Catalyst-Free Halogenation of α-Diazocarbonyl Compounds with N-Halosuccinimides: Synthesis of 3-Halooxindoles or Vinyl Halides

Article abstract of DOI:10.1021/acs.orglett.6b01346

A novel catalyst-free halogenative cyclization of N-aryl diazoamides with N-halosuccinimides (NXS) is reported for the synthesis of 3-halooxindoles through a carbene-free mechanism. N-Aryl diazoamides reacted with NXS under mild and catalyst-free conditio

Full text of DOI:10.1021/acs.orglett.6b01346

Letter
pubs.acs.org/OrgLett
Catalyst-Free Halogenation of α‑Diazocarbonyl Compounds with
N‑Halosuccinimides: Synthesis of 3‑Halooxindoles or Vinyl Halides
Chaoqun Ma, Dong Xing,* and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular
Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
S
* Supporting Information
ABSTRACT: A novel catalyst-free halogenative cyclization of N-aryl
diazoamides with N-halosuccinimides (NXS) is reported for the synthesis
of 3-halooxindoles through a carbene-free mechanism. N-Aryl diazoamides
reacted with NXS under mild and catalyst-free conditions to afford the
corresponding 3-halooxindoles in good yields. This transformation is
proposed to proceed through diazonium ion formation followed by
intramolecular Friedel−Crafts alkylation.
α-Diazocarbonyl compounds have been extensively used as
metal carbene precursors in a variety of transition-metal-
catalyzed transformations, such as X−H insertion (X = C, N, O,
Si and S), ylide formation, cyclopropanation, rearrangement,
etc. (Scheme 1, eq 1).1 On the other hand, thanks to the
N-Halosuccinimides (NXS) have been extensively used as
electrophilic halogenating agents in organic synthesis. However,
there are no examples where NXS has been used as an electron-
deficient species to react with α-diazocarbonyl compounds via
carbene-free pathways.8 In 2014, Zhu and co-workers utilized
relatively active 1,3-dihalo-5,5-dimethylhydantoin as the halo-
genating agents to react with α-diazocarbonyl compounds for a
sequential halogenation/semipinacol rearrangement under
Lewis base catalysis (Scheme 2A).9 Very recently, Li, Huang
Scheme 1. General Reaction Pathways of α-Diazocarbonyl
Compounds
Scheme 2. Reaction Pathways for NXS-Involved
Transformations of α-Diazocarbonyl Compounds via
Carbene-Free Transformations
electron-rich character of the diazo carbon from its resonance
structure, α-diazocarbonyl compounds react readily with
electron-deficient species through carbene-free mechanisms
without the aid of transition metal catalysts.2 The resulting
diazonium ion intermediates can be further intercepted by
electron-rich species in either an inter- or intramolecular
manner to give different types of products. Within this context,
proton sources such as carboxylic acids, alcohols or water,3
organoboron compounds,2c,4 carbonyl groups,5 imines,6 or α,β-
unsaturated carbonyl compounds7 have been extensively
utilized as electron-deficient sources for such types of
transformations (Scheme 1, eq 2). Given these advantages,
the introduction of new types of electrophilic-deficient species
that will allow the establishment of novel carbene-free
transformations from α-diazocarbonyl compounds is still highly
desirable.
and co-workers developed a gem-aminofluorination of diazo-
carbonyl compounds with N-fluorobenzenesulfonimide (NFSI)
under catalyst-free conditions (Scheme 2B).10 As part of our
ongoing research interest in exploring novel transformations
with an N-aryl diazoamide,11 we envisioned that NXS would
react with the N-aryl diazoamide to give the corresponding
Received: May 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01346
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
diazonium ion, which would further undergo intramolecular
Friedel−Crafts alkylation with concomitant extrusion of N2 gas
to afford 3-halooxindoles (Scheme 2C). We hoped that the
intramolecular Friedel−Crafts alkylation pathway would
provide a favorable driving force for the proposed trans-
formation to proceed under mild and catalyst-free conditions.
The produced 3-halooxindoles are important building blocks
for constructing 3,3-disubstituted oxindoles, which are common
structural motifs found in a number of natural products and
pharmaceuticals.12,13 Therefore, the current method would
provide a convenient and efficient alternative for rapidly
accessing a variety of 3-halooxindole moieties.
