after isolation by chromatography,
and temperatures of reaction are quoted. [a] With LiHMDS used in
place of KHMDS.
100
100
100
100
120
1
1
69
[a] Reactions performed on a 0.1 mmol scale. KHMDS (1.0 m in
THF)=potassium bis(trimethylsilyl)amide, NaHMDS (1.0 m in
THF)=sodium bis(trimethylsilyl)amide, LiHMDS (1.0 m in
THF)=lithium bis(trimethylsilyl)amide. [b] Reactions requiring 608C
and below were heated conventionally. Reactions requiring heating
above 608C were performed under microwave irradiation. [c] Yield
1
determined by H NMR using 1,3,5-trimethoxybenzene as an internal
standard. Isolated yield in parentheses (0.2 mmol scale reaction).
Initial attempts with NaHMDS at ambient temperature
only afforded trace amounts of product (Table 1, entry 1).
However, at elevated temperatures 2-benzylbenzamide
1
underwent Truce–Smiles rearrangement to give triaryl-
methane 2 (Table 1, entries 2, 3). A base screen identified
KHMDS as the optimal choice (Table 1, entries 3–5), with
THF and Et O as the best performing solvents (See SI).
2
Slightly lower yields were obtained when the KHMDS
stoichiometry was reduced from 2.0 or if the reaction
temperature was elevated to 1208C (Table 1, entries 6, 7).
Key indicators of the spectroscopic assignment of the
structure of the product are shown in the scheme in Table 1.
With optimised conditions identified for the rearrange-
ment of 1 we investigated the generality of the reaction.
Firstly, we explored the scope of aromatic rings that undergo
N to C migration (Scheme 2). As with other conformationally
[
16,17]
accelerated Truce–Smiles rearrangements,
even of electron-rich (4a and 4b) and ortho-functionalised
4c and 4d) aromatic rings proceeded cleanly at elevated
migration
(
temperatures. Fluorinated aromatic rings (4e and 4 f) were
likewise successfully incorporated into their triarylmethanes,
with 4 f forming even at ambient temperature. The migrations
of both chlorinated and brominated aromatics required lower
reaction temperatures to avoid protodehalogenation, but
were all ultimately successful (4g–i). Heterocyclic triaryl-
methanes could also be formed, with 4-, 3-, and 2-substituted
pyridines all migrating in excellent yield (4j–l).
Scheme 3. Scope of benzylic aryl groups (red and black aryl groups)
for the Truce–Smiles rearrangement reaction. Reactions were carried
out on a 0.20 mmol scale. Yields of product after isolation by
chromatography. R=-C(O)NHMe. Reactions requiring heating at 608C
and below were performed thermally. Reactions requiring heating
above 608C were performed in a microwave oven. [a] Performed at
508C. [b] Performed on a 3.7 mmol scale. [c] Performed at 558C.
[d] Performed at 208C. [e] Performed at 308C. [f] Performed at 1008C.
The ring coloured red in the schemes plays the role of an
anion-stabilising group, and extensive variation in this ring
was explored, as indicated in Scheme 3. The reaction was
unaffected by variation in this position, tolerating a variety of
substituents, including methoxy, methyl, phenyl, and fluoro
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groups (6a–6d). Substitution in the ortho position was not
detrimental, with products containing more hindered ortho-
tolyl and 1-naphthyl groups forming readily (6e and 6 f).
Triarylmethanes containing 3,4-disubstituted phenyl rings
bearing methyl, fluoro, and a dibenzothiophene heterocycle
were likewise all formed in good yield (6g–6i). Substitution
on the third ring, the benzamide ring itself (coloured black),
was also possible—significantly even with the substituent
ortho to the amide, a position which imposes a significant
the transformation of this group to other substituents (or
none) was explored (Scheme 5). N-Nitrosation of triaryl-
[28]
methane 6a formed N-nitrosoamide 9,
converting the
amide to an activated acyl group. In one pot, 6a was readily
converted onwards to carboxylic acid 10 by basic hydrolysis.
The carboxylic acid of 10 was removed by a copper-catalysed
[
29]
decarboxylation, revealing the “traceless” triarylmethane
product 11. Alternatively, the N-methylbenzamide of 6a
could be used as a useful synthetic handle in, for example, an
unoptimised palladium-catalysed annulation to yield the N-
[
23]
conformational restraint (6j).
[30]
Alternative starting materials in which the migrating ring
formed part of a heterocyclic precursor allowed the rear-
rangement to form products containing medium ring lactams
methyl isoquinolone 12.
(
Scheme 4). Thus the tetrahydroquinoline 7a was readily
expanded to the 10-membered lactam 8a upon treatment of
base. Similar reactivity was shown with the tetrahydronaph-
thyridine 7b, and with the benzo-fused 7-ring starting
material 7c, as well as with the dihydro dibenzazepine-
derived 7d, each forming their respective 10 and 11-mem-
bered lactams (8b–8d). The conformational restriction char-
acteristic of medium rings gives them particular interest in
[
24]
medicinal chemistry, and ring expansion has proved to be
a viable method for the preparation of medium-ring hetero-
[
25a]
cycles,
circumventing the difficulties associated with
entropically and enthalpically unfavourable cyclisa-
[
18b,25–27]
tions.
8a–d constitute the first reported examples of
medium ring-containing triarylmethane analogues.
The rearrangement leads to products that carry a secon-
dary amide substituent. To explore the potential broadening
of this synthetic approach to a more general range of targets,
Scheme 5. Synthetic modifications of rearrangement product 6a.
Yields of product after isolation by chromatography.
