An intramolecular C(sp3)-H imination using PhI-m CPBA

Article abstract of DOI:10.1039/c8cc09100e

Herein, a highly exothermic primary amine-polyvalent iodine reaction has been used successfully for selective functionalization of acidic C(sp³)-H groups for a dehydrogenative C-H imination reaction by 4H elimination. Overall, C(sp³)-H imination at 1,5 distances was readily done via organocatalysis using PhI (10 mol%)-mCPBA under ambient conditions.

Full text of DOI:10.1039/c8cc09100e

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An Intramolecular C(sp3)−H Imination using PhI-mCPBA
Anima Bose, ‡ Saikat Maiti, ‡ Sudip Sau and Prasenjit Mal*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein, highly exothermic primary amine - polyvalent iodine towards synthesis of C-N bonds have become a fundamental
reaction has been used successfully for selective functionalization subject of study in organic chemistry.
of acidic C(sp3)-H group for a dehydrogenative C-H imination
reaction by 4H elimination. Overall, C(sp3)−H imination at 1,5
distances was readily done via organocatalysis using PhI (10 mol
%)-mCPBA under ambient condition.
Enzyme mediated selective oxidation of unactivated aliphatic
C-H bonds are well-known since time immemorial. However, it
remains challenging for the synthetic chemists due to
unviability of suitable reagents.1 The C(sp3)-H bonds are
considered to be less reactive than C(sp2)-H because of their
higher thermodynamic stability. Development of synthetic
methods for the conversion of undirected C(sp3)-H bonds to
suitable functionalities are of great importance in fundamental
research.2 Therefore, chemists have investigated on selective
catalysts for functionalization of C-H bonds to C-N bonds via
dehydrogenative
pathway.
The
approaches
on
Figure 1. Iodine(III) in intramolecular aliphatic C-H amination reactions. a)
Gaunt’s Pd-catalyzed C-H amination method.7 b) Shi’s intramolecular C-H
amination reaction.8 c) Our 1,5 aliphatic-CH2 - aryl-NH2 imination approach using
organocatalysis.
dehydrogenative C(sp3)-H amination of non-prefunctionalized
systems are mainly known either using metal catalyzed or by
radical initiated pathway.3 Compared to C(sp3)-H aminations,
imination reactions are more challenging since the formation
of imines from -CH2 and -NH2 combination with 4H elimination
is thermodynamically unfavorable.4 In 2016, Alabugin and co-
workers reported a Fe(II)-catalyzed oxidative C-H imination
reaction5 through single electron transfer (SET). Later, the
same group established a transition metal-free approach for
Dehydrogenative coupling between C-H and N-H bonds
represent the state of art practice in C-N bond synthesis due to
non-requirement of prefunctionalization of substrates. Gaunt
and co-workers established the synthesis of three membered
strained heterocycle aziridine via aliphatic C-H amination using
Pd(II)-catalyst (Figure 1a).7 Similarly, for synthesis of γ-lactams
by 2H elimination, Shi and coworkers have shown
intramolecular C-H amination reaction via iodoarene-catalysis
(Figure 1b).8 Moreover, the present work is based on 4H
elimination for direct functionalization of two aliphatic-C(sp3)H
and two aryl-N(sp3)H intramolecularly at 1,5 positions. This
single step imination protocol works in absence of any metal
or strong base via organocatalysis at room temperature
(Figure 1c). Thus an additive free approach based on
intramolecular C(sp3)-H imination reaction via organocatalysis
is developed using PhI (10 mol %)-mCPBA.9 Use of the simplest
organoiodine compound PhI as catalyst is the crucial
advantage of this protocol.
similar transformation using BuOK under aerobic condition.6
t
Nevertheless, these methods hold certain limitations like use
of transition metals as catalysts, strong bases in excess
amount, etc.
Due to their abundance in pharmaceutically active
compounds and natural products, it’s hard to exaggerate the
significance of nitrogen-based heterocycles. As a result, effort
School of Chemical Sciences, National Institute of Science Education and
Research (NISER), HBNI, Bhubaneswar, PO Bhimpur-Padanpur, Via Jatni, District
Khurda, Odisha 752050, India
‡Equally contributing authors
†Electronic Supplementary Information (ESI) available: Contains experimental and
DFT calculations details. See DOI: 10.1039/x0xx00000x
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Table 1. Condition Optimization.
