Vicinal Diamination of Arenes with Domino Aryne Precursors

Article abstract of DOI:10.1021/acs.orglett.6b01747

Vicinal diamination of domino aryne precursors was achieved with sulfamides. The reaction proceeds through a two-aryne pathway, accepting two N-nucleophiles at the 1,2-positions of an arene ring. Symmetrical and unsymmetrical diaminobenzenes were readily obtained.

Full text of DOI:10.1021/acs.orglett.6b01747

Letter
pubs.acs.org/OrgLett
Vicinal Diamination of Arenes with Domino Aryne Precursors
Lu Li,† Dachuan Qiu,† Jiarong Shi, and Yang Li*
School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing, P. R. China, 400030
S
* Supporting Information
ABSTRACT: Vicinal diamination of domino aryne precursors
was achieved with sulfamides. The reaction proceeds through a
two-aryne pathway, accepting two N-nucleophiles at the 1,2-
positions of an arene ring. Symmetrical and unsymmetrical
diaminobenzenes were readily obtained.
construction of this structural motif, especially the unsym-
metrical ones, requires multistep manipulation4 or transition-
metal-catalyzed processes.5 The reaction via an aryne
intermediate to reach this framework owns certain advantages,
i.e., mild and transition-metal-free conditions. Recently, the
Greaney group reported a protocol to prepare 1,2-heteroatom-
functionalized arenes via three-component coupling of aryne
with two heteroatoms (Scheme 1b).6 Mechanistically, a one-
pot, two-step procedure was applied in which the first N-
nucleophile attacked the aryne intermediate and then the
second amino group was incorporated through a Cu(I)-
catalyzed coupling of an aryl Grignard intermediate with O-
benzoyl N,N-dialkyl hydroxylamines. Our previous successes in
employing a domino aryne precursor in the preparation of
benzothiazole derivatives7 and 1,3-diaminobenzenes8 encour-
aged us to examine the possibility of vicinal diamination with
our reagent (Scheme 1c).
ucleophilic reactions are among the most prevalently
1
Ninvestigated reaction types in aryne chemistry.
The
formal triple-bond character of a standard aryne intermediate,
however, can only accommodate a nucleophile as well as an
electrophile in a nucleophilic reaction. Mechanistically, it is
prohibited to accept two nucleophiles simultaneously at the
vicinal positions of a standard aryne triple bond under
traditional aryne reaction conditions. To overcome this
drawback, a domino aryne precursor with the ability to
sequentially generate two aryne intermediates has been
conceived to fulfill this task under transition-metal-free
conditions. Herein we report our discovery of a 1,2-diamination
reaction of arenes from sulfamides and domino aryne
precursors.
1,2-Diaminobenzenes are important substructures in both
natural products and medicines, including a norepinephrine
inhibitor,2 a kinase inhibitor (staurosporine),3 and an
antipsychotic drug (clozapine) (Scheme 1a). Usually the
Our previous study7a,8 disclosed that the acidity of the NH
proton is the key for the success of the initial nucleophilic
attack on aryne intermediate i, which further warrants the
generation of the second aryne intermediate ii, since
protonation could be a competing side reaction after the
nucleophilic attack. On the basis of these concerns, we started
to look for two-amino subunits with a proper “linker”. A
carbonyl linker was first examined, and it was found that N,N′-
diphenylurea did not react with the aryne intermediate at all.
When benzamidine derivatives9 were employed as thioamide
analogues, no desired diamination products were obtained.
These observations could be explained by the fact that the
mismatched nucleophilic property/NH acidity tuned by the
electron-withdrawing group on these substrates interrupted the
desired domino aryne process. A similar phenomenon has also
been previously reported by the Larock group.10
Scheme 1. Background and Proposal
We then turned our attention to the sulfonyl group, a
stronger electron-withdrawing group than the carbonyl group,
as the electron-tuning factor on the amine, expecting that
sulfonyl groups could be used to tune the pKa of the NH to a
Received: June 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01747
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
suitable range. With this assumption in hand, sulfonamide 2a
was prepared and examined (Table 1). Gratifyingly, when 2a
Scheme 2. Reactions of TPBT 1a with Furan
Table 1. Optimization of 1,2-Diamination
“F”/base
(equiv)
additive
(equiv)
T
(°C)
yield of 3a
b
entry
solvent
(%)
bond. Hence, the TMS group on TPBT 1a would become
more vulnerable to nucleophilic attack, allowing nucleophiles
other than fluoride (i.e., oxygen) to generate aryne i. This
observation is essential, since it indicates that our TPBT
reagent does not necessarily have to rely on the traditional
fluoride-based aryne generation method. The advantage of
using potassium carbonate as the activating species is that it
allows TPBT to adapt broader functional group scope than
under fluoride-based conditions, such as the presence of
commonly used trialkylsilyl protecting groups in complex
molecule synthesis.