We initiated our exploration by investigating the reaction of
N-methyl-N-phenyl diazoacetamide (1a) with N-bromosucci-
nimide (NBS). Without the addition of any catalysts or
additives, a clear gas release was observed when a solution of 1a
in CH2Cl2 was added dropwise to a solution of NBS in CH2Cl2.
After completion of the addition, 3-bromooxindole 2a and the
β-H elimination product 3a were obtained in 92% combined
yield and an 88:12 ratio (Table 1, entry 1). In order to improve
Table 2. Substrate Scope
yield of 2
ratio
(2:3)
b
c
entry NXS
1
R1
R2
R3
(%)
1
NBS
NCS
NIS
1a
1a
1a
1b
1c
1d
1e
1f
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
88
85
96
92
85
69
63
60
60
95
92
72
89
86
81
93:7
>95:5
>95:5
>95:5
94:6
2
3
4
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
p-Me
5
p-MeO
p-F
6
74:26
67:33
64:36
75:25
<5:95
<5:95
>95:5
>95:5
>95:5
90:10
7
p-Cl
p-Br
o-Me
o-Br
2,6-Cl2
m-Me
H
8
9
1g
1h
1i
d
d
10
11
12
13
14
15
1j
1k
1l
a
Table 1. Optimization of the Reaction Conditions
H
Bn
1m
H
Me
a
Reaction conditions: 1a (0.1 mmol) dissolved in 1.0 mL of CH2Cl2
was added to a stirred solution of NXS (0.2 mmol) in 1.0 mL of
b
c
CH2Cl2 in a dropwise manner. Isolated yield of 2. Detected by crude
d
1H NMR. Isolated yield of 3.
b
c
entry
solvent
t (°C)
yield of 2a (%)
ratio (2a:3a)
substituent groups had a profound effect on the chemo-
selectivity between the Friedel−Craft alkylation product 2 and
the β-H elimination product 3. For substrates bearing para-
substituents, electron-donating groups provided high chemo-
selectivity (up to >95:5) while electron-withdrawing ones gave
only moderate chemoselectivity (Table 2, entries 4 and 5 vs
entries 6−8). An ortho-methyl substituted substrate (1g) gave
poor chemoselectivity despite its electron-donating nature,
probably owing to its steric effect for the alkylation step (Table
2, entry 9). When an ortho-bromo substituted substrate (1h)
was used, the chemoselectivity was completely switched to β-H
elimination product 3h (Table 2, entry 10). A 2,6-dichloro
substituted substrate (1i) also gave the corresponding vinyl
bromide product in good yield (Table 2, entry 11). With a
meta-methyl substituted substrate (1j), the cyclization occurred
exclusively at the para-position of the methyl group, affording
the desired product in 72% yield with excellent chemo-
selectivity (Table 2, entry 12). Diazoamides with ethyl or
benzyl substituents at the diazo carbon also gave corresponding
3-bromooxindoles in high yields with excellent chemo-
selectivities (Table 2, entries 13−14). However, the substrate
bearing a phenyl substituent at the diazo carbon failed to give
the desired cyclization product. N-Benzyl protected diazoamide
(1m) also yielded the desired 3-bromooxindole in good yield
with high chemoselectivity (Table 2, entry 15). With
tetrahydroquinoline-derived diazoamide (1n) as the substrate,
the corresponding tricyclic 3-bromooxindole product (2n) and
the vinyl bromide product (3n) were obtained in high yields
with a 1:1 ratio (Scheme 3).
1
2
3
4
5
6
7
8
CH2Cl2
toluene
Et2O
25
25
25
25
25
25
25
0
81
39
57
40
37
59
77
88
88:12
48:52
67:33
50:50
42:58
75:25
85:15
93:7
THF
EtOH
EtOAc
CHCl3
CH2Cl2
a
Reaction conditions: 1a (0.1 mmol) in 0.5 mL of the corresponding
solvent was added to a mixture of NBS (0.1 mmol) in 0.5 mL of the
corresponding solvent in a dropwise manner. Isolated yield of 2a.
Determined by crude H NMR.
b
c
1
the chemoselectivity of the desired Friedel−Crafts alkylation
product over the undesired β−H elimination product, a series
of condition optimizations was conducted. Among different
solvents being tested, CH2Cl2 gave the highest chemoselectivity
(Table 1, entries 2−7). With CH2Cl2 as the solvent, reducing
the reaction temperature to 0 °C improved chemoselectivity to
93:7 while the yield remained unaffected (Table 1, entry 8).
Further reducing the reaction temperature to −10 °C led to a
very slow decomposition of 1a as observed by the reduced gas
evolution from the reaction mixture.