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DOI: 10.1039/C8CC09100E
entry
oxidant
(equiv)
catalyst
(mol %)
---
---
---
---
---
---
solvent
time (h) yield
a
%
1
2
3
4
5
6
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
HFIP
TFE
DCM
ACN
DCE
1,4-
1.5
2
16
16
16
16
82
72
18
NR
NR
50
Dioxane
HFIP
HFIP
HFIP
7
8
9
PIFA (2)
PhI(OPiv)2 (2)
mCPBA
---
---
PhI (20)
1.5
1
1.5
55
61
75
(2.25)
10
11
12
13
14
15
16
17
18
mCPBA (2.5)
mCPBA (2.5)
mCPBA (2.5)
mCPBA (2.5)
PIDA (2)
mCPBA (2.5)
mCPBA (2.5)
mCPBA (2.5)
mCPBA (2.5)
PhI (20)
PhI (20)
PhI (20)
PhI (10)
HFIP
TFE
1.5
2
3
84
68
89
89
80
73d
53
65
78e
HFIP:DCMb
HFIP:DCMb
HFIP:DCMc
HFIP:DCMc
HFIP:DCMc
HFIP:DCMc
HFIP:DCMc
Scheme 1. a) Observed exothermic reactions. b) The oxidative C-N bond
formation by two aliphatic-C(sp3)H and two aryl-N(sp3)H imination. c) The
hypothesis of acidic C-H functionalization.
4
1.5
16
4
4
4
PhI (5)
Ar1I (10)
Ar2I (10)
PhI (10)
Iodine and ammonia mixture is known as contact explosive due
to formation of NI3.10 The hypervalent iodines as oxidizer11 are
known to react violently with amines.12 Therefore, performing
any synthetic transformations using basic amines and
polyvalent iodine reagents by simply mixing them at room
temperature is difficult.13 Generally, the hyper reactivity of
such primary amines is controlled by converting them into
aReaction condition: 0.208 mmol of 1a (1.0 equiv) in 1.5 mL solvent at room
temperature.
bisolated
yields
after
column
chromatography.
cHFIP:DCM ratio is 2:1 v/v. dAfter 16 h starting material remaining. Ar1 = 4-Me-
C6H4, Ar2= 4-NO2-C6H4; eUnder argon atmosphere.
secondary amine with introduction of carbonyl or sulfonyl During optimization (Table 1), N1,N1-dibenzylbenzene-1,2-
groups at N-center. In this work, the synergic reactivity of diamine (1a) was subjected to react under various conditions.
unprotected primary amine and adjacent tertiary amine is Delightfully, when 1a was treated with 2.0 equiv of PhI(OAc)2
controlled using in situ generated Iodine(III) from iodobenzene (PIDA) in HFIP,15 the desired intramolecular C(sp3)-H imination
(PhI)-mCPBA (meta-chloroperbenzoic acid) combination.14 reaction led to 82% yield of 2a (1-benzyl-2-phenyl-
When either aniline or N,N-dibenzylaniline was reacted with benzo[d]imidazole) (entry 1) within 1.5 h at room temperature
iodine(III) reagents, an uncontrolled reaction was observed under open atmospheric condition. The structure of 2a was
and no selective product formation could be detected (Scheme unambiguously confirmed by single crystal X-ray analysis.
1a). The N1,N1-dibenzylbenzene-1,2-diamine (Scheme 1b) However, the reaction in TFE (2,2,2-trifluoroethanol) led to
which is an integrated system of aniline and N,N- 72% yield of product within 2 h (entry 2). Other solvents like
dibenzylaniline led to successful formation of 1-benzyl-2- dichloromethane (DCM), acetonitrile (ACN) and 1,2-
phenyl-benzo[d]imidazole under iodine(III) reaction condition. dichloroethane (DCE), 1,4-dioxane gave inferior results (entry
Interestingly, the reaction went smoothly without any over 3-6).
Similarly,
the
reactions
using
PIFA
oxidation. In order to maximize the contact of the reacting (bis(trifluoroacetoxy)iodobenzene)
or PhI(OPiv)2 (bis(tert-
amines with iodine(III) reagents, the control experiments butylcarbonyloxy)iodobenzene) were also not encouraging
shown in Scheme 1 were done by simply mixing of the (entry 7-8). Interestingly, organocatalytic version of the
components at room temperature.13b Similar observation was reaction was more successful than the use of stoichiometric
made when the reaction was carried out in 1,1,1,3,3,3- iodine(III) reagents. Among the conditions examined, the
hexafluoroisopropanol (HFIP)15 solvent. We anticipated that optimum condition was found to be with 10 mol % of PhI, 2.5
the violent reaction by the basic aniline could be controlled equiv of mCPBA and 4 h reaction time (entry 13). Lowering the
intramolecularly due to the presence of benzylic methylene catalyst loading to 5 mol % (entry 15) and varying the
(CH2) group bearing acidic hydrogens. These benzylic CH2- organoiodine catalyst to 4-iodotoluene or 4-nitroiodobenzene
groups not only acted as amine-iodine(III) reaction controller (entry 16, 17) led to inferior results. When the reaction was
but also helped for the oxidative C-N bond formation by 1,5 performed under argon atmosphere, no improvement of the
aliphatic-CH2 - aryl-NH2 imination.
result was observed (entry 18).
