Thermally induced reaction of diazoamides with isatins: A complementary approach to the 3,3′-bioxindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.07.053

An efficient and thermally induced reaction of diazoamide with isatin under mild reaction conditions is described, which provides a complementary approach to the 3,3′-bioxindole in high yields with excellent diastereoselectivity. In comparison to the metal-catalyzed versions, this is the only example under catalyst-free conditions via a non-carbene reaction pathway.

Full text of DOI:10.1016/j.tetlet.2017.07.053

Accepted Manuscript
Thermally induced reaction of diazoamides with isatins: a complementary ap-
proach to the 3,3'-bioxindole derivatives
Yang Zheng, Ming Bao, Lihua Qiu, Xinfang Xu
PII:
S0040-4039(17)30909-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.053
TETL 49135
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 June 2017
13 July 2017
14 July 2017
Please cite this article as: Zheng, Y., Bao, M., Qiu, L., Xu, X., Thermally induced reaction of diazoamides with
isatins: a complementary approach to the 3,3'-bioxindole derivatives, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.07.053
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Thermally induced reaction of diazoamides
with isatins: a complementary approach to
the 3,3'-bioxindole derivatives
Leave this area blank for abstract info.
Yang Zhenga, Ming Baoa, Lihua Qiua, *, Xinfang Xua, b,*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R. China
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China

1
Tetrahedron Letters
journal homepage: www.els evier.com
Thermally induced reaction of diazoamides with isatins: a complementary approach
to the 3,3'-bioxindole derivatives
Yang Zheng a, Ming Bao a, Lihua Qiu a, *, Xinfang Xu a, b, *
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou
215123, P. R. China
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and thermally induced reaction of diazoamide with isatin under mild reaction
conditions is described, which provides a complementary approach to the 3,3’-bioxindole in
high yields with excellent diastereoselectivity. In comparison to the metal-catalyzed versions,
this is the only example under catalyst-free conditions via a non-carbene reaction pathway.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Transition-metal-free
3,3’-bioxindole
catalyst-free
diazoamide
difunctionalization
1. Introduction
derivatives selectively. These efficient approaches have emerged
Bioxindole is a useful synthon in synthetic organic chemistry,1
and this moiety is prevalently existing as an important structural
unit in complex natural products and pharmaceutical agents (Fig.
1).2 Thus, the development of efficient approaches for the
construction of bioxindole skeletons is of continuing interest in
organic synthesis. Generally, they are prepared via formal
homodimerization3 or heterodimerization4 of isatin derivatives.
For example, in 2008, Overman disclosed an effective method
for the synthesis of 3-hydroxy-3,3’-bioxindoles via a two-step
process, including enolization and following Lewis-acid-
promoted Mukaiyama aldol addition (Scheme 1a).5 Recently,
Hu's group reported a straightforward access to the bioxindole
derivatives by trapping the zwitterionic intermediate (Scheme 1b,
B) with isatin6a or other electrophiles.6b-e Later, the ylide trapping
reaction7 with isatins was expanded by Shi8 and Muthusamy9
independently, which also directly produced the bioxindole
as promising and economically attractive alternative for the
construction of bioxindole frameworks; however, the reactions
require the expensive dirhodium catalyst. In particular, in the
preparation of pharmaceuticals or their candidates, the
development of novel strategy involving the use of inexpensive,
non-toxic, or no transition-metal catalyst under environmentally
benign conditions is highly desirable.
In contrast to the traditional reactions involving metal
carbene,10 the metal-carbene-free transformation of diazo
compounds has emerged as
a complementary paradigm
recently,11 and these reactions have shown unique merits in
experimental simplicity and under mild reaction conditions. For
example, the carbon of the diazo group could act as a synthetic
equivalent of a 1,1-dipole for the gem-difunctionalization, which
will react with the electrophile to form a diazonium ion
intermediate, and then can be intercepted by a nucleophile.12-17 In
11c,12
this context, electrophilic reagents, including proton,
organoboron reagents,13 carbonyl compounds,14 imines15 and α,β-
unsaturated carbonyl compounds16 have been investigated.
Recently, Zhu,17a Huang,17b Hu17c and our group17d,17e have
independently disclosed that the halogenic cation could be used
as the electrophile in this transformation. Inspired by these works
and as a continuation of our own interest in this area, herein, we
report a thermally induced reaction of isatin with diazoamide,
which provides a novel approach for the direct construction of
Figure 1. Representative bio-active compounds containing bioxindole unit.