Our proposed mechanism for the rearrangement that
leads to the triarylmethane products starts with deprotona-
tion of the 2-benzylbenzamide 1 by KHMDS (Scheme 6a).
[
31]
The DMSO pK values of HMDS (26) and diarylmethane
(
a
[31]
33.5–28) suggest that the equilibrium between 2-benzyl-
benzamide 1 and carbanion 13 may lie in favour of the
protonated form, although the carbanion is additionally
stabilised by the amide group. Nonetheless, enough carbanion
must be formed to allow the rate of attack on the migrating
ring, which initiates an intramolecular S Ar reaction, to be
N
sufficiently high that it is synthetically useful. Protonation of
product amide anion 14 by the aqueous quench yields the
desired triarylmethane product.
Further details of the reaction mechanism were explored
by in situ infra-red spectroscopy (React-IR). Addition of
KHMDS to a solution of 3h in THF (Scheme 6b) led to decay
ꢀ
1
of the amide carbonyl stretching frequency (1652 cm ) as
ꢀ
1
a new absorption appeared at 1560 cm (Scheme 6c). This
band was assigned to the carbonyl group of the amide anion of
4h, confirmed by addition of KHMDS to triarylmethane 4h
Scheme 4. Scope of the ring-expanding rearrangement reaction. Reac-
tions were carried out on a 0.80 mmol scale. Yields of product after
isolation by chromatography.
1
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ꢀ
Figure 1. Hammett plot of log(k /k ) against s at 228C, consistent
R
H
with rate-determining rearrangement. The gradient (1 = +4.0) is
consistent with substantial charge build-up on the aryl substituent
during the rearrangement. Error bars represent 1 standard deviation in
a single direction.
formed in good yield at much lower temperatures when the
migrating ring is electron-deficient. Nonetheless, the facility
with which even the p-OMe group of 4a undergoes intra-
Scheme 6. A) Proposed reaction pathway, with approximate C=O
stretching frequencies. B) In situ infra-red trace of the reaction of N-
aryl 2-benzylbenzamide 3h, showing diagnostic changes in carbonyl-
stretching frequencies. C) Plot of absorbance against time for peaks at
molecular S Ar points to the importance of the conforma-
N
tional restriction inherent in the amide starting materials as
a major factor in accelerating the absolute values of these rate
ꢀ
1
ꢀ1
1
652 cm (3h, starting material) and 1560 cm (4h, product anion).
D) Deuterium-exchange study with N-aryl 2-benzylbenzamide 3h.
[22]
constants over corresponding intermolecular variants.
Murphy and Tuttle
[
32]
have shown that the 1 value is
insufficient as an indicator of whether a reaction proceeds
to generate an authentic sample of its amide anion (See SI).
by a Meisenheimer complex or by a concerted S Ar reaction,
N
No C=O signal corresponding to reaction intermediate 13 was
but given the lack of stabilisation offered to any intermediate
anion in most substrates the reaction very likely falls into the
latter class, along with other similar recently described
seen, an observation consistent either with rate limiting C-
deprotonation, or with rate limiting rearrangement from an
undetectably low concentration of the anion. These two
possibilities were distinguished by carrying out the rearrange-
ment of 3h in the presence of deuterated HMDS, quenching
the reaction before complete consumption of starting mate-
rial (Scheme 6d). Deuterium incorporation at the benzylic
position of 3h indicated that deprotonation is fast and
[
14–18]
reactions.
In summary, a base-mediated intramolecular S Ar reac-
N
tion of N-aryl 2-benzylbenzamides to form triarylmethanes of
varied structure is made possible by conformationally induced
rate acceleration of an otherwise apparently unfavourable
intramolecular S Ar reaction. This methodology is tolerant of
N
reversible, confirming that the rearrangement (S Ar) step is
rate-determining.
a range of functional groups and aromatic rings, with the
resulting triarylmethane products amenable to subsequent
constructive or defunctionalising transformations. Novel
medium ring-containing triarylmethane scaffolds may be
prepared by an n to n + 4 ring expanding variant of the
rearrangement. React-IR, deuteration, and Hammett analysis
support an empirical mechanistic model in which reversible
deprotonation generated a low concentration of a benzyl
anion which undergoes rate-determining nucleophilic substi-
tution on the migrating ring.
N
Classical nucleophilic aromatic substitution reactions
require electron-deficient migrating groups, yet the results
presented in Schemes 2 and 4 suggest that the rate of this
reaction is largely independent of the nature of the electro-
philic ring. The role of electronic effects in this reaction was
therefore investigated using a Hammett plot. KHMDS was
added at 228C to a series of N-aryl 2-benzylbenzamides, with
the formation of triarylmethane amide anion monitored by
React-IR. Under these conditions, the formation of the
triarylmethane amide anion from the 2-benzylbenzamide
followed first-order kinetics, and the linear section of a plot of Acknowledgements
ln([14] ꢀ[14] ) against time gave a rate constant k for each
1
t
obs
substrate (Figure 1). A Hammett plot of log(k /k ) versus the
The work was supported by the EPSRC Centre for Doctoral
Training in Catalysis and the EPSRC Centre for Doctoral
Training in Technology Enhanced Chemical Synthesis.
R
H
ꢀ
substituent constant s yielded a value for 1 of + 4.0,
indicating substantial build-up of negative charge on the
migrating ring during the reaction. This significant depend-
ꢀ
ence on s explains why the products in Scheme 2 may be
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Wang, N. Qiu, Y. Kong, W. Zeng, Y. Zhang, J. Zhao, J. Org.
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The authors declare no conflict of interest.
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Keywords: Hammett plot · medium ring · S Ar · triarylmethane ·
Truce–Smiles rearrangement
N
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