2 | J. Name., 2012, 00, 1-3
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Under the optimized condition, the generality of the with 2.0 equiv of radical scavenger TEMPO (2,2,6,6-
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reaction was explored with a wide range of substrate scope Tetramethylpiperidin-1-yl-oxyl) under stDaOnId: 1a0r.d103c9o/nCd8CitCio0n9,1020aE
(Table 2). Benzyl amines having electron donating methoxy (- was isolated in 74% yield (Scheme 2a) which ruled out the
OMe) group (2b
benzimidazoles up to 88-92% yield. Electron withdrawing reaction. The substrate
halide functionalities in the aryl rings attached to active condition and the formation of dihydrobenzimidazole type
hydrogens (2j 2k 2m), also could not affect the yields of the intermediate (Scheme 2b) was detected by ESI-MS
reactions (75-80%). The exclusive chemoselectivity of the (supporting information, Fig. S103). Therefore, detection of
reaction for the substrates 2e-2h and 2j-2m was controlled by substrate could suggest the involvement of iminium ion as
,
2d
,
2g,
2h
,
2l) resulted in 1,2-disubstituted possibility of any radical intermediate formation during the
3
was treated under standard
,
,
4
4
the electronic environment of the CH2 group. The benzylic the key intermediate during the reaction. When substrate 1w
hydrogens are more acidic than aliphatic systems. Therefore, was treated under standard condition no desired product
exclusive
regioselective
product formation was observed (Scheme 2c). Thus, presence of at
dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline (2i) was isolated least one aryl ring is necessary to stabilize the adjacent
in 78% yield from the corresponding 2-(3,4-dihydroisoquinolin- carbocation in the reaction pathway.
2-yl)aniline (1i).
Table 3. Electronic effects of N-alkyl substituents.
Table 2. Scope of C-H imination reaction.
Reaction conditions:
1 (1.0 equiv), PhI (10 mol %), mCPBA (2.5 equiv), HFIP/DCM
(2:1v/v, 1.5 mL), rt, 4 h.
For symmetrical dibenzyl amines, single isomer of
benzimidazoles (2a-2d) were obtained in good yields (Table 2).
However, electronic control could be established while
handling of unsymmetrical dibenzyl amines (Table 3). Mixture
of isomers were obtained out of which major product was the
imination involving benzylic carbon center attached with more
electron rich arenes. The methoxy group containing substrates
Reaction conditions: 1 (1.0 equiv), PhI (10 mol %), mCPBA (2.5 equiv), HFIP/DCM
(2:1 v/v, 1.5 mL), rt, 4 h.
(2p-2r) resulted in formation of products with good to
excellent overall yield (up to 91%). Electron withdrawing
chloro substituent at para position (2u) also participated in
reaction successfully to give 85% overall yield. Sterically
hindered ortho methyl substituted derivatives
(2s, 2t)
underwent smooth reaction to give nearly 75% product
formation. The X-ray analysis was helpful to elucidate the
structure of minor isomer 2s’. The major isomer 2s was
determined by 1H and 13C NMR characteristic peaks. Also,
consistency of NMR characteristic peaks was helpful in
determination of isomeric distributions for other compounds.
Control experiments shown in Scheme 2 helped to
establish the mechanism of the reaction. When 1a was treated
Scheme 2. Control experiments.
