Charge-Transfer Complex Promoted Regiospecific C?N Bond Cleavage of Vicinal Tertiary Diamines

Article abstract of DOI:10.1002/adsc.201800591

A catalyst-free, charge-transfer complex promoted coupling of sulfonyl chlorides with vicinal tertiary diamines to generate sulfonamides is presented. Mechanistic studies showed that these reactions are proceeded via charge transfer of vicinal tertiary diamines to sulfonyl chlorides, forming the unstable sulfonyl quaternary ammonium like complexes which induced the regiospecific intramolecular C?N bond cleavage of vicinal tertiary diamines. (Figure presented.).

Full text of DOI:10.1002/adsc.201800591

Title: Charge-Transfer Complex Promoted Regiospecific C-N Bond
Cleavage of Vicinal Tertiary Diamines
Authors: ying fu, Qin-Shan Xu, Chun-Zhao Shi, Cai-Qin Xiao, and
Zhengyin Du
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10.1002/adsc.201800591
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Charge-Transfer Complex Promoted Regiospecific C-N Bond
Cleavage of Vicinal Tertiary Diamines
Ying Fu,a,* Qin-Shan Xu,a Chun-Zhao Shi,a Zhengyin Dua and Caiqin Xiaob
a College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, 730070, China.
Email: fuying@iccas.ac.cn
b Department of Chemistry and Chemical Engineering, Jiuquan Vocational Technical College, Jiuquan, 735000, China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
catalyst-free, charge-transfer complex
promoted coupling of sulfonyl chlorides with vicinal
tertiary diamines to generate sulfonamides is presented.
Mechanistic studies showed that these reactions are
proceeded via charge transfer of vicinal tertiary diamines to
sulfonyl chlorides, forming the unstable sulfonyl
quaternary ammonium like complexes which induced the
regiospecific intramolecular C-N bond cleavage of vicinal
tertiary diamines.
Keywords: C-N bond cleavage; charge-transfer complex;
self-promotion; sulfonamide; vicinal tertiary diamine
Scheme 1. Strategies for C-N bond activation.
Tertiary amines are widely found in natural
products, pharmaceuticals and synthetic compounds.
Commonly, tert-amines are more stable and
accessible than corresponding sec-amines. However,
owing to the high C-N bond dissociation energy,[1]
tert-amines are rarely employed as nitrogen sources
in organic synthesis. To address this issue, a large
variety of transition metal catalyzed protocols[2]
employing Pd,[3] Rh,[4] Ni,[5] Ag,[6] Cu[7] and Fe[8] etc.
as catalysts have been successively developed and
various structurally diverse amines or their
derivatives were efficiently prepared. Additionally,
C-N bonds of tertiary amines could be cleaved via I2[9]
or free radical[10] participated reactions.
Contrary to the intense research efforts on C-N
bond activation of monoamines, the development of
using diamines as nitrogen sources is still in its
infancy. In this respect, aminals (gem-diamines) have
been shown as promising electrophiles in metal-
catalyzed nucleophilic addition reactions.[11] Recently,
Huang and co-workers have demonstrated that C-N
bonds in aminals were cleaved with Pd(0) to form
electrophilic cationic Pd-alkyl species[12] (Scheme 1,
eq 1). Nevertheless, vicinal diamines,[13] widely used
in medicinal products, ligands and chiral auxiliaries
in asymmetric synthesis, have hitherto not been
recognized as nitrogen sources to build nitrogen
containing compounds.
The charge-transfer complex (CT complex) is
formed through a partial transfer of electronic charge
between molecules whereby a reactive partial bonded
complex rather than a stable chemical bond is
formed.[14] In this respect, Huang et al.[15]
demonstrated that the formation of an tert-amine-I2
charge-transfer complex could activate the inert C-N
bond to realize a Ni-catalyzed carbonylation of
benzylamines via direct insertion of CO into the C-N
bond (Scheme 1, eq 2). Based on these promising
progresses on C-N bond dissociation and our interests
on the preparation of sulfur containing compounds
from readily available sulfonyl chlorides,[16] we
herein report a CT complex promoted reaction of
sulfonyl chlorides with vicinal tertiary diamines in
which C-N bonds are regiospecifically cleaved to
produce sulfonamides in high yields. Notably, these
reactions are carried out without using metal catalysts,
oxidants or ligands, thus afford a novel “deep green”
approach for C-N bond dissociation. To the best of
our knowledge, this chemistry is the first
straightforward transformation of vicinal diamines
into amino compounds via C-N bond cleavage.
