Iodine-catalyzed synthesis of N, N ′-diaryl-o-phenylenediamines from cyclohexanones and anilines using DMSO and O2 as oxidants

Article abstract of DOI:10.1039/c8cc05320k

A novel I₂-catalyzed cross-dehydrogenative aromatization of cyclohexanones and anilines to synthesize N,N′-diaryl-o-phenylenediamines has been unprecedentedly developed with dimethyl sulfoxide and oxygen employed as mild terminal oxidants. To prove the rationality of the two separate dehydration steps of the proposed mechanism, a resulting I₂-catalyzed cross-dehydrogenative aromatization of cyclohexenones and anilines to synthesize diarylamines has also been reported.

Full text of DOI:10.1039/c8cc05320k

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DOI: 10.1039/C8CC05320K
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Iodine-catalyzed synthesis of N,N'-diaryl-o-phenylenediamines
from cyclohexanones and anilines using DMSO and O2 as oxidant
Mingteng Xiong, Zhan Gao, Xiao Liang, Pengfei Cai, Heping Zhu and Yuanjiang Pan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
novel I2-catalyzed cross-dehydrogenative aromatization of
cyclohexanones and anilines to synthesize N,N'-diaryl-ο-
phenylenediamines has been unprecedentedly developed.
Dimethyl sulfoxide and oxegen are employed as the mild terminal
oxidant. To prove the rationality of the two separate dehydration
steps of the proposed mechanism, a resulting I2-catalyzed cross-
dehydrogenative aromatization of cyclohexenones and anilines to
synthesize diarylamines has also been report.
Arylamines are core frameworks of diverse active molecules
which are closely relevant to functional materials,
Scheme 1 Strategies for the synthesis of arylamines
pharmaceuticals, agrochemicals, etc.1 Therefore, constant prepare
N,N’-diaryl-o-phenylenediamines
were
either
attention has been paid to the preparation of arylamines in a employing the traditional Buchwald-Hartwig amination which is
simple and efficient process over the past few decades.2 sometimes troublesome and limited because of harsh
Undoubtedly, the traditional methods to construct C‒N bond of conditions and existence of heavy metals10 or utilizing complex
11
arylamines include Buchwald-Hartwig couplings3, Ullmann-type materials via multi-step reaction processes6,
(Scheme 2).
Reactions4 and Chan-Lam couplings5 (Scheme 1a). Moreover, Therefore, search and development of a simple, metal-free and
arylamines, especially diarylamines, can be accessed from the easy-to-handle reaction to form this molecule is necessary and
cyclohexanones and anilines via cross-dehydrogenative glamorous.
aromatization (Scheme 1b).6 In 2012, Deng6a, Li6b and Yoshikai6c Recently, the combination of iodine and dimethylsulfoxide as an
reported the Pd-catalyzed synthesis of diarylamines from efficient and green oxidative system has attracted the chemists’
cyclohexanones, respectively. Lemaire’s group subsequently attention and has been widely applied in the construction of C‒
described the dehydrogenative alkylation, catalyzed by a N, C‒C, C‒O, C‒S bonds.12, 13 The I2/DMSO system involves prior
heterogeneous Pd/C catalyst under argon atmosphere without iodination and succedent Kornblum oxidation14, and catalytic
solvent, to synthesize arylamines from nonaromatic amount of iodine is regenerated in the reaction from the
6e
substrates.6d,
In addition, Maycock developed an oxidation of HI via the mild oxidant DMSO. (Scheme 3a). The
aromatization process to prepare secondary arylamines from concept of metal-free and green chemistry has revolutionized
cyclohexenones under metal-free condition.7
the chemists’ view in seeking more interesting reaction by using
Compared with diarylamines, however, N,N'-diaryl-o- the I2/DMSO system. In 2016, Jiao et al. first describe I2-
phenylenediamines, as core structures of various medicines8 catalyzed conversion of simple cyclohexanones to catechols by
and vital precursors of plenty of N-heterocyclic carbenes9, have using DMSO as solvent and oxidant (Scheme 3b).15 Inspired by
been underexploited throughout history. The few ways to
the
concept,
we
speculated
that
N,N’-diaryl-o-
phenylenediamine derivatives could be obtained from
cyclohexanones and anilines via the I2-catalyzed cross-
dehydrogenative arylation (Scheme 3c).
To examine the feasibility of this proposed strategy, we carried
out the reaction of p-toluidine 1a and cyclohexanone 2a with
Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, P. R.
China. E-mail: panyuanjiang@zju.edu.cn;
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
catalytic amount of I2 (20 mol%) in DMSO at 120℃ , as expected,
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Table 1 Optimization of reaction conditionsa
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DOI: 10.1039/C8CC05320K
Entry
Catalyst
(equiv.)