Based on the observations from control experiments, a
plausible mechanism for the imination reaction is shown in
Scheme 3a. The role of mCPBA as oxidant is to transform
iodobenzene into iodine(III) species and itself gets reduced
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into meta-chlorobenzoic acid (mCBA). Being substituted with method. We anticipate that this C-H imination method might
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DOI: 10.1039/C8CC09100E
two alkyl groups, the tertiary amine group is expected to have have a worthy impact in synthesizing complex molecular
greater nucleophilicity than free amine towards iodine(III) architectures. Also, expected that the mechanistic
reagent. Thus nucleophilic attack from nitrogen center of understanding will enable certain methods for reactivity
tertiary amine to iodine center of the in situ generated control of other non-directed C(sp3)-H bonds for many
iodine(III) reagent (either PhI(OCO-C6H4-Cl)2 or PhIO)9a produce heterocycle synthesis.
iminium ion intermediate
iodobenzene.16 The iminium ion could exist in an alternate SM thank CSIR (India) and SS thanks NISER for fellowship.
resonance benzylic carbocation form which is stabilized by
5
with the reductive elimination of
We thank Nabin Sarkar (NISER) for crystallography. AB and
6
adjacent aryl group. The monovalent iodobenzene is further
oxidized by additional amount of mCPBA to regenerate
iodine(III). Intramolecular nucleophilic addition of primary
amine to benzylic carbocation resulted in the formation of
Conflicts of interest
“There are no conflicts to declare”
cyclic intermediate
the help of iodine(III) oxidant facilitated the aromatization to
give 1,2-disubstituted benzimidazole by another 2H
elimination. The use of fluorinated solvents to perform
hypervalent iodine mediated transformations are well
established in literature.15 So, being non-nucleophilic and
highly polar in nature, the solvent HFIP is expected to stabilize
the cationic intermediates.17
7. Further oxidation of intermediate 7 with
Notes and references
2
1.
2.
3.
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Angew. Chem. Int. Ed., 2015, 54, 8287; (c) G. Pandey and
R. Laha, Angew. Chem. Int. Ed., 2015, 54, 14875; (d) G. He,
Y. Zhao, S. Zhang, C. Lu and G. Chen, J. Am. Chem. Soc.,
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Chem. Soc., 2012, 134, 7262.
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(a) X. Hu, G. Zhang, F. Bu, L. Nie and A. Lei, ACS Catal.,
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(c) R. Marcus, V. Piret and O. Berit, Angew. Chem. Int. Ed.,
2016, 55, 8928.
5.
6.
7.
8.
9.
Scheme 3. a) Plausible mechanism of the reaction and b) Understanding the
10.
11.
I. Tornieporth-Oetting and T. Klapötke, Angew. Chem. Int.
Ed. Engl., 1990, 29, 677.
K. C. Nicolaou, P. S. Baran, R. Kranich, Y.-L. Zhong, K.
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O. Hassel, Science, 1970, 170, 497.
(a) K. Monir, M. Ghosh, S. Mishra, A. Majee and A. Hajra,
Eur. J. Org. Chem., 2014, 1096; (b) T. K. Achar and P. Mal,
Adv. Synth. Catal., 2015, 357, 3977.
S. Murarka and A. P. Antonchick, in Hypervalent Iodine
Chemistry, ed. T. Wirth, Springer International: Cham,
Switzerland, 2016, pp. 75.
I. Colomer, A. E. R. Chamberlain, M. B. Haughey and T. J.
Donohoe, Nat. Rev. Chem., 2017, 1, 0088.
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regioselectivity by stereo-electronic control.
The origin of regioselectivity could be explained in terms of
relative stability of benzylic carbocations aided by adjacent aryl
group. The more electron rich the arene, higher will be the
stability of carbocation. Thus after cyclization, corresponding
benzimidazole 2v was generated as the major isomer (Scheme
3b).
In summary, an organocatalytic intramolecular benzylic C-H
imination via 4H elimination is reported. The reactivity of
unprotected primary amine with iodine(III) reagent has been
controlled with the help of acidic hydrogens available within
the vicinity. Overall, two C(sp3)-H and two N(sp3)-H bonds were
functionalized in a single step for a C-N coupling reaction. The
use of simplest iodoarene PhI with 10 mol % loading and
mCPBA as inexpensive oxidant, room temperature and open
atmospheric conditions are the key advantages for this
12.
13.
14.
15.
16.
17.
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DOI: 10.1039/C8CC09100E
An Intramolecular C(sp3)−H Imination using PhI-mCPBA
Development of sustainable methods for the activation of less reactive undirected C(sp3)-H
bonds is challenging but desired in organic synthesis. The present manuscript demonstrates
selective activation of acidic C(sp3)-H group for a dehydrogenative C-H imination by 4H
elimination using PhI (10 mol %)-mCPBA as organocatalysis.
reaction control by acidic C-H
C(sp3)-H Activation
4[H]
-
N
N
C
N
N
Ar
H2
PhI (10 mol %)-
Ar
mCPBA
iodine(III)
H
H
uncontrolled reaction
1,5 H2C-NH2 Coupling