Highly selective sp3 C-N bond activation of tertiary anilines modulated by steric and thermodynamic factors

Article abstract of DOI:10.1039/c7gc02775c

A highly selective sp³ C-N cleavage of tertiary anilines was achieved using the TBN/TEMPO catalyst system. When N,N-diaklylanilines (alkyl, benzyl) were employed, the N-CH₃ bond was selectively cleaved via radical C-H activation. Moreover, when the allyl group was installed, totally reverse selectivity was observed. It is worth noting that the solvent effect is also crucial to obtain high reaction efficiency and selectivity.

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Highly Selective sp3 C-N Bond Activation of Tertiary Anilines
Modulated by Steric and Thermodynamic Factors
XiaodongJia, *,a Pengfei Li, b Yu Shao, c Yu Yuan, a Honghe Ji, b Wentao Hou, b Xiaofei Liu, b and
Xuewen Zhang a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly selective sp3 C-N cleavage of tertiary anilines was
achieved using TBN/TEMPO catalyst system. When N,N-
diaklylanilines (alkyl, benzyl) were employed, the N-CH3 bond was
selectively cleaved via radical C-H activation. While allyl group was
installed, totally reverse selectivity was observed. It is worth
noting that solvent effect is also crucial to obtain high reaction
efficiency and selectivity.
1) Activation of allyl amines:
R4 R3
N
Nu
R2
H
Nu
R1
R1
R2
Metal
2) Activation of aminals:
NR2
[Pd]
NR2
NR2
P
P
H
Nu
Pd
NR2
Nu
The C−N bond, as one of the most abundant chemical bonds, is
ubiquitous in organic synthetic intermediates, biomolecules,
drugs and natural products. Therefore, considerable efforts
were devoted to construction of C-N bond for synthesis of
3) Activation of N,N-dialkylanilines:
R1
R1
N
R1
N
H
[Pd]/[Cu]
CO, O2
+
R2
O
[1]
H
amines, amides and other nitrogen-containing compounds.
H
R2
In contrast, due to the high C
−N bond dissociation energy and
its inherently inert reactivity, the cleavage of C
−N bond still
Fig. 1 Activation of sp3 C-N bond.
remain a great challenge in synthetic society. Recently, with
the development of transition-metal catalyzed activation of
activated by low-valent metal via oxidative addition (Fig. 1, eq
1). Since 2012, Huang and co-workers developed a series of C-
N bond activation in aminals initiated by oxidative addition
inert chemical bonds, such as C− C−C −
H, [2] [3] and C O bonds,[4]
C-N bond activation has become one of the hottest topic in
organic chemistry.[5-8] Generally, two kinds of transition-metal-
catalyzed C-N cleavage were investigated extensively: (1)
[9]
between the aminal and Pd(0) complex (Fig. 1, eq 2). It is
worth noting that in these work, both the aminomethyl moiety
and the amino nucleophile could be successfully incorporated
into the desired products without any atom loss. Different
from above strategies, Huang also established a new way for
oxidative C-N bond activation in tertiary amines promoted by
C-H activation in 2011. [10a] In this transformation, the C-N bond
oxidative addition of transition-metal to C − N bond, (2)
formation of imine or iminium species. Based on these
strategies, various C-N bonds were activated to facilitate useful
and applicable transformations, in which the nitrogen-
containing substrates were utilized as nitrogen and/or carbon
sources for the synthesis of the desired products. [6-10]
was cleaved via an iminium-type intermediate. Using the same
[10]
Among them, cleavage of sp3 C-N bond is highly desirable.
strategy,
Lei reported an elegant palladium/copper-
[8a]
Pioneered by Trost’s work in 1980,
a series of activation of
catalysed domino process of tertiary anilines, constructing 3-
methyleneindolin-2-one skeleton in good yields (Fig. 1, eq 3).
[10b] Recently, Jiao and co-workers also achieved a Rh-catalyzed
aerobic oxidative cyclization of anilines, alkynes, and CO, in
allylic amines were achieved, [8] in which the C-N bond was
which the C-N bond of tertiary anilines was efficiently cleaved.
[10e]
From these work, we can see that activation of C-H bond
adjacent to nitrogen is a candidate to trigger further C-N bond
cleavage. However, these methods suffered from
shortcomings, such as high reaction temperature, using of
transition metals and poor site-selectivity. With the
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[11]
development of radical C-H activation,
we wondered (TBN)/TEMPO catalyst system, in which the site-selectivity is
whether C-N cleavage could be achieved under mild conditions, readily modulated by steric hindrance and thermodynamic
especially avoiding using of transition metals (metal free).
factors (Fig. 2).
