An improved synthetic method of phenazine-1-carboxylic acid

Article abstract of DOI:10.14233/ajchem.2015.18757

An improved synthetic method of a natural fungicide, phenazine-1-carboxylic acid, was reported. In brief, the process constitutes of (a) one-pot synthesis of 1-methyphenazine (IV) from pyrocatechol and 3-methyl-2-aminoaniline, (b) Wohl-Ziegler bromination of IV, (c) hydrolyzation of 1-bromomethylphenazine (III) in aqueous solution of Na2CO3/N,N-dimethylformamide (1.1:1, v/v), (d) oxidation of 1-phenazinemethanol (II) by O2 under the catalyzation of N-bromosuccinimide. This method provided an effective synthesis of phenazine-1-carboxylic acid in the overall yield of 66 %.

Full text of DOI:10.14233/ajchem.2015.18757

Asian Journal of Chemistry; Vol. 27, No. 9 (2015), 3355-3360
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18757
An Improved Synthetic Method of Phenazine-1-carboxylic Acid
*
Q.Y. ZHAN, X.L. ZHU, H. HUANG, Q. LIU and H.J. ZHU
Department of Applied Chemistry, College of Sciences, Nanjing Tech University, Nanjing 211816, P.R. China
*Corresponding author: Fax: +86 25 83172358; Tel: +86 25 58139480; E-mail: zhuhj@njtech.edu.cn
Received: 17 September 2014;
Accepted: 13 January 2015;
Published online: 26 May 2015;
AJC-17255
An improved synthetic method of a natural fungicide, phenazine-1-carboxylic acid, was reported. In brief, the process constitutes of (a)
one-pot synthesis of 1-methyphenazine (IV) from pyrocatechol and 3-methyl-2-aminoaniline, (b) Wohl-Ziegler bromination of IV, (c)
hydrolyzation of 1-bromomethylphenazine (III) in aqueous solution of Na2CO3/N,N-dimethylformamide (1.1:1, v/v), (d) oxidation of
1-phenazinemethanol (II) by O2 under the catalyzation of N-bromosuccinimide. This method provided an effective synthesis of phenazine-
1-carboxylic acid in the overall yield of 66 %.
Keywords: Natural fungicide, Phenazine-1-carboxylic acid, One-pot, Oxidation.
the ring of phenazine was catalyzed by enzymes encoded in
the conserved ‘phz operon’ through symmetrical head-to-tail
double condensation of two chorismic acid7,19-27. For the
biosynthetic method, wide-type strains were reported to
produce only 200-300 mg/L of phenazine-1-carboxylic acid
and even the new optimization strain M18MSU1 was found
to give 4771.2 mg/L22. However, the disadvantages of the
biological fermentation, such as low yield, the effluent and
the offscum, restricted the large-scale production of phenazine-
1-carboxylic acid.
Although the studies on chemical synthesis of phenazines
had attracted wide interest28-33, only three methods to phena-
zine-1-carboxylic acid were reported. Method 1 disclosed a
method to phenazine-1-carboxylic acid in two steps (Scheme-
I)6,31-32. Ullmann coupling of substituted anilines (I-1) and 2-
halogeno-3-nitrobenzoic acid (I-2) yielded substituted N-
phenyl-3-nitro-anthranilic acids (I-3). Then, reductive cycliza-
tion of I-3 provided phenazine-1-carboxylic acid (I). Mean-
while, it was possible to isolate varying amounts of substituted
N-phenyl-3-aminoanthranilic acid (I-4), which was the direct
reduction product of the nitro group without ring formation.
This was one important factor causing the low yield of method
1.Another noteworthy factor was that I-2 could not be commer-
cially available. Method 2 disclosed another method in only
26 % yield (Scheme-I)9. Condensation of cyclohexane-1,2-
dione (I-5) with substituted 2,3-diaminobenzoic acids (I-6)
furnished substituted 6,7,8,9-tetrahydro-1-carboxy-phenazine
(I-7), which was dehydrogenated with Pd/C in 3d, gave
substituted phenazine-1-carboxylic acid. The yield of method
INTRODUCTION
Substituted phenazine cores are important biologically
active structures and are usually found in natural products,
pesticides and antibiotics1-7. Majority of the natural products
phenazine derivatives are produced by diverse genera of
bacteria8-13 and existing knowledge indicates that dozens of
them originate from either phenazine-1,6-dicarboxylic acid
(PDC) or phenazine-1-carboxylic acid (PCA, I) (Fig. 1)14-17
.