With the readily obtained optimization conditions in hand,
we further investigated the substrate scope for this catalyst-free
halogenative Friedel−Crafts reaction. N-Chlorosuccinimide
(NCS) and N-iodosuccinimide (NIS) both reacted with 1a
smoothly to afford the corresponding 3-halooxindoles in
excellent yields with excellent chemoselectivities (>95:5)
(Table 2, entries 2 and 3). Utilizing NBS as the halogenating
agent, various substituted diazoamides were then investigated.
Diazoamides containing both electron-donating and -with-
drawing groups on the aryl ring generally gave the desired
cyclizing products in high yields. The electron propensity of the
We further tried to apply the current halogenating/Friedel−
Craft alkylation strategy to the synthesis of 3-fluorooxindoles.
By employing selectfluor as the fluorinating reagent under
standard reaction conditions, the desired 3-fluorooxindole
product was not observed. However, with the addition of 1
equiv of K2CO3 and MeCN as the solvent, the corresponding
B
DOI: 10.1021/acs.orglett.6b01346
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Bromination of Tetrahydroquinoline-Derived
Diazoamide 1n
Scheme 6. Control Experiments and Intermolecular KIE
Experiment
3-fluorooxindole product 2b-F was afforded exclusively in 77%
yield (Scheme 4).
Scheme 4. Fluorination of Diazocarbonyl Compound 1b
Scheme 7. Synthesis of Vinyl Halide Compounds
To demonstrate the synthetic efficiency of this trans-
formation, we explored a gram scale synthesis of 3-
bromooxindole 2a. The reaction was complete after the slow
addition of diazoamide 1a over 5 min. When the reaction was
finished, simply washing the reaction mixture with water and
further recrystallization from Et2O afforded 2a in 78% yield
(Scheme 5).
number of cross-coupling reactions.14 Therefore, the current
method offers a very convenient and easily executed method for
the synthesis of such compounds.
Scheme 5. Gram-Scale Synthesis of 2a
In summary, we have developed a highly convenient and
efficient method for the synthesis of 3-halooxindoles starting
from N-aryl diazoamides under catalyst-free conditions. This
transformation is proposed to proceed through the formation
of a halogenated diazonium ion from NXS and N-aryl
diazoamide via a carbene-free pathway. The generated
diazonium ion intermediate further underwent intramolecular
Friedel−Craft alkylation with concomitant extrusion of N2 gas
to give a variety of 3-halooxindoles. Also, when starting from
suitable α-diazocarbonyl substrates, the halogenated diazonium
ion intermediate could also undergo efficient β-H elimination
to produce vinyl halide products in high yields.
After the completion of the NBS-involved transformation,
the C−H insertion product was not detected. Nonetheless, to
preclude the possibility of a rapid transformation involving a
stepwise C−H insertion followed by direct halogenation.
Several control experiments were conducted. Under standard
reaction conditions, the C−H insertion product 1a′ from 1a
gave no 3-halooxindole products (Scheme 6, eq 3). For the
fluorination reaction, since 1 equiv of K2CO3 was required, it
was more likely to undergo a stepwise pathway. However,
subjecting oxindole 1b′ to the standard reaction conditions also
gave no desired product (Scheme 6, eq 4). These results
partially indicated that this transformation proceeded through a
halogenation/Friedel−Craft type alkylation pathway. To
further gain some insight into the mechanism of this
transformation, an intermolecular kinetic isotope effect (KIE)
experiment was conducted. The KIE (kH/kD = 1.5) indicated
that the C−H bond cleavage should not be the rate-
determining step (Scheme 6, eq 5). This transformation
proceeded smoothly in the presence of 2 equiv of TEMPO,
indicating that a radical process was unlikely involved.
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.6b01346.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dxing@sat.ecnu.edu.cn.
*E-mail: whu@chem.ecnu.edu.cn.
Notes
The formation of β-H elimination products inspired us to
develop a practical method for the synthesis of vinyl halides.
For example, under the mild and catalyst-free conditions, 2-
diazo-1-phenylpropan-1-one 4 was smoothly converted into the
vinyl bromide or vinyl iodide in high yields (Scheme 7). Vinyl
bromides have generally been utilized as useful reagents in a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial supports from NSF of China (21332003, 21402051)
are greatly acknowledged.
■
C
DOI: 10.1021/acs.orglett.6b01346
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Org. Lett. XXXX, XXX, XXX−XXX