2
Tetrahedron Letters
Via Mukaiyama aldol reaction (basic conditions):
(a)
R
(entry 5-7), which was determined by the proton NMR of the
crude reaction mixture (see Figure S4 and S5), and the syn
O
1. TBSOTf, Et3N
2. BF3.OEt2
R
HO
configuration of the obtained product
3 was determined
OH
according to the reported reference.6a Although comparable yield
was achieved at higher temperature (entry 7, 100 oC, 76% yield),
the diazo compound started to decompose at this point, and it
turened out not be easy for the purification. In addition, fully
conversion of 1a to 4a could be observed in the absence of 2a
under these conditions (see Figure S3).
R'
O
+
-78 oC to -50 o
C
N
R1
N
N
N
R2
R2
R1
R'
O O
OTBS
2008
et. al.
N
R1
via
Overman,
A
Via zwitterionic intermediate (
):
(b)
Metal-catalysis
O
R1
N2
R
HO
Rh2(OAc)4
With the optimized reaction conditions in hand, we next
investigate the generality of this thermally induced reaction by
exploring the reaction between various diazoamides and isatins
(Table 2). The substrates scope was quite general and the
substitutions on the nitrogen or on the aromatic ring had little
impact on the reaction to give the corresponding products
in >72% yields (Table 2, entry 1-9), although temperature
adjustment was applied in some cases to achieve high yields (see
note c, d and f). Interestingly, water could be used as the solvent
in the case with α-methyl diazoamide 1j, and higher isolated
yield was observed for product 3j compared to the result under
standard conditions (entry 10, 83% vs 50%).18 In addition, these
conditions could be expanded to the reaction of 1a with N-
unprotected isatin 2b to produce 3k in 60% yield (entry 11). The
scope of the reaction with respect to isatin 2 was further
evaluated. In general, the N-methyl isatin 2c and isatins with
electron-donating or electron-withdrawing substituents on the
aromatic ring all resulted in good yields with high
diastereoselectivities (entries 12-15, 3l-3o).
+
O
R
R'
R3
N
R3
Rh
R1
O O
N
R2
O
R'
R1
N
N
R2
2012
et. al.
N
O
via
Hu,
R2
B
- N2
(c) Hypothesis for this work (no-catalyst):
O
R1
N2
R
N2
O
No-catalyst
R'
R
O
+
N
N
R2
O
85 o
C
N
R2
R1
R3
N
R3
R'
O
O
via
C
Scheme 1. General accesses to the 3,3’-bioxindole skeletons.
bioxindole derivatives under catalyst-free conditions. In
comparison to the reported significant achievement in catalytic
non-carbene transformations of diazo compounds with carbonyl
compounds, including epoxidation disclosed by Gong,14a and
formal insertion reactions reported by Ryu14b-14d and Feng14e-14g
independently, we envisaged an non-carbene pathway via the
diazonium ion intermediate C followed by intramolecular
Friedel−Crafts alkylation for the synthesis of bioxindoles
(Scheme 1c).
Table 2. Substrate Scopea.
2. Results and Discussion
Initially, we investigated the reaction of N-methyl-N-phenyl
diazoamide (1a) and N-benzyl isatin (2a) under thermal
conditions. Solvents were screened at 70 C, and trifluorotoluene
(PhCF3) was found superior to the other solvents and gave the
desired product in 55 % isolated yield (Table 1, entry 1-4). In the
reaction with acetonitrile, the byproduct 4a was isolated in 60%
yield, which was generated from the the Pschorr reaction of diazo
compound 1a. Subsequently, the temperature was explored and
the best result was obtained in 75% yield at 90 oC with >95:5 dr
R1/R2/R3 (1)
Me/H/H (1a)
R4/R5 (2)
Bn/H (2a)
Bn/H (2a)
Bn/H (2a)
Bn/H (2a)
Bn/H (2a)
Bn/H (2a)
Bn/H (2a)
Bn/H (2a)
3
Entry
Yield (%) b
o
1
2
3c
4c
5
3a
3b
3c
3d
3e
3f
75
72
75
73
72
78
75
76
4-BrBn /H/H (1b)
4-NO2Bn/H/H (1c)
Et /H/H (1d)
Me/H/4-Br (1e)
Me/H/4-OMe (1f)
Me/H/3-OMe (1g)
Me/H/2-OMe (1h)
6
7
3g
3h
Table 1. Optimization of the reaction conditionsa.
8
9d
10
11
Me/H/4-CF3 (1i)
Me/Me/H (1j)
Me/H/H (1a)
Bn/H (2a)
Bn/H (2a)
H/H (2b)
3i
3j
75
50 (83)e
60f
3k
12
13
14
15
Me/H/H (1a)
Me/H/H (1a)
Me/H/H (1a)
Me/H/H (1a)
Me/H (2c)
Bn/5-F (2d)
Bn/5-Me (2e)
Bn/7-CF3 (2f)
3l
3m
3n
3o
82
78
77
82
Yield of 3a
Entry
Solvent
T (oC)
dr
(%)b
20 (60)c
51
1
2
3
4
5
6
7
MeCN
THF
70
70
3a, >95:5
3a, >95:5
3a, >95:5
3a, >95:5
3a, >95:5
3a, >95:5
3a, >95:5
a The reaction was carried out with 1 (0.3 mmol) and 2 (0.15 mmol) in PhCF3
o
(2.0 mL) at 90 C for 12 h. The diazoamide 1 was added as a solution in 1.0
Toluene
PhCF3
PhCF3
PhCF3
PhCF3
70
52
mL of PhCF3 via syringe pump in 50 min.
b Isolated yields.
70
55
c Reaction was carried out at 105 oC.
d Reaction was carried out in PhCl (2.0 mL) at 130 oC.
80
65
Reaction was carried out in H2O (2.0 mL) at 90 oC, and all the materials
e
90
75
76d
100
were added in one-time.
f Reaction was carried out at 70 oC.
a The reaction was carried out with 1a (0.3 mmol) and 2a (0.15 mmol) in
solvent (2.0 mL) for 12 h. The diazoamide 1a was added as a solution in 1.0
mL of the same solvent via syringe pump in 50 min.
b Isolated yields.
In order to gain insight into the reaction mechanism, control
experiments were carried out. When 4a was used as the starting
material, instead of 1a, under standard conditions, the bioxindole
c Yield of 4a.
d Excess of the diazo compound 1a was decomposed.

