The first synthesis of 7-prenylisatin

Article abstract of DOI:10.1016/j.mencom.2019.03.018

The first synthesis of 7-prenylisatin, an isatin-type antibiotic with prominent activity against Bacillus subtilis, has been accomplished in 16% overall yield from 2-methylbut-3-en-2-ol and aniline via a five-step procedure. The protocol includes the arom

Full text of DOI:10.1016/j.mencom.2019.03.018

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 172–173
The first synthesis of 7-prenylisatin
Dawei Liang* and Yueqiu Wang
School of Pharmacy and Medical Laboratory Science, Ya’an Polytechnic College, 625000 Ya’an, Sichuan,
China. E-mail: ldawei@yahoo.com
DOI: 10.1016/j.mencom.2019.03.018
The first synthesis of 7-prenylisatin, an isatin-type antibiotic
with prominent activity against Bacillus subtilis, has been
accomplished in 16% overall yield from 2-methylbut-3-en-2-ol
and aniline via a five-step procedure. The protocol includes
the aromatic aza-Claisen rearrangement and the Sandmeyer
isonitrosoacetanilide isatin synthesis as key steps.
5 steps
NH2 16% overall yield
H
OH
N
+
O
O
Natural products play an important role in drug discovery in
2­yl) carbonate in 94% yield.11 Then N­(2­methylbut­3­en­2­yl)­
aniline was obtained in 76% yield by the reaction of the latter with
aniline upon treatment with Pd(PPh ) (2 mol%) in THF–DMF
1
–5
recent decades, and some of them serve as leads for pharma­
6
ceuticals development or as tested compounds in clinical trials.
3
4
The identification of 7­prenylisatin 1 produced by the actino­
mycete Streptomyces sp. MBT28 was reported in 2015. Its
(20:1, v/v) at room temperature. The aza­Claisen rearrangement
of N­(2­methylbut­3­en­2­yl)aniline was carried out with
7
structure was established via NMR­based metabolomics and
multivariate data analysis. When tested against Bacillus subtilis,
p­TsOH (10 mol%) in MeCN–H O (10:1, v/v) at 70°C to
construct the ortho­substituted phenyl group in the key precursor
2
1
2–15
7
­prenylisatin 1 exhibited the minimal inhibitory concentration
2, which was isolated in 57% yield.
Compound 2 was charac­
–1 7
1
(MIC) value of ca. 25 mg ml . The published data for other
terized by H NMR spectrum with methylene protons triplet at
d 2.63 ppm; the absence of proton signal at the ortho­position
of aniline corresponded to the result of N­prenylated aniline
rearrangement through migration of the prenyl group to the
isatin­type compounds also demonstrate their antibacterial, anti­
fungal, and cytotoxic properties,8
–10
making them promising
leads in drug discovery. Despite prominent bioactivity and the
related biosynthetic results, the chemical synthesis of 7­prenyl­
isatin 1 has never been reported to date. We describe herein the
first synthesis of this compound, which would benefit its structure–
activity relationship (SAR) investigations as well as the further
design of (prenyl)isatin analogues.
†
ortho­position. With the key precursor 2 in hand, we turned to
the construction of the pyrrolidinedione moiety. The Sandmeyer
isonitrosoacetanilide isatin synthesis strategy was adopted.1
The treatment of the ortho­substituted phenyl aniline 2 with
chloral hydrate, Na SO , hydrochloric acid and hydroxylamine
6–19
2
4
In our retrosynthetic analysis we planned to create the
,3­pyrrolidinedione skeleton of compound 1 by the Sandmeyer
hydrochloride at 80°C for 1.5 h afforded isonitrosoacetanilide 3
in 76% yield. At the final step, the intramolecular cyclization of
‡
2
isonitrosoacetanilide isatin synthesis including intramolecular
cyclization of isonitrosoacetanilide 3, which could be obtained
by one­pot condensation of ortho­substituted aniline 2, chloral
hydrate and hydroxylamine hydrochloride. In turn, compound 2
could be synthesized via the aza­Claisen rearrangement starting
from N­(2­methylbut­3­en­2­yl)aniline, which could be easily
prepared via a direct palladium­catalyzed coupling of aniline
with tert­butyl (2­methylbut­3­en­2­yl) carbonate.
For the synthesis of the key precursor 2 (Scheme 1),
commercially available 2­methylbut­3­en­2­ol was reacted with
n­BuLi (1.0 mol equiv.) in dry THF at 0°C to afford lithium
alcoholate, and the solution was subsequently treated with
di­tert­butyl dicarbonate to give tert­butyl (2­methylbut­3­en­
compound 3 occurred in concentrated sulfuric acid at less than
70°C, andthenafterheatingto80°Cforca. 10min, 7­prenylisatin
†
For experimental details and characteristics of the compounds obtained,
see Online Supplementary Materials.
‡
(E)-2-(Hydroxyimino)-N-[2-(3-methylbut-2-en-1-yl)phenyl]acetamide 3.
A solution of Na SO (23.1 g, 162 mmol) in water (33 ml), 2­(3­methyl­