As a more than simple secondary metabolite produced by
various pseudomonad strains, phenazine-1-carboxylic acid is
also a natural excellent fungicide due to its effectiveness against
various phytopathogens, low toxicity to humans and animals
and environmental friendliness18-19
.
COOH
N
N
Fig. 1. Phenazine-1-carboxylic acid (PCA, I)
In 1989, phenazine-1-carboxylic acid was firstly found
in P. fluorescens 2-7920-22. In 2011, phenazine-1-carboxylic
acid was registered as a new synthesized biologically fungicide
named ‘Shenqinmeisu’by the Ministry ofAgriculture of China,
which attracted wide attention from all around the world22.
Now, phenazine-1-carboxylic acid was mainly isolated from
P. aeruginosa strain M18 in the biosynthetic pathway where

3356 Zhan et al.
Asian J. Chem.
1
2
3
Method
R
COOH
R
COOH
COOH
NO2
H
N
H
N
NH2
N
X
K2CO3, Cu
DMF
NaBH4
NaOH
H2N
N
R
O2N
COOH
R=H,F
I-1
X=Br,Cl,I
I-2
I
I-3
I-4
Method
COOH
COOH
COOH
NH2
O
N
N
N
Pd/C
3d
MeOH
NH2
N
O
X
X
X
X=CH3, OCH3
I-5
I-6
I-7
I-8
Method
CH3
CH3
CH3
H
N
NH2
NH2
OH
N
Cl2
150-240oC
O2
AIBN
OH
V-1
N
H
N
V
IV-1
IV
CCl3
COOH
N
N
N
H2O
N
IV-2
I
Scheme-I: Reported synthetic methods of phenazine-1-carboxylic acid
2 was lower and the route needed long reaction time. These
drawbacks of these two routes made them unsuitable for
the synthesis of phenazine-1-carboxylic acid. Recently, our
group reported the method 3, which comprised condensation,
oxidation, chlorination and hydrolyzation starting from 3-
methylbenzene-1,2-diamine (V) and pyrocatechol (V-1)33
(Scheme-I).
Based on the previous work, an improved synthetic
method of phenazine-1-carboxylic acid was developed. The
route starting from V and V-1, includes condensation in one-
pot, bromination with N-bromosuccinimide (NBS), hydroly-
zation in 0.5 % Na2CO3 aqueous solution/N,N-dimethylform-
amide (1.1:1,v/v) and oxidation with O2, employing readily
available and non-metallic reagents showed in Scheme-II. For
CH3
CH3
N
NH2
NH2
OH
OH
1) 210-220oC,10h
2) air, 210-220oC, 3h
NBS, BPO
CCl4, 80oC, 4h
N
86%
80%
IV
V
V-1
CH2Br
CH2OH
N
COOH
N
N
0.5% Na2CO3
DMF, 80oC,2h
NBS, AIBN,MeCN
O2, 80oC,10h
N
N
N
98%
98%
III
II
I
Scheme-II: Synthetic route of phenazine-1-carboxylic acid

Vol. 27, No. 9 (2015)
An Improved Synthetic Method of Phenazine-1-carboxylic Acid 3357
further application in scale synthesis of phenazine-1-carboxylic
acid, the overall yield was up to 66 % by optimizing each step.
