Diamination of Domino Aryne Precursor with Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.6b01334

The reaction of a domino aryne precursor with sulfonamides efficiently afforded both 1,3-diaminobenzenes and trisubstituted 1,3-diaminobenzenes by simply varying the reaction conditions. Mechanistic study supports the sequential formation of two transient aryne intermediates involved in the reaction.

Full text of DOI:10.1021/acs.orglett.6b01334

Letter
pubs.acs.org/OrgLett
Diamination of Domino Aryne Precursor with Sulfonamides
Dachuan Qiu, Jia He, Xiao Yue, 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: The reaction of a domino aryne precursor with
sulfonamides efficiently afforded both 1,3-diaminobenzenes and
trisubstituted 1,3-diaminobenzenes by simply varying the reaction
conditions. Mechanistic study supports the sequential formation of two
transient aryne intermediates involved in the reaction.
1,3-Diaminoarenes are privileged subunits in both natural
products and medicines, including anticancer drug (Gleevec),
antibiotics (Ciprofloxacin, Levofloxacin, Rufloxacin, and
Tigecycline), and the natural indolo[3,2-a]carbazole Ancor-
inazole (Figure 1).1 Synthetically, the most commonly utilized
diamination approaches involve transition-metal catalyzed
amination of halobenzenes (e.g., Buchwald−Hartwig2 or
Ullman3 reactions). The restricted usage of transition metals
in the late stage of drug synthesis prompts people to seek
transition-metal-free as well as environmentally friendly
manipulation conditions.
via aryne intermediates, its harsh conditions restrict the
application of this method.
To overcome the 1,2-difunctionalization limitation by a
standard aryne intermediate, we recently developed a domino
aryne precursor, which can feature a sequential formation of
two aryne intermediates during the reaction.7 The nature of this
aryne precursor to accept two nucleophiles via a domino aryne
process inspired us to explore the synthetic application of this
compound with other nucleophiles. Herein, we report our
study on diamination reactions of this domino aryne precursor
with sulfonamides.
Scheme 1. Previous and Current Work
Figure 1. Selected 1,3-diaminobenzene structures.
As an alternative approach to transition metal catalysis,
arynes can be directly trapped by a wide range of dienes,
dipoles, and nucleophiles to generate substituted aromatics.4
The advantage of employing aryne intermediate in the C−N
bond formation resides primarily in its high efficiency as well as
instant incorporation of two vicinal functional groups.5 As for
diamination reaction, however, only limited approaches are
known via aryne chemistry.6 For example, the Beller group
reported the construction of 1,3-diaminobenzenes from 1,3-
dichlorobenzene, where they used a strong base (t-BuOK)
under high temperature (Scheme 1a).6a A stepwise generation
of two aryne intermediates was proposed, and the regioselective
formation of the 1,3-diaminobenzene was explained by “the
higher acidity of the hydrogen in position 2 of the aromatic
ring”. Although this approach could gain 1,3-diaminobenzenes
As shown in Scheme 1b, when the second nucleophile
attacks aryne intermediate ii intermolecularly, a regioselective
amination could be conceived and 1,3-diaminobenzenes would
be produced via nucleophilic attack of the second amine species
on the 3-position of intermediate ii. The origin of the selectivity
relies on the electron-withdrawing inductive effect of the amino
Received: May 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01334
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Letter
group on aryne ii, which has been well-studied previously.4c,8
Furthermore, in the absence of a proton source, intermediate iii
would be trapped by an electrophile, resulting in a trisubstituted
1,3-diaminobenzene derivative.
Scheme 2. Substrate Scope of 1,3-Diamination
Table 1. Varying EWGs on Aniline
b
entry
R-
product
yield (%)
1
2
3
4
5
6
7
8
9
4-MeC6H4SO2- (2a)
PhSO2- (2b)
4-CIC6H4SO2- (2c)
MeSO2- (2d)
CF3SO2- (2e)
Ac- (2f)
3a
3b
3c
3d
3e
67
57
75
60
87
0
CF3CO- (2g)
Bz- (2h)
0
0
Boc- (2i)
0
a
Conditions: slow addition of TPBT 1 (0.3 mmol) in MeCN (10 mL)
to 2 (0.4 mmol) and CsF (1.2 mmol) in MeCN (10 mL) over 8 h at
b
room temperature. Isolated yield.