We initially chose p-tosyl chloride (1a) and
tetramethylethylenediamine (TMEDA, 2a) as model
substrates to investigate the coupling reaction. Indeed,
1
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10.1002/adsc.201800591
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.a,b
Table 2. Scope of sulfonyl chlorides.a
Entry
Solvent
CH2Cl2
CH2Cl2
THF
1,4-dioxane
toluene
DMF
Temp/°C Time/h 3a/%
1
2
3
4
5
6
7
8
RT
40
65
90
90
90
90
90
12
12
12
1
1
1
n.r c
56
63
77
84
69
CH3CN
CH3CN
1
1
86f
93d,e/88f
a)
The reaction was performed under Ar atmosphere with
1a (1.0 mmol), 2a (1.55 mmol) in solvent (6 mL) under
b)
designate reaction temperature. Yields were determined
by crude 1H NMR analysis. c) n. r. = no reaction. d) CaH2 (4
e)
f)
mg, 1.0 mmol) was added. Determined by GC-MS
Isolated yield.
no reaction occurred when CH2Cl2 was used as
solvent at room temperature (Table 1, entry 1). The
reaction temperature has an apparent impact on the
formation of 3a. When the reaction system was
heated to 40 °C in CH2Cl2 for 12 h, sulfonamide 3a
was produced in 56% isolated yield (Table 1, entry 2).
In other reaction medium such as THF, 1,4-dioxane,
toluene, CH3CN and N,N-dimethylformamide (DMF),
3a was formed in moderate to good yields (Table 1,
entries 3-7). The best result was obtained by
performing the reaction in presence of an equimolar
amount of CaH2 in CH3CN, affording 3a as a sole
product (88% isolated yield, 93% yield based on GC-
MS analysis,[17] entry 8). Careful experimental studies
showed that this reaction system is highly sensitive to
moisture as which would immediately decompose the
in situ formed CT-complex intermediate into
a) Isolated yields based on sulfonyl chlorides.
chloride, were well applied, giving the corresponding
heteroaromatic sulfonamides (3n-3p) in high yields.
Notably, even highly sterically hindered 2,4,6-
trimethylbenzenesulfonyl chlorides and 2,4,6-
triisopropylbenzenesulfonyl chlorides were also
applicable with moderate yields of sulfonamides
obtained (3k and 3l). Aliphatic sulfonyl chlorides
screened, besides cyclopropanesulfonyl chloride (3q,
89%), all failed to give the desired sulfonamide
products[18] (3r-3t). The advantage of using TMEDA
as dimethylamine surrogate could also be viewed by
the fact that TMEDA is a commercially available
liquid while dimethylamine is a gaseous substance,
making it more difficult to deal with.
N,N,N’,N’-tetramethylethane-1,2-diaminium
4-
methylbenzenesulfonate chloride as the byproduct.
Thus, in order to fully remove the residual moisture
out of the reaction system, it is optimal to add a little
amount of CaH2 as which is an inert desiccant to both
sulfonyl chlorides and tertiary amines even under
heating condition.
With the optimized reaction conditions in hand, we
started to investigate the substrate scope with respect
to sulfonyl chlorides. As shown in Table 2, a wide
range of sulfonyl chlorides with TMEDA (2a) could
be applicable to this reaction system under the
optimized conditions. Aromatic sulfonyl chlorides
with electron-withdrawing and electron-donating
groups reacted with 2a to give the corresponding
N,N-dimethylsulfonamides in good to excellent yields
(3b-3m). This process could tolerate a variety of
functional groups such as halogens, NO2, OCF3 and
esters (3c-3j and 3o), which provided the possibility
for further functionalization. Heteroaromatic sulfonyl
chlorides, as represented by 2- and 3-
thiophenesulfonyl chlorides and 8-quinolinesulfonyl
Further investigations showed that vicinal tertiary
diamines other than TMEDA were also promising
substrates for the present transformation and the
representative results are summarized in Table 3. In
this context, aromatic sulfonyl chlorides reacted
smoothly with aliphatic tertiary ethylenediamines to
give the corresponding tertiary sulfonamides (4a-4l)
in good to excellent yields. Notably, sterically
hindered N,N,N’,N’-tetraisobutylethylenediamine and
N,N,N’,N’-tetraisopropylethylenediamine
were
capable to convert aromatic sulfonyl chlorides into
tertiary sulfonamides (4c, 4d, 4f, 4h & 4j) in good
yields. To our satisfaction, tertiary N-aryl
ethylenediamines were compatible to our reaction
conditions, providing the desired tertiary N-
arylsulfonamides in high yields (4n-4t) as well.
To further investigate the applicability of vicinal
tertiary diamines to this transformation, three vicinal
tertiary oligoamines were then screened using p-tosyl
2
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10.1002/adsc.201800591
Advanced Synthesis & Catalysis
Table 3. Sulfonylation of vicinal tertiary diamines other
than TMEDA.a
Scheme 3. Control experiments.
the regioselectivity profile of C-N bond cleavage in
vicinal tertiary oligoamines.