Oxidant/additive
Solvent
Yield
b/ %
(equiv.)
1
2
3
4
5
6
7
8
9
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
KI (0.2)
I2 (0.2)
I2 (0.5)
-
DMSO
HMPA
t-AmylOH
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
19
37
28
22
29
54
46
73
57
Scheme 2 Synthetic strategies of N,N’-diaryl-o- phenylenediamines
DMSO (5)
DMSO (5)
the
desired
product
N,N’-bis(4-methylphenyl)-o-
DMSO (5) / Oxone (3)
DMSO (5) / AcOH (1)
DMSO (5) / MsOH (1)
DMSO (5) / MsOH (1)
DMSO (7) / MsOH (0.4)
DMSO (7) / MsOH (0.4)
1
phenylenediamine 3a was detected in 19% yield by H NMR
method (Table 1, entry 1). Thereafter, the yield increased
slightly when the reaction was carried out in only a few polar
solvents such as HMPA and t-Amyl-OH by using DMSO as
oxidant (Table 1, entries 2-3). Moreover, the addition of several
co-oxidants (Oxone and BzOOBu-t) and drying agent16 (Na2SO4,
MgSO4) did not make any difference to reaction efficiency
(Table 1, entries 4). Gratifyingly, the better result, 54% yield,
could be obtained when MsOH was chosen as an additive
compared to other Brønsted and Lewis acid additives such as
CH3COOH (Table 1, entries 5-6), perhaps the Brønsted acid
could facilitate the dehydration condensation process.17 And
among the various iodine-containing catalysts including KI, NIS
and so on, I2 delivered the desired compound 3a in the highest
yield (Table 1, entries 6-7). Subsequently, extensive
investigations in reaction parameters such as dosage,
temperature and time were executed, and the optimized
a Reaction conditions: 1a (4equiv.), 2a (0.25 mmol), catalyst (20 mol%), DMSO,
additive, solvent (1 mL), stirred at 120 ℃ under air for 12 h. b Determined by 1H
NMR analysis using benzyl ether as an internal standard. c 100 ℃.
that I2 and DMSO played a critically important role in this
transformation (for optimization details, seeing SI).
With the optimal reaction conditions in hand, the substrate
scope of reaction in regard to aniline derivatives
cyclohexanone derivatives was explored (Table 2). For one
thing, various moderately electron-rich anilines, including alkyl,
methoxyl and halo-substituted anilines, were converted
smoothly to the corresponding products 3a-3f and 3h in
moderate yield, however, weak electron-withdrawing groups
1 and
2
resulted in the inferior yield of products such as 3g, 3i, 3x and
3y. For another thing, steric hindrance effect, significantly
decreasing the yield of products 3j-3m, was observed in the
transformation when ortho-substituted anilines were used.
Table 2 Synthesis of N,N’-diaryl-o-phenylenediamines
Scheme 3 The application of the I2/DMSO catalytic system
conditions were established, leading to the 73% yield (Table 1,
entries 9-10). Noteworthily, nitrogen and oxygen atmosphere
both resulted in significant decrease in yield, perhaps because
low concentration oxygen could promoted the regeneration of
I2 from HI and anilines could be oxidized under high
concentration oxygen condition.18 Unsurprisingly, the reaction
did not proceed in the absence of I2 or DMSO which indicated
a Reaction conditions: 1 (4 equiv.), 2 (0.25 mmol), I2 (20 mol%), DMSO (7 equiv.),
MsOH (0.4 equiv.), HMPA (1 mL),stirred at 120 ℃under air for 12 h. b Isolated yield.
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Obviously, the reaction efficiency was greatly affected by the
electronic effect and space resistance of substituted groups on
aromatic ring, perhaps because electron-deficient anilines or
large steric hindrance groups could weaken the nucleophilicity
of amino group, leading to the suppression of nucleophilic
attack. Gratifyingly, cyclohexanones, bearing the para-orienting
groups such as alkyl, aryl, methoxy and functional groups, were
converted favourably under the optimized conditions and the
corresponding products 3n-3w were isolated in yield up to 89%.
Interestingly, product 3a was obtained exclusively when 4-
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DOI: 10.1039/C8CC05320K
Scheme 5 Proposed mechanism
methoxy,
4-acetamino
and
2-chloro-substituted
synthesize α-enaminone C2 in 12% isolated yield under similar
conditions (Scheme 4c). When the ratio of reactants was
changed, a small amount of 3a and C3 were simultaneously
detected through TLC, NMR and GC-MS analysis (Scheme 4d),
proving that the whole tentative reaction routes indeed
cyclohenxanones were used, indicating that a reverse Michael
addition reaction may occur in these reactions. Furthermore,
unexpected results were observed for 2-methylcyclohexanone
and β-tetralone that 3v and 3w were main products with little
N,N'-diaryl-ο-phenylenediamines detected. Nevertheless,
aliphatic amines, secondary amines, heterocyclic amines and
strongly electron-deficient anilines such as 3-nitroaniline as well
as α-tetralone were not effective substrates in this reaction.