As shown in Table 1, when N-tosylated aniline 2a reacted
with TPBT 1 in the presence of CsF, 1,3-diaminobenzene 3a
was obtained in 67% isolated yield (entry 1) (see Table S1 in
the Supporting Information for its detailed optimization
conditions). We hypothesized that different electron-with-
drawing groups (EWGs) on aniline nitrogen could tune both
the pKa of the N−H proton and the nucleophilicity of the
aniline nitrogen.5e Indeed, drastic reactivity change was
observed by varying the R group on aniline (Table 1). When
sulfonamides were employed, the yields varied from 57% to
87% (entries 1−5), and triflate 3e was found to be the best
substrate. The meta-diaminated structure of 3e could be
confirmed by X-ray single crystallographic analysis (Table 1).
In contrast, amides with other protecting groups, such as acetyl
(Ac), trifluoroacetyl, benzoyl (Bz), and t-butoxycarbonyl (Boc),
gave no desired products (entries 6−9).
a
Conditions: slow addition of TPBT 1 (0.3 mmol) in MeCN (10 mL)
to 2 (0.4 mmol) and CsF (1.2 mmol) in MeCN (10 mL) over 8 h at
b
c
room temperature. Isolated yield. Both CsF and Cs2CO3 were used.
d
Yield was determined by 1H NMR spectroscopy using 1,3,5-
After identifying triflyl (Tf) as the best EW group, we further
explored the substrate scope. As shown in Scheme 2, when Tf-
protected anilines were employed, 1,3-diaminated products
could be obtained in good to excellent yields. This reaction is
highly efficient and tolerates various functional groups, such as
halogen (3k, 3l, 3p, and 3v), cyano (3n and 3s), nitro (3q),
and methoxycarbonyl (3r) groups, which are incompatible with
either Grignard reagents or strong bases.6 In addition, a
substituent on the ortho-, meta-, and para-position of aniline
could all afford the corresponding 1,3-diaminobenzenes. When
ortho-substituted substrates were employed, diminished yields
were obtained. The trend for these decreased yields is parallel
with the increased size of the substituents. For instance, when
the sizes of the substituents on aniline follow a OMe > Me ≈ Cl
trend, the yields would contrastingly change. Moreover, this
transformation can be scaled up on gram scale. At last, when
benzylamine analogue 2x was used with CsF as the activating
reagent, there was no desired product observed. Interestingly,
by using both CsF and Cs2CO3 as the bases, diaminobenzene
3x was obtained in 62% NMR yield. This observation could be
trimethoxybenzene as an internal standard.
explained by a lower acidity of the NH on benzyl analogue and
hence stronger base Cs2CO3 is needed to deprotonate 2x.
Further investigation on other aliphatic amines, however, failed
to give the desired products.
Moreover, we could prepare unsymmetrical diaminobenzene
with a modified protocol. When a 1:1 mixture of triflated p-
methylaninline 2j and p-cyanoaninline 2n was used under
diamination conditions, an unsymmetrical diamine 3y could be
obtained in 42% yield, along with two symmetrical 1,3-
diaminobenzenes 3j and 3n in ∼20% yield each (eq 1). This
example exhibits a potential of TPBT 1 in the preparation of
unsymmetrical 1,3-diaminobenzene analogues. To identify the
source of the proton on the 2-position, a deuterium-labeling
experiment was conducted. By employing deuterated acetoni-
trile as the solvent, TPBT 1 reacted with 2j to give the
deuterated product 3j−d with 25% deuteration, suggesting that
B
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Scheme 4. Intramolecular Sulfonyl Group Migration
the proton sources are from both the N−H of 2j and the
solvent (eq 2).
An extended application of TPBT 1 was also pursued,
namely the introduction of three functional groups on the
consecutive positions of a benzene ring, which could be
accomplished by capturing an electrophile other than a proton
in the final stage of the transformation (intermediate iii in
Scheme 1b). The Larock group previously exhibited a 1,3-
migration of trifluoroacetyl (−COCF3) as well as trifluor-
omethanesulfinyl (−SOCF3) groups via aryne chemistry, when
the corresponding aniline derivatives were used.5e Although
thia-Fries rearrangement has been reported with Tf migration
from the oxygen of an OTf group,9 as a competing side reaction
in the aryne generation process, there is no precedent for Tf
migration from NTf. To fulfill our goal to migrate one of the Tf
groups to the 2-position in intermediate iii, we decided to
extrude the proton sources within the reaction system.