The reaction scope of 1,2-diamination was then explored. As
shown in Scheme 3, functional groups on aniline, such as
methyl (3b), halogens (3c and 3d), nitrile (3e), methoxy (3f),
and methoxycarbonyl (3g) groups, are well-tolerated under the
reaction conditions, no matter if they are electron-withdrawing
or electron-donating groups. Unsymmetrical diaryl substrates
could afford unsymmetrical diaminobenzenes (3h and 3i) as
well. Moreover, a dibenzyl substrate works well, giving 3j in
73% yield. Unsymmetrical aryl alkyl substrates were tested as
well. When phenyl−benzyl substrate 2k was used, 3k was
obtained in 68% yield. Functional groups on the benzyl subunit,
such as 4-F and 4-Me substituents, could also produce the
diaminobenzenes 3l and 3m, respectively. Slightly enhancing
the steric hindrance did not affect the reaction efficiency, and
3n was obtained in 45% yield. However, phenyl cyclopentyl
sulfamide gave no desired product 3o at all, primarily because
of the steric repulsion of the cyclopentyl group.
It is worth mentioning that the diaminobenzene framework
with unsymmetrical aryl and aliphatic amine subunits has
recently emerged in norepinephrine inhibitors (see Scheme
1a).2 Our approach could quickly construct a series of SO2-
bridged unsymmetrical 1,2-diaminobenzenes, where other
methods would require multistep manipulation. Another
advantage of using sulfamides to prepare 1,2-diaminobenzenes
is their potential conversion to other useful compounds, such as
benzimidazoles or N-heterocyclic carbenes (NHCs). Our
approach also provides an alternative way to synthesize
unsymmetrical 1,2-diaminobenzenes under transition-metal-
free conditions.12 As an example, the diamination product 3a
can be readily converted to 1,2-diamine 5 via LAH reduction,
exhibiting the potential of using 3 to prepare a variety of NHCs
(eq 1).12,13
1
2
CsF (6.0)
no
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhMe
80
80
80
80
80
80
80
50
rt
73
no
Cs2CO3 (6.0)
Cs2CO3 (3.0)
no
48
3
CsF (4.0)
54
4
TBAF (4.0)
KF (4.0)
trace
54
5
18-c-6 (4.0)
18-c-6 (2.0)
18-c-6 (4.0)
18-c-6 (4.0)
18-c-6 (4.0)
18-c-6 (4.0)
18-c-6 (4.0)
18-c-6 (4.0)
18-c-6 (4.0)
18-c-6 (4.0)
6
K2CO3 (3.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
80
7
85
8
73
9
68
10
11
12
13
14
100
80
80
rt
78
dioxane
DME
77
69
DCM
trace
trace
THF
65
a
Conditions: slow addition of 1a (0.3 mmol) in solvent (10 mL) to 2a
(0.2 mmol) in solvent (10 mL) over 8 h. Isolated yields.
b
was treated with 2-(trimethylsilyl)-1,3-phenylenebis-
(trifluoromethanesulfonate) (TPBT) (1a) in MeCN in the
presence of CsF, the 1,2-diaminated product 3a was obtained in
73% isolated yield (entry 1). Further investigation revealed that
Cs2CO3 itself could afford 3a in 48% yield (entry 2). The
combination of CsF and Cs2CO3 did not further enhance the
yield (entry 3). Although the yield is low in entry 2, the
reaction did not require fluoride ion to kick out the TMS
group. When different fluoride sources were used, diminished
yields were obtained (entries 4 and 5). Intriguingly, the reaction
with K2CO3/18-crown-6 afforded 3a in 85% yield at 80 °C
(entry 7). Decreasing the reaction temperature only gave lower
yields (entries 8 and 9). Other solvents were screened, such as
toluene, dioxane, DME, DCM, and THF, and MeCN was
found to be the best solvent (entries 10−14).
An intriguing character of this TPBT reagent emerged at this
stage: the fluoride-free conditions provided the best yields in
1,2-diamination reactions (Table 1). In contrast, it has been
generally recognized that the activation of a standard Kobayashi
aryne precursor requires the use of a fluoride source to “kick
out” the TMS group.11 What species is responsible for the
generation of 3-triflyloxybenzyne (i) from TPBT 1a? Indeed,
when high-purity K2CO3 (99.99% from Aldrich)/18-crown-6
was used in the reaction of TPBT 1a with furan, the adduct 4
was obtained in 80% yield, which is comparable with that using
CsF (85% yield) as the activating reagent (Scheme 2). Without
18-crown-6, 4 could still be obtained in 70% yield with K2CO3.
In contrast, in the absence of both activating reagents, no
cycloaddition product 4 was observed. Because there were no
other possible nucleophiles in the reaction system, especially
when high-purity K2CO3 was utilized, carbonate had to be
responsible for the nucleophilic species to activate TPBT 1a.