Table 1. Optimization of reaction conditions
Entry
1
Solvent
MeCN
MeCN
MeCN
MeCN
DCE
Initiator
TBPA+.b
TBHP c
TEMPO c
TBN d
TBN d
TBN d
TBN d
TBN d
TBN d
TBN d
TBN d
TBN d
TBN d
TBN d
TEMPO
none
none
-
Yield (%) a
N. R.
2
N. R.
3
N. R.
Fig. 2 Selectivity control of sp3 C-N bond activation (this work).
4
none
none
none
none
none
1 eq
53 (29) e
44 (28)e
33 (51)e
47 (24)e
49 (28)e
93 f (93) g
92 (<5%) e, g
It is well-known that the sp3 C-H bond adjacent to nitrogen is
relatively active and can readily undergo homolytic cleavage
(via oxidative deprotonation, H-abstraction, etc) to the
5
6
CHCl3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
MeCN
7
corresponding free radical. In our previous research on radical
[12]
C-H functionalization,
various sp3 C-H bond adjacent to
8
nitrogen could be smoothly oxidized under radical cation
9
induced aerobic conditions, and in some cases, C-N cleavage
[12d-e]
process occurred.
Encouraged by these results, we
10
11
12
13
14
0.2 eq
0.1 eq
0.1 eq
0.1 eq
0.2 eq
questioned whether the C-N bond in tertiary amines could also
be broken via radical mediated mechanism. However, how to
93 (<5%) e,
94 (<5%) e,
g
generate the
α-amino radical intermediate selectively is a
g, h
long-standing challenging problem in radical chemistry, in
which the site selectivity is controlled by the balance of various
factors, such as thermodynamic driving force, bond
dissociation energy (BDE), steric hindrance, polarity matching
effect,[13] solvent effect and so on. Recently, significant
progress on site-selective functionalization was achieved
g, h
84 (7%) e,
trace h, i
a
Yield of crude product 1HNMR using 1,3,5-trimethoxyl-benzene as internal
standard. b In the presence of 10 mol % TBPA+.. c 1 equivalent of the initiator and
in the case of TBHP, 10 mol % of CuBr was added. d 1.5 equivalent of TBN was
added. e Yields in parentheses is the nitro-products. Under O2. Under air.
Room temperature. i Under argon atmosphere.
through the application of radical hydrogen atom transfer
[14]
f
g
h
(HAT).
For example, Murphy reported a site-selective and
contra-thermodynamic HAT reaction of trialkylamines, in
which functionalization on N-CH3 group was favored by using
[14c]
To validate our hypothesis, we commenced our studies by
attempting the C-N cleavage of N,N-dimethylaniline 1a under
different reaction conditions, and the results were compiled in
Table 1. Firstly, some bulky radical initiators such as TBPA+.
(tris(4-bromophenyl)aminiumhexachloroantimonate), TBHP/
CuBr and TEMPO were tested (entries 1-3). Unfortunately, no
desired reaction occurred. After extensive survey of literatures,
the bulky radical cation of DABCO.
Very recently,
MacMillan also described a polarity-match-based selective sp3
C–H alkylation via the combination of photoredox, nickel and
HAT catalysis, steering by the conventional BDE-driven
model.[14d] However, for tertiary anilines, the C-H bonds of
methyl and methylene groups are both electron-rich (hydridic),
[16]
and furthermore, the BDE difference is very subtle (91.7 vs
[15]
TBN was declared to liberate the NO2 and tert-butoxyl
91.6 kcal/mol, Fig. 2),
which are not competent to achieve
radicals in the presence of dioxygen. These radicals might
abstract a hydrogen atom from the hydridic C-H bond to
produce the corresponding carbon-centered free radical.
Therefore, the model reaction was conducted in the presence
of TBN (1.5 eq) and dioxygen. To our satisfaction, the reaction
proceeded extremely fast, and the substrate 1a was fully
highly selective transformations. Consequently, we questioned
whether a sterically bulky radical initiator could be employed
to surmount the influence of BDE and thermodynamic stability
on the site-selectivity, providing a radical intermediate on the
less hindered position (Fig. 2). If this idea is feasible, the
selective C-N bond cleavage could be fulfilled by further
iminium intermediate formation and following decomposition.