Satisfyingly, toluene was found to be the ideal solvent. As
shown in Scheme 3, several activating reagents were tested, and
K2CO3/18-c-6 was found to be the best one with exclusive
formation of product 4a. All the other conditions employing
the fluoride anion, however, gave a significant amount of 1,3-
diaminobenzene 3j (Scheme 3). Intriguingly, fluoride ion was
found to be no longer necessary in this transformation. This
observation could be explained by the fact that the HF
produced during the reaction would protonate intermediate iii
before Tf migration. Although aryl amine gave products in
good to high yields under the reaction conditions, aliphatic
amine could not afford the desired product (Scheme 4).
a
Conditions: slow addition of 1 (0.3 mmol) in toluene (5 mL) to 2
(0.4 mmol), K2CO3 (0.8 mmol), and 18-c-6 (0.4 mmol) in toluene (5
mL) over 10 h at 100 °C. Isolated yield.
b
incorporate two nitrogen- and one sulfur-based functional
groups on a benzene ring at the same time with a strict N, S, N
sequence but also extends the reaction pattern of the domino
aryne precursor to a different adding sequence (1,3,2- vs 1,2,3-)
toward 1,2,3-trisubstituted arenes.
We are curious whether the diamination reactions indeed
undergo the domino aryne process or not. Several observations
could support the proposed pathways in Scheme 1b: (a) the
formation of adduct 5 from TPBT 1 and furan suggests the
generation of 3-triflyloxybenzyne (i) (eq 3); (b) the reaction of
TPBT 1 with both aniline 2s and furan in the same pot gave a
mixture of 5, 6, and 3s in a 1.9:1.0:1.4 mol ratio (Scheme 5),
Scheme 3. Optimization for Tf Migration
Scheme 5. Mechanistic Studies
By exploring the reaction scope, a list of the Tf migration
products 4 could be obtained in good to high yields (Scheme
4). Efforts to migrate a Ts group when aniline 2a was
employed, however, gave solely the 1,3-diamination product 3a,
presumably because of the weak migration ability of the Ts
group. This transformation is, to some extent, important, since
triflylbenzene (aryl triflone) is known as the substructure of
medicines, such as Ponazuril and anticancer drug Navitoclax
(ABT-263). The success of this operation not only allows us to
C
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and 2s. These results indicate that the formation of 6 must
proceed through the second aryne intermediate iv. Moreover,
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the amounts of the products, suggests that the sequential aryne
process is indeed a major path in this transformation.
In summary, as an alternative, mild, and efficient transition-
metal-free strategy, diamination reactions of a domino aryne
precursor with sulfonamides were reported. This TPBT reagent
is unique and unprecedented in the preparation of both 1,3-
diaminobenzene and trisubstituted 1,3-diaminobenzene by
simply varying the reaction conditions. Mechanistic study
reveals that the reaction proceeds through a sequential aryne
pathway. Our ongoing work includes the development of new
domino aryne transformations.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01334.
(9) (a) Charmant, J. P. H.; Dyke, A. M.; Lloyd-Jones, G. C. Chem.
Commun. 2003, 380−381. (b) Dyke, A. M.; Gill, D. M.; Harvey, J. N.;
Hester, A. J.; Lloyd-Jones, G. C.; Munoz, M. P.; Shepperson, I. R.
Angew. Chem., Int. Ed. 2008, 47, 5067−5070. (c) Hall, C.; Henderson,
J. L.; Ernouf, G.; Greaney, M. F. Chem. Commun. 2013, 49, 7602−
7604. (d) Yoshida, S.; Uchida, K.; Igawa, K.; Tomooka, K.; Hosoya, T.
Chem. Commun. 2014, 50, 15059−15062.
Experimental details for all chemical reactions and
measurements (PDF)
X-ray single crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: y.li@cqu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge research support of this
work by NSFC (21372268 and 21372266) and Fundamental
Research Funds for the Central Universities
(106112016CDJZR228806).
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