necked flask equipped with an efficient reflux condenser. The
mixture was heated at 80 °C for 2 h under stirring. Then, the
mixture was cooled and poured into water (100 mL) and
extracted with EtOAc (50 mL × 3). The obtained EtOAc extract
was washed with 0.2 N HCl (30 mL × 2) and finally washed
with saturated NaCl solution. After drying with anhydrous
Na2SO4, the organic layer was concentrated in vacuum to get
the crude product. The residue was purified by recrystallization
to obtain II (7.6 g, 98.4 %) as yellow solid. m.p. 132-134 °C;
1H NMR (CDCl3, 400 MHz) δ: 4.50 (t, J = 6.4, 1H), 5.33 (d,
J = 6.3, 2H), 7.72-7.78 (m, 2H), 7.84 (t, J = 4.1, 2H), 8.14-
8.24 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 143.7, 142.4,
141.9, 138.8, 138.7, 130.7, 130.6, 130.3, 129.6, 129.5, 129.2,
128.2, 63.9; ESI-MS m/z: 211.1 (100 %).
Synthesis of phenazine-1-carboxylic acid (I): To one
three necked flask was added compound II (12.0 g, 57.1 mmol)
and anhydrous MeCN (100 mL). Then azobisisobutyronitrile
(1.0 g, 5.7 mmol) and NBS (5.1 g, 22.8 mmol) were added
into the mixture under O2 atmosphere with stirring. The reac-
tion mixture was heated at 80 °C for 10 h. The solution was
chilled and poured into water, then was extracted with EtOAc
(50 mL × 3). After dried with anhydrous Na2SO4, the organic
layer was concentrated in vacuum to get the crude product.
The residue was purified by recrystallization to obtain the target
compound I (12.6 g, 98.2 %) as yellow powder. m.p. 240-242
°C; 1H NMR (CDCl3, 400 MHz) δ: 7.88-7.98 (m, 2H), 8.18-
8.26 (m, 2H), 8.44 (t, J = 4.3, 2H), 8.89 (d, J = 7.2, 1H), 15.5
(s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 164.9, 143.0, 142.3,
139.9, 138.7, 136.4, 134.1, 132.2, 130.7, 129.2, 129.0, 126.9,
123.8; ESI-MS m/z: 225.0 (100 %).
EXPERIMENTAL
Unless otherwise specified, all reagents was procured from
commercial sources and used without further purification.1H
NMR and 13C NMR spectra were recorded on a Bruker 400
MHz spectrometer. Mass spectra were recorded on a mass
spectrometry (MS) spectrometer VG12-250 MS. Melting
points (m.p.) were taken on an X-4 microscope electro thermal
apparatus. Reactions were monitored by reverse phase HPLC
on a Varian 1200 chromatograph equipped with a Symmetry
Shield RP column (C18, 150 mm × 4.6 mm). Content by HPLC
refers to chromatographic area percentage. The column tempe-
rature was at 25 °C and the flow rate of mobile phase (CH3OH/
H2O = 7/3, v/v) was to 1.0 mL/min.
Synthesis of 1-methylphenazine (IV): To a round bottom
flask was charged compound V (22.4 g, 0.18 mol) and V-1
(29.7 g, 0.27 mol). The reaction mixture was heated at 210-
220 °C for 10 h under N2. Then the mixture was heated for
another 3 h under air. After cooling to room temperature, it
was diluted with EtOAc and washed with 40 % NaOH aqueous
solution (100 mL), water (50 mL × 2). The organic layer was
then dried with Na2SO4 and the solvent was removed under
reduced pressure. Yellow powder was obtained, yield 80 %.
m.p.106-109 °C; 1H NMR (CDCl3, 400 MHz) δ: 2.92 (S, 3H),
7.62-7.64 (m, 1H), 7.69-7.73 (m, 1H), 7.78-7.85 (m, 2H), 8.07
(dd, J1 = 8.8, J2 = 1.6, 1H), 8.20-8.25 (m, 1H), 8.26-8.29 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ: 143.6, 143.2, 143.1,
142.7, 137.9, 130.4, 130.2, 130.1, 129.9, 129.5, 129.4, 127.5,
17.7; ESI-MS m/z: 195.0 (100 %).