Herein, we report an efficient approach to highly selective sp3
C-N activation of tertiary anilines using tert-butyl nitrite
consumed, providing
a complicated mixture. By GC-MS
analysis, not only C-N cleaved product 2a, but also nitration
compound 3a were detected (entry 4-8), together with other
unidentified compounds. Encouraged by these promising
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results, one equivalent of TEMPO was added into the reaction groups, such as CF3, CHO and CO2Me, did not exert negative
mixture to intercept the generated radical intermediate, and effect on the C-N bond cleavage, providing the desired
[17]
avoid possible side reactions.
It turns out that in the products (2e-g) in high yields with slightly elongated reaction
presence of TEMPO, the reaction was singularized, affording time. It is worth noting that aniline with aldehyde group, which
the desired nitrosamine in 93% yield (entry 9). After further is susceptible under oxidative conditions, could also afford the
optimization of catalyst loading and reaction temperature desired product 2f in 89%, implying good functional group
(entries 9-12), 1.5 equivalent of TBN and 0.1 equivalent of tolerance of this mild reaction conditions. Even nitro group
TEMPO at room temperature under air atmosphere were substituted aniline gave the desired product 2h in 98% yield.
found the best reaction conditions, and the N-nitrosoaniline 2a N,N-dimethylanilines bearing ortho- and meta-substituents
was obtained in 94% yield (entry 12). 1,4-Dioxane was also an underwent smooth reactions, giving the desired products in 86%
alternative solvent, giving 2a in a slightly decreased yield to 92% isolated yields (2j-l). Importantly, for substrate 1i and 1l
(entry 13). In the absence of dioxygen, no reaction occurred, 1,4-dioxane as the solvent was crucial to avoid nitration side-
implying that both TBN and dioxygen are crucial to initiate the products. [18] When 2,4- disubstituted N,N-dimeylanilines were
,
C-H and consecutive C-N activation (entry 14).
NO
employed as the substrates, the reaction also took place
smoothly to furnish the desired product in high yields (2m-n).
The reaction of N,N-dimethylpyridin-2-amine was also tested
under the standard reaction conditions, and different from
aniline derivatives, this substrate exhibited lower reactivity,
providing the corresponding demethylation product in 30%
yield at 45 oC.
Me Me
Me
N
N
TBN (1.5 eq)
TEMPO (0.1 eq)
air, r.t., MeCN
R
1
R
2
NO
NO
NO
NO
NO
Me
Me
Me
Me
Me
N
N
N
I
N
N
Me
NO
R
R
N
N
TBN (1.5 eq)
TEMPO (0.1 eq)
air, r.t., 1,4-dioxane
Br
Cl
Me
CF3
2e, 84% (2 h)
2a, 93% (0.5 h) 2b, 95% (0.5 h) 2c, 91% (2 h) 2d, 90% (0.5 h)
NO NO
Me
Me
NO
Me
Me
Me
N
N
N
NO
NO
Me
Me
1
2
N
N
NO
NO
NO
NO
Et
Pr
Br
Bu
N
N
N
N
CO2Me
NO2
CHO
2f, 89% (2 h)
2i, 75% (2 h) a
2g, 87% (2 h) 2h, 98% (5 h)
2j, 92% (2 h)
NO
NO
Me
Me
Me
Me
Me
Me
NO
NO
Me
Me
N
N
N
N
2p, 91% (2 h) 2q, 80% (2 h) 2r, 87% (2 h)
2s, 80% (2 h)
Me
Cl
NO
NO
N
N
NO
NO
NO
Tol
N
Ph
N
N
N
Me
Cl
Me
2l, 86% (2 h) a
a 1,4-dioxane as the solvent
Br
Me
2k, 91% (2 h)
2m, 85% (4 h) 2n
, 91% (2 h)
2o, 30% (45oC, 10 h)
Me
Me
Me
Me
2t, 90% (1 h) 2u, 90% (4 h)
2v, 88% (1h)
2w, 99% (3h)
Scheme 1. Reaction scope on anilines
Scheme 3. C-N bond cleavage of unsymmetric anilines
As one reviewer’s suggestion, the reactivity of N,N,N’,N’-
tetramethyl-p-phenylenediamine
4
was also evaluated
(Scheme 2). Under the standard conditions, a mixture of 5a
and 5b were isolated. At higher temperature, the
mononitrosation product 5a was isolated in 74% yield with
trace amount of 5b. Interestingly, when the reaction time was
extended to 6.5 h, dinitrosation product 5b was obtained in 66%
yield and only trace amount of mononitrosation product was
detected. These results show that in this substrate, the C-N
bond cleavage occurred stepwise, and the control of reaction
time is essential to achieve higher selectivity.