3
product 3a was also obtained in 65% yield (eq 1). This result
indicates that an alternative pathway involving indolone as the
intermediate, which forms from corresponding diazoamide 1, is
also possibly coexisting in this reaction. Further comparison is
carried out between this control reaction of 4a and the template
reaction with 1a by detecting the conversions at different reaction
times. As shown in Figure 2, the template reaction (blue line)
gives higher conversions when compared to the results with
indolone 4a (red line) at the same reaction times. Based on these
results and previous observations,17 reaction mechanism through
the diazonium ion intermediate C followed by an intramolecular
Friedel−Crafts alkylation is proposed (Scheme 1c). However, the
pathway that through indolone followed by reacting with isatin
via aldol type addition also contribute to the formation of desired
product 3 (see Table S1 and Figure S2). And further studies are
needed to unambiguously establish the reaction transformation.
Supplementary data associated with this article can be found,
in the online version, at http://
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Support for this research from the National Natural Science
Foundation of China and NSFC of Jiangsu (NSFC21602148,
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Program Development (PAPD) of Jiangsu Higher Education
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5
Highlights
• Thermally induced reaction of
diazoamides with isatins.
• Mild approach to the 3,3'-bioxindole
derivatives.
• Good to high yields with excellent
diastereoselectivity.
• gem-Difunctionalization of diazo
compounds via a non-carbene process under
catalyst-free conditions.