RESULTS AND DISCUSSION
Synthesis of 1-(bromomethyl)phenazine (III): Compound
IV (10 g, 51.5 mmol), NBS (13.7 g, 77.2 mmol) and benzoyl
peroxide (1.41 g, 8.8 mmol) were dissolved in CCl4 (150 mL)
in a two necked flask equipped with an efficient reflux
condenser. The mixture was stirred for 4 h at reflux. After
completion of the reaction, the mixture poured into water (100
mL) and extracted with dichloromehtane (DCM) (50 mL ×
3). The obtained DCM was dried with anhydrous Na2SO4 and
concentrated in vacuum. The residue was purified by flash
chromatography on silica gel with ethyl acetate-petroleum
ether (1:15, v/v) to give the intermediate III (12.1 g, 86.3 %)
as yellow solid. m.p. 163-165 °C; 1H NMR (CDCl3, 400 MHz)
δ: 5.35 (s, 2H), 7.77-7.81 (m, 1H), 7.85-7.88 (m, 2H), 7.96 (d,
J = 6.7, 1H), 8.21-8.25 (m, 2H), 8.30-8.34 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ: 143.6, 143.4, 142.9, 141.2, 136.8, 131.0,
130.9, 130.6, 130.5, 130.2, 130.1, 129.5, 28.4; ESI-MS m/z:
272.9 (100 %) and 274.9 (97 %).
Synthesis of 1-methyphenazine (IV): The synthesis of
IV via condensation of V and V-1 at 230 °C for 24-50 h to
give the intermediate 1-methyl-5,10-dihydrophenazine (IV-
1) and its subsequent conversion under O2 in 2-7 h had been
reported33. In this paper, one-pot method was found to be carried
out instead of two-steps method, which was advantageous with
respect to reaction time and purification. Therefore, the inter-
mediate IV was obtained in one-pot by condensation of V and
V-1 at 210-220 °C for only 10 h and then oxidation with air at
210-220 °C for 3 h in 80 % yield.
Synthesis of 1-bromomethylphenazine (III):As per the
reported process, III was obtained in 57 % yield under Wohl-
Ziegler bromination condition34. Therefore, the study was
started by the reported process and got the required compound
III in low yield contaminated with the byproduct 1-(dibromo-
1
methyl)phenazine (III-1). III-1 was identified by H NMR,
1-(Dibromomethyl)phenazine (III-1) as yellow solid. m.p.
13C NMR and isolated. In order to enhance the yield of III and
minimize the level of III-1, the equivalent of NBS and benzoyl
peroxide (BPO) was investigated and the results were summa-
rized in Table-1. In the initial trial, the reactions were carried
out in different equivalent of NBS in 0.16 equivalent of benzoyl
peroxide (entries 1-4). The optimum quantity of NBS was
found to be 1.5 equivalent in which III was present in 84.6 %
with a better yield (determined by HPLC) along with 5.3 % of
III-1 (entry 3). Due to the incomplete reaction of IV in 10.1 %,
the equivalent of benzoyl peroxide was further screened using
1
158 -161 °C; H NMR (CDCl3, 400 MHz) δ: 7.87-7.95 (m,
3H), 8.22-8.31 (m, 3H), 8.34 (s, 1H), 8.49-8.51 (dd, J1 = 7.1,
J2 = 0.94, 1H); 13C NMR (CDCl3, 100 MHz) δ: 143.8, 142.7,
142.4, 140.0, 138.1, 131.4, 131.2, 131.1, 131.0, 130.2, 130.0,
129.5, 35.8; ESI-MS m/z: 352.9 (100 %), 350.8 (50 %) and
354.9 (50 %).
Synthesis of 1-phenazinemethanol (II): Compound III
(10 g, 36.6 mmol) was dissolved in the mixture of DMF (80
mL) and 0.5 % Na2CO3 aqueous solution (88 mL) in a three

3358 Zhan et al.
Asian J. Chem.