Scheme 2. Sequential cleavage of p-phenylenediamine derivative
With the best reaction conditions established, the substituents
on aniline varied to evaluate the functional group tolerance
(Scheme 1). In general, the N,N-dimethylanilines with both
electron-withdrawing and -donating groups on the phenyl ring
were well tolerated with good to excellent yields under this
protocol. Aniline derivatives substituted with the halogens Cl,
Br and I afforded the corresponding N-nitrosoanilines in
excellent yields (2a-c). A comparable yield was obtained for
the substrate with methyl group (2d). Electron-withdrawing
Having succeeded in the C-N bond activation of symmetric
N,N-dialkylanilines, we decided to apply this methodology to
more challenging substrates. Then, the reactions of
unsymmetric N,N-dialkylanilines were performed to test the
selectivity of this C-N activation. However, when the reaction
of N-ethyl-N-methylaniline was conducted in MeCN, a mixture
was obtained, in which the N-CH3 cleavage was favored (ratio:
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6 : 1; for details, see ESI). To our delight, when 1,4-dioxane was
chosen as the reaction solvent, excellent selectivity was
achieved, giving the demethylation product 2p in 91% yield
[19]
(Scheme 3).
Similar selectivity was also observed for n-
propyl, n-butyl and n-pentyl, yielding the expected products
2q-2s in 80%, 87% and 80% yields, respectively. Bulky group
did not decrease the reaction efficiency, and N-nitrosoaniline
2t was obtained in 90%. Significantly, N-iso-propylaniline
underwent the selective C-N cleavage quite well, and the N-
CH3 bond was cleaved exclusively (2u), supporting the steric
hindrance controlled site-selectivity. Several diphenylamine
derived substrates, such as 1v and 1v, were also compatible
with this process to afford the desired products 2v−2w in high
yields. For products 2u and 2v, two sets of signals were
observed in 1H and 13C NMR. It is attributed to that N-
nitrosamines can exhibit syn and anti-orientations due to the
restricted rotation of the N–N bond. [16g]
To our surprise, when using dialkylanilines containing only N-
CH2R positions, the C-N cleavage process were seriously
disturbed by nitration on phenyl ring, in which less bulky
substrates shown slightly higher preference to undergo C-N
cleavage (see ESI). These results also supported that the
reaction efficiency was strongly affected by the steric
hindrance over thermodynamic stability of the radical
intermediate and BDEs. To enhance the BDE-driven model
counteracting the steric congestion (for the BDE of allyl C-H
bond, see Fig. 2), the reaction of allyl group substituted
anilines were investigated under the standard conditions
(Scheme 4). Consistent with our prediction, when the allyl
group was installed on nitrogen, reverse site-selectivity was
observed. No matter methyl group and other alkyl groups
existed, the C-N cleavage occurred exclusively on N-allyl bond,
providing the N-nitrosoanilines in 85% to 90% yields (2d-s).
Critical to the success of this reaction was the use of 1,4-
dioxane as the solvent, which avoided the formation of
demethylation products (see ESI). Interestingly, when diallyl
group substituted starting material 6a was employed, only one
allyl group was efficiently cleaved (7a). To further verify this
steric hindrance modulated site-selectivity, the reactions of a
series of N-methyl-N-benzylanilines were investigated under
the standard reaction conditions. Although BDE of the benzylic
C-H bond is lower than the methylic one (85.4 vs 91.7 kcal/mol,
Fig. 2), [15] preference to N-Me selectivity was observed (7b-e).
We reason that this abnormal selectivity is attributed to the
fact that benzyl group is more sterically encumbered than allyl
group. Differently, for N-benzylanilines, MeCN as the solvent
gave higher site-selectivity, favoring N-Me cleavage (see ESI for
details). The exact reason remains unknown.