To gain further insights into the reaction
mechanism, a series of control reactions were then
performed (Scheme 3). At first, heating a mixture of
TsCl 1a (1.0 mmol) and Et3N (3.1 mmol) in CH3CN
at 90 °C for 1h gave 4% isolated yield of sulfonamide
4a, with most of TsCl remained in the reaction
system (eq. 1), indicating that, without oxidant,
metallic catalyst or I2, intermolecular C-N bond
cleavage of an aliphatic tertiary amine is difficult to
realize..[19] The more nucleophilic N-methylpiperidine
could react with 1a at the same condition to yield N-
demethylated sulphonamide 8 in 52% isolated yield,
further supported the regioselectivity that the less
sterically hindered N-CH3 bonds in amines other than
tertiary ethylenediamines are prone to cleave via
intermolecular process. Furthermore, reaction of 1a
with 1,4-dimethylpiperazine at same condition led to
a quite complicated quaternary ammonium salts,
verifying the general recognition that C-N bond
cleavage of vicinal tertiary diamines preferentially
occur via intramolecular pathway.
In order to verify if a CT complex indeed formed
in these reactions, TMEDA (2a) in MeCN was added
to a solution of TsCl (1a) in MeCN at room
temperature. Upon addition, the color immediately
changed from colorless to yellowish (Figure 1A). The
UV−Vis absorption spectra of 1a and 2a were
measured separately and combined (Figure 1B).
Accordingly, 0.05 M solutions of compounds 1a and
2a and a mixture of the two were prepared in MeCN
and analyzed. When mixing 1a and 2a, a new tailing
band from 330 to 475 nm appeared (Figure 1B, inset
shows deconvoluted absorbance spectrum), which is
attributed to the CT complex arising from charge
transfer from 1a to 2a.
a) Isolated yields based on sulfonyl chlorides.
chloride (TsCl, 1a) as the sulfonylating agent
(Scheme 2). Under the optimized conditions, reaction
of N,N,N',N'-tetramethylpropane-1,3-diamine 5a with
1a could produce the desired product 3a albeit the
yield dramatically dropped to 30%.
A
N-
demethylated sulfonamide 6 arose to be the major
byproduct (16% yield), indicating that only in vicinal
tertiary diamines, the sterically hindered -CH2-NMe2
bonds, rather than the less sterically hindered CH3-N
bonds, are fractured in these reactions. This
regioselectivity was further manifested by reaction of
1a with N,N,N',N'-tetramethylhexane-1,6-diamine 5b
whereby a rather complicated reaction system was
produced. Only trace amounts of 3a was detected by
TLC analysis. The major isolated product was the N-
demethylated sulfonamide 7 (28%). Remarkably,
pentamethyldiethylenetriamine (5c) reacted with 1a
smoothly to afford 3a in excellent yield, highlighting
On the basis of the above mentioned experiments
and relevant results reported, a plausible mechanism
is proposed in Scheme 4. First, charge transfer of
tertiary ethylenediamine (II) to aromatic sulfonyl
chloride (I) delivers a partially bonded sulfonyl
quaternary ammonium like CT complex (III), a
highly reactive intermediate as which would be
decomposed immediately by moisture. The sulfonyl
quaternary ammonium moiety in (III), now a good
leaving group, facilitate the intramolecular
nucleophilic addition of NR2 to the β-CH2 to furnish
Scheme 2. Sulfonylation of tertiary oligoamines with TsCl.
3
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10.1002/adsc.201800591
Advanced Synthesis & Catalysis
diamines (1.55 mmol) was then added dropwise over 5 min.
The reaction mixture was stirred at the same temperature
for 1h. After cooling to ambient temperature, the reaction
mixture was dissolved in ethyl acetate and adsorbed on
silica gel. Purification by silica gel column
chromatography gave desired sulfonamides.
Acknowledgements
The authors are grateful for nancial support from the National
Natural Science Foundation of China (No. 21762040, 21262030).
Figure 1. (A) Photos of 1a (TsCl), 2a (TMEDA), and 1a +
2a in MeCN (0.05 M). (B) UV−Vis absorption spectra of
1a (0.05 M), 2a (0.05 M), and their mixture (1a + 2a) in
MeCN. Insert: the CT band of (1a + 2a).
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4
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10.1002/adsc.201800591
Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
Charge-Transfer Complex Promoted Regiospecific
C-N Bond Cleavage of Vicinal Tertiary Diamines
Adv. Synth. Catal. Year, Volume, Page – Page
Ying Fu,* Qin-Shan Xu, Chun-Zhao Shi, Zhengyin
Du and Caiqin Xiao
6
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