involved 1, 2-cyclohexanedione
dehydration processes and subsequent aromatization instead
of one-step dehydration to give putative intermediate
Based on the aforementioned observations,
mechanism was proposed in Scheme 5. Initially, electrophilic
iodization of cyclohexanones took place in the presence of
iodine catalyst to liberate α-iodo cyclohexanone , which
undergoes Kornblum oxidation to form 1,2-cyclohexanedione
, followed by the first dehydration condensation with primary
arylamine to liberate α-enaminone , and similarly another
dehydration synthesis occurs to α-enaminone imine , followed
by further electrophilic iodization to generate intermediate
finally product can be accessed from intermediate through
B and the two separate
I
.
a
possible
2
A
B
C
D
E,
3
E
HI elimination and tautomerism. In addition, iodine catalyst can
be regenerated for the next catalytic cycle by oxidation of HI in
the presence of oxidants DMSO and O2.16 The critical point of
this proposed mechanism is that dehydration process (step
i)
should occur predominantly prior to overoxidation of 1, 2-
cyclohexanedione
B into catechol (step ii) in the presence of
excess anilines and Brønsted acid.17b, 17d
To justify the existence of two-step dehydration rather than
putative intermediate I, we speculated that cross-
dehydrogenative aromatization could be achieved from the
Scheme 4 Control experiments
To fully clarify the reaction mechanism, we attempted to isolate
some intermediates by manipulating the reaction conditions
and investigated some control experiments (Scheme 4). Firstly,
the reaction performed smoothly in the presence of TEMPO
indicating that the radical process might not be involved in the
reaction of anilines
1 and cyclohexenones 4 by using I2/DMSO
system which potentially provided a more convenient process
to obtain diarylamines under metal-free condition7.
And the optimal condition was determined as shown in Table 3
through the simple condition screening process. Under the
reaction (Scheme 4a). Furthermore, 1, 2-cyclohexanedione B,
optimized conditions, different anilines 1 and cyclohexenones 4
which could be obtained from cyclohexanones 2a via
electrophilic iodization and succedent Kornblum oxidation
according to the previous reports15, could be converted into 3a
in moderate yield under the standard conditions (Scheme 4a).
were subjected to the reaction. Obviously, para-substituents of
anilines such as tert-butyl, methoxy and trifluoromethyl were
shown to be favourably compatible with the reaction
conditions, and the corresponding diarylamines 5a, 5b, 5f and
5e were isolated with up to 84% yield. In addition, anilines
bearing alkyl, nitro group, and halo groups at meta and ortho
In the aforementioned optimization process, α-enaminone
C
was detected through 1H NMR and TLC analysis and we
accidentally found that the reaction of 4-methoxyaniline 1e and
cyclohexanone 2a was terminated to exclusively produce
α-enaminone C1 with an isolated yield of 15% when solvent was
positions also gave diarylamines in excellent yields, such as 5c
-
5d and 5g 5i. On the other hand, anilines were also arylated
-
successfully with functionalized cyclohexanone derivatives in
good yields. Several accessible cyclohexenones were also
converted smoothly to the
NMP at 80
℃ . Moreover, the target molecule 3e was obtained
in 51% yield when α-enaminone C1 was subjected to the
optimum conditions (Scheme 4b) and, interestingly,
cyclohexanone 2a could react with N-methylaniline to
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Table 3 Synthesis of diarylamines
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Reaction conditions:
1
(0.25 mmol),
4
(3 equiv.), I2 (20 mol%), DMSO (8
b
1
, 1463-1473.
equiv.), 12M HCl (0.5 equiv.), HMPA (1 mL), at 110
Isolated yield. c 1H NMR yield.
℃ under air for 20 h.
7
8
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diarylamines 5h-5m in good yield. However, 1-tetralone was
not effective substrate in the reaction.
Conclusions
9
In conclusion, we firstly applied the I2/DMSO system to
synthesize N,N'-diaryl-o-phenylenediamines from easily
accessible cyclohexanones and anilines. And the speculative
two-step dehydration could be justified by the control
experiments and the second reaction. Obviously, DMSO and O2
both serve as the oxidants to regenerate I2 from HI. In general,
the metal-free system, convenient operation and facile reaction
conditions endow the transformation with potentiality of
synthetic application in many research areas, especially
biomedical field in which the toxicity of heavy metals and harsh
reaction conditions are sometimes destructive. What’s more,
further studies about aliphatic amines and heterocyclic amines
as well as synthetic applications are underway in our laboratory.
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Conflicts of interest
There are no conflicts to declare
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