Scheme 4. C-N activation of N-allyl and benzylanilines
To gain some preliminary understanding of the reaction
mechanism, a series of control experiments were carried out
under the standard conditions (Scheme 5). First, in the
absence of TBN and dioxygen, respectively, no reaction
occurred (eq 1 and 2), suggesting that the reaction was
initiated by the TBN derived free radicals. To confirm the
existence of NO2 radical, one equivalent of styrene was added
to the reaction solution, and the corresponding nitrostyrene
was detected by GC-MS (eq 3). [16d] From the above results, we
assume that the C-N bond cleavage might probably be enabled
by intermolecular HAT between TBN derived free radicals and
N,N-dialkylanilines. Then, an intramolecular KIE experiment
was conducted (eq 4), affording KIE value in 6.44. This KIE
value indicated that the C-H bond cleavage might be engaged
in the rate-determining step. Next, a HRMS experiment of the
reaction mixture was performed (eq 5), and to our delight, the
signal at m/z 197.9910 (calcd for C8H9BrN+, 197.9913) was
detected. This signal is related to the mass of an iminium
intermediate, verifying that the C-N bond might be cleaved
through the decomposition of this iminium intermediate.
Interestingly, we also detected trace amount of TEMPO
oxoammonium (calcd for C8H18NO+, 156.1383; found,
156.1390), which might be derived from oxidation of TEMPO
radical. To determinate the real catalyst, the C-N activation
reaction of aniline 1r was performed in the presence of TEMPO
oxoammonium (eq 6). However, no reaction occurred. While
in the presence of TBN (1.5 eq), the desired product 2r was
1
detected in 23% H NMR yield (eq 7). These results supported
that the C-N bond cleavage is promoted by TBN, and excluded
the participation of TEMPO oxoammonium.
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Scheme 6. Proposed mechanism.
Conclusions
In summary, we developed an efficient catalyst system to
achieve selective C-N bond activation. This reaction is initiated
by radical sp3 C-H bond activation, whose selectivity is well
modulated by steric hindrance and thermodynamic factors. In
the case of N,N-dialkylanilines with bulkier substituents (alkyl,
Bn, etc), the N-CH3 bond cleavage was highly preferred. When
allyl group was installed on nitrogen, the BDE of the C-H bond
adjacent to nitrogen was obviously lowered, and thoroghly
reverse selectivity was observed. It should be pointed out that
the site-selectivity of C-H/C-N activation is affected by various
factors, such as thermodynamic driving force, BDE, steric
hindrance, polarity matching effect, solvent effect and so on,
and the overall outcome is the result of synergism of these
effects. Compared with traditional method of transition-metal
enabled C-N bond activation, this reaction is featured by mild
reaction conditions (room temperature and air atomosphere),
high efficiency (up to 99% yield), good functional group
tolerance (halogens, CF3, CHO, CO2Me, etc.) and greener
catalyst system (metal free). Further applications and more
variants of this C-N activation are still underway in our
laboratory.
Scheme 5. Control experiments
Based on the experimental results and previous reports
related to TBN, a possible mechanism was proposed for this
novel C-N activation/N-N formation process (Scheme 6).
Supported by strong literature precedent, [16] we believed that
a peroxynitrite radical and tert-butoxyl radical were formed by
aerobic cleavage of the N-O bond of TBN. The bulky tert-
butoxyl radical preferred to abstract a hydrogen from the less
crowed N-Me site, providing an
selectivity). When allyl group exists, the thermodynamic
factors overcome the steric effect, generating a more stable
amino radical (N-allyl selectivity). In the presence of TEMPO,
the generated -amino radical intermediate was trapped, and
after elimination of TEMPOH, an iminium intermediate was
α-amino radical A (N-Me
α-
α
B
Acknowledgements
afforded. Decomposition of the iminium ion released an N-
This work was financially supported by National Natural
Science Foundation of China (NNSFC, No. 21362030 and
21562038) for supporting our research. The authors also thank
Jiangsu Provincial Natural Science Foundation (BK20161328)
for financial support.
alkylaniline with expelling of formaldehyde. Concurrent with
the formation of intermediate B, the NO2 radical, which was
generated from the secondary reaction between the
peroxynitrite radical and TBN, abstracts a hydrogen atom from
TEMPOH to regenerated TEMPO, together with nitrous acid.
Finally, a classical N-nitrosation between N-alkylaniline and the
nitrous acid occurred, giving the N-nitrosamine derivatives in
high yields.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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L. Buchwald, Top. Curr. Chem. 2002, 219, 131; b) T. Wang,
N. Jiao, Acc. Chem. Res. 2014, 47, 1137; c) B. Schlummer, U.
Scholz, Adv. Synth. Catal. 2004, 346, 1599; d) G. Song, F.
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