The weakened C2−Si bond of TPBT 1a can be attributed to
the two electron-withdrawing OTf groups, which could pull
more electron density away from the phenyl carbon−silicon
To expand the scope of domino aryne reagents, TPBT
analogues 1b−1g were prepared with different substituents on
the arene ring (see the Supporting Information for the
B
DOI: 10.1021/acs.orglett.6b01747
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Organic Letters
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Scheme 3. 1,2-Diamination of TPBT
Scheme 4. Reactions with Various TPBTs
a
Conditions: slow addition of 1 (0.3 mmol) in MeCN (10 mL) to 2a
(0.2 mmol), K2CO3 (0.8 mmol), and 18-crown-6 (0.8 mmol) in
b
c
MeCN (10 mL) over 8 h. Isolated yields are shown. The reaction
was performed at rt.
electron-donating substituent, i.e., a methyl group (1c), gave
relatively high yields, whereas electron-withdrawing substitu-
ents, i.e., phenyl (1d), fluoride (1e), and chloride (1f), resulted
in diminished yields. It is worth noting that the halogens on
TPBTs 1e and 1f could be further transformed to other
functional groups via cross-coupling reactions, exhibiting a
potential for these products in further manipulation. In the case
of TPBT 1g, however, there was no observation of the desired
products. This study reveals that the additional functional
group on TPBT dramatically affects the reaction efficiency.
To study the regioselectivity issue of domino aryne
precursors whenever the additional substituents make the
framework unsymmetrical, TPBTs 1h and 1i were prepared
(Scheme 5). When TPBT 1h with a vicinal methyl group was
a
Conditions: slow addition of 1a (0.3 mmol) in MeCN (10 mL) to 2
(0.2 mmol), K2CO3 (0.8 mmol), and 18-crown-6 (0.8 mmol) in
MeCN (10 mL) over 8 h. Isolated yields are shown.
b
preparation procedures for these reagents). Because there are
two topological arrangements of TPBT reagents, namely
symmetrical 1a and unsymmetrical 1b, we wondered whether
the unsymmetrical TPBT 1b could exhibit similar reactivity as
1a. As shown in Scheme 4, to our surprise, unsymmetrical
TPBT 1b acts quite differently from TPBT 1a. A significant
amount of TPBT 1b was found decomposed at elevated
temperature in the reaction. When the reaction temperature
was decreased, diaminobenzenes 3a could be obtained in 38%
yield, which is still less efficient than the reaction with TPBT 1a
(Table 1). Since both TPBTs 1a and 1b could afford the same
aryne intermediate, 3-triflyloxybenzyne (i), the low reaction
efficiency with 1b should come from the inadequate aryne
generation step. The different aryne generation efficiencies of
these two TPBTs might be explained by their different electron
distribution patterns of the benzyne rings, which substantially
increases the side reaction for TPBT 1b before aryne i could be
generated.
Scheme 5. Regioselectivity Study with Unsymmetrical
TPBTs
used in the 1,2-diamination reaction, the product ratio of 3p
and 3p′ was 1:1.6 with an overall yield of 47%. Moreover, when
TPBT 1i with a vicinal isopropyl group was utilized, the
reaction gave a mixture of 3u and 3u′ in 59% yield with a ratio
of 1:2.1, which was only slightly enhanced compared with the
product ratio for TPBT 1h (Scheme 5). The low product ratios
in these reactions indicate that both the methyl and isopropyl
groups on TPBT framework do not significantly affect the
A series of TPBT 1a analogues 1c−1g were then examined
(Scheme 4). Under the optimal reaction conditions achieved in
Table 1, TPBTs 1c−1f afforded the desired products in various
yields, demonstrating that these reagents could be commonly
utilized in domino aryne processes. In general, TPBTs with an
C
DOI: 10.1021/acs.orglett.6b01747
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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preference for which OTf departs during the course of
generating the first aryne intermediate i. Moreover, these
results also indicate that the steric hindrance imposed by them
is ignorable.
In conclusion, vicinal diamination of arenes has been
achieved using sulfamides and domino aryne precursors. The
reaction proceeds under mild and transition-metal-free
conditions with a broad substrate scope. K2CO3 was found to
be efficient in generating the aryne intermediate from TPBT.
Both symmetrical and unsymmetrical diaminobenzenes were
obtained with high efficiency. TPBTs with additional
substituents on the benzene ring were also studied. Future
work includes the development of other applications of domino
aryne precursors.
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ASSOCIATED CONTENT
* Supporting Information
■
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3133.
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(9) Yao, T. Tetrahedron Lett. 2015, 56, 4623−4626.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01747.
(11) A recent example also exhibited the ability of carbonate to
activate a Kobayashi aryne precursor. See: Yoshida, S.; Hazama, Y.;
Sumida, Y.; Yano, T.; Hosoya, T. Molecules 2015, 20, 10131−10140.
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Experimental details for all chemical reactions and
measurements (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*y.li@cqu.edu.cn
Author Contributions
†L. L. and D. Q. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge research support of this
work by the National Natural Science Foundation of China
(21372268 and 21372266) and the Fundamental Research
Funds for the Central Universities (106112016CDJZR228806).
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DOI: 10.1021/acs.orglett.6b01747
Org. Lett. XXXX, XXX, XXX−XXX