2
4
but­2­en­1­yl)aniline 2 (1.47 g, 9 mmol), hydrochloric acid (1.23 ml,
2
2
7 mmol), and finally a solution of hydroxylamine hydrochloride (1.89 g,
7 mmol) in water (9 ml) were added to a stirred solution of chloral hydrate
(1.62 g, 10 mmol) in water (21 ml) at room temperature. The mixture was
heated to 80°C for 1.5 h and then cooled to room temperature. The
residue was extracted with EtOAc (3×30 ml), the organic phases were
washed with brine, dried over anhydrous MgSO , filtered and concentrated
4
in vacuo. The crude product was purified by chromatography on silica gel
(
EtOAc–light petroleum, 1:10) to afford compound 3 (1.5 g, 76%) as
–1
yellow oil. IR (n/cm ): 1130, 1255, 1315, 1460, 1620, 1670, 2960, 3390,
3455. H NMR (400 MHz, CDCl ) d: 1.76 (s, 3H, Me), 1.83 (s, 3H, Me),
1
i
ii
3
H
H
2.85 (t, 2H, CH2, J 5.2 Hz), 4.18 (br.s, 1H, NH), 4.91–4.83 (m, 1H, CH),
N
NH2
N
6
(
.61 (s, 1H, CH), 6.91–6.83 (m, 2H, Ar), 7.11 (t, 1H, Ar, J 9.6 Hz), 7.58
t, 1H, Ar, J 8.0 Hz), 7.88 (br.s, 1H, OH). 13C NMR (100 MHz, CDCl3)
d: 18.1 (Me), 27.9 (Me), 37.9 (CH ), 113.2 (CH), 117.7 (Ar), 121.6 (Ar),
N
O
O
OH
2
O
2
3
1
1
27.2 (Ar), 128.3 (Me C), 131.5 (Ar), 134.9 (Ar), 140.1 (Ar), 142.9 (CH),
2
+
Scheme 1 Reagents and conditions: i, chloral hydrate, Na SO , aq. HCl,
146.8 (C=O). HRMS (ESI), m/z: 233.1283 [M+H] (calc. for C13H17N2O2,
m/z: 233.1285).
2
4
NH OH·HCl, H O, 80°C; ii, H SO , 70°C.
2
2
2
4
©
2019 Mendeleev Communications. Published by ELSEVIER B.V.
–
172 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2019, 29, 172–173
was isolated as the main product in 51% yield. The H, 13C
§
1
Online Supplementary Materials
1
NMR and HRMS data of the synthesized compound 1 were
close to the reported ones for the natural sample. Therefore,
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.03.018.
7
our synthetic strategy may be considered as an efficient one from
the viewpoint of simple steps, low­cost materials, mild reaction
conditions and easy operations, and definitely has a potential for
the synthesis of other isatin derivatives.
In conclusion, the first synthesis of 7­prenylisatin was developed
from commercially available 2­methylbut­3­en­2­ol and aniline
using a five­step procedure involving the aromatic aza­Claisen
rearrangement of N­prenylated aniline and the Sandmeyer reaction
for preparing isonitrosoacetanilide isatin as key steps. The synthetic
strategy can provide rapid access to various analogues of (prenyl)
isatin derivatives, which is helpful in evaluation of biological
activity and search for new lead compounds.
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This work was supported by the Applied Basic Research and
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of Ya’an (2017YYJSKF15). We are grateful to Mr. Wei Wang
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1
1
1
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§
7
-Prenylisatin 1. Concentrated H SO (7 ml) was warmed to 50°C
2 4
with stirring, then (E)­2­(hydroxyimino)­N­[2­(3­methylbut­2­en­1­yl)­
phenyl]acetamide 3 (0.81 g, 3.5 mmol) was added in batches to keep the
temperature between 60 and 70°C. After that, the mixture was heated to
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8
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water with continuous stirring for ca. 30 min. The orange precipitate was
filtered off, washed with water and recrystallized from EtOH–H O (1:1,
v/v) to afford compound 1 (0.38 g, 51%) as orange solid, mp 177–180°C.
IR (n/cm ): 1120, 1240, 1310, 1475, 1610, 1655, 1690, 2970, 3410. H
NMR (400 MHz, CDCl ) d: 1.75 (s, 3H, Me), 1.77 (s, 3H, Me), 3.26 (d,
2
1
1
1
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2
4
638.
13
(d, 1H, Ar, J 7.8 Hz), 7.48 (d, 1H, Ar, J 7.8 Hz). C NMR (100 MHz,
CDCl ) d: 18.5 (Me), 26.6 (Me), 30.0 (CH ), 118.1 (CH), 120.5 (Ar),
3
2
1
1
24.2 (Ar), 124.5 (Ar), 125.5 (Me C), 136.4 (Ar), 139.8 (Ar), 148.2 (Ar),
59.1 (C=O), 183.2 (C=O). HRMS (ESI), m/z: 216.1017 [M+H] (calc.
2
+
for C H NO , m/z: 216.1019).
Published data for comparison. H NMR (600 MHz, CDCl ) d: 1.78
13
14
2
7
1
3
(
br.s, 3H, Me), 1.80 (d, 3H, Me, J 1.2 Hz), 3.31 (br.d, 2H, CH , J 7.2 Hz),
2
5
7
2
1
.24 (m, 1H, CH), 7.06 (t, 1H, Ar, J 7.8 Hz), 7.39 (br.d, 1H, Ar, J 7.8 Hz),
.49 (br.d, 1H, Ar, J 7.8 Hz). 13C NMR (125 MHz, CDCl ) d: 18.3 (Me),
3
5.9 (Me), 29.7 (CH ), 118.4 (CH), 120.0 (Ar), 123.7 (Ar), 124.0 (Ar),
2
25.1 (Me C), 136.1 (Ar), 139.1 (Ar), 147.9 (Ar), 159.2 (C=O), 183.1
2
+
(
C=O). HRMS (ESI), m/z: 216.1018 [M+H] .
Received: 3rd October 2018; Com. 18/5708
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