TABLE-1
EFFECTS OF REACTION CONDITIONSa ON THE YIELD OF III
Content by HPLCb
Entry
n(IV):n(NBS):n(BPO)
Yield (%)c
IV (%)
76.2
36.7
10.1
2.1
65.6
5.4
3.2
III (%)
23.7
60.3
84.6
82.2
32.3
88.8
73.8
III-1 (%)
0
2.9
5.3
15.7
2.1
5.5
1
2
3
1.00:1.00:0.16
1.00:1.30:0.16
1.00:1.50:0.16
1.00:1.60:0.16
1.00:1.50:0.12
1.00:1.50:0.17
1.00:1.50:0.18
20.5
56.6
81.3
79.2
26.8
86.3
70.9
4
5
6d
7
22.9
aReaction conditions: the compound IV, NBS and benzoyl peroxide (BPO) were in CCl4 at reflux; bHPLC; cIsolated yield; dStarting material (4 %)
was recovered.
1.5 equivalent of NBS (entries 3, 5-7). Increasing the amount
of benzoyl peroxide from 0.12 to 0.17 equivalent improved
the yield of III from 26.8 to 86.3 % and then the yield decreased
to 70.9 % which the equivalent was to 0.18. The optimized
conditions showed that 0.17 equivalent of benzoyl peroxide
and 1.5 equivalent of NBS achieved the good result of III
(88.8 %) with only 5.5 % of III-1 and 4 % of IV was isolated
and recovered.
Synthesis of 1-phenazinemethanol (II): The hydrolyzation
of III to produce II was carried out under the catalyst of a
base in different reaction conditions in our process showed in
Table-2. First, the initial study was conducted on 0.5 % Na2CO3
aqueous solution and the yield was only 20.8 % (entry 1).
Considering to the poor soluble of III in water, two different
reaction system in the mixtures of 0.5 % Na2CO3 aqueous
solution-nonpolar solvent [1,2-dichloroethane and toluene]
were also investigated and gave poor yield, even tetrabutyl-
ammonium bromide (TBAB) was added (entries 2-3). Reac-
tions in polar solvents (EtOH, THF, DMF and 1,4-dioxane)
were further tried for improving the yield (entries 4-7). The
reaction proceeded successfully and the corresponding product
II was obtained in 98.4 % yield in DMF (entry 7). Meanwhile,
the investigations on the effect of the temperature in DMF
revealed that the yield of II was slightly influenced from 60 to
100 °C, but the reaction time could be obvious shorten from
4.5 to 0.5 h (entries 7-9). In addition, different concentrations
of Na2CO3 aqueous solution were studied in DMF. Increasing
of the concentration from 0.1 to 10 (wt %), the yield ranged
from 98.4 to 69.6 % (entries 7, 10-14). Furthermore, some
other bases (K2CO3, NaHCO3, KHCO3, NaOH and KOH) were
screened (entries 15-19), but only K2CO3 gave good yield in
92.8 %. Taking all these into account, II was achieved in 98.4 %
yield in the mixture of 0.5 % Na2CO3 aqueous solution and
DMF at 80 °C for 2 h.
Synthesis of phenazine-1-carboxylic acid (I): Most of
the reported methods for oxidation of primary alcohols to
carboxylic acids were under metal catalysis, including high-
valent metal salts (CrO3, KMnO4, RuO4, RuCl3/H5IO6, etc.)35,
or transition metal (Pd, Ru, W, Re, Cu, etc.)36. However, these
oxidative methods exhibited some limitations, such as stringent
reaction conditions, high cost, high reagent load, or toxicity
of the metal. Recently, several green methods, using O2 as
oxidant and catalyzing by irradiation in the presence of bromo
sources, or a base, were developed37-43. In this paper, a new
method was developed to achieve the target product in the
presence of NBS and azobisisobutyronitrile (AIBN) under O2
TABLE-2
EFFECTS OF REACTION CONDITIONSa ON THE YIELD OF THE COMPOUND II
Entry
1
2
3
4
Solvent
–
Base
Concentration of base (wt %)
Time (h)
10.0
15.0
20.0
30.0
4.0
4.5
2.0
4.5
0.5
9.0
1.5
2.5
1.0
3.5
3.0
4.0
4.5
Yield (%)e
20.8
32.8
47.4
59.4
80.2
96.7
98.4
97.5
80.3
95.2
89.4
82.5
78.1
69.6
92.8
83.2
80.0
72.5
69.4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.8
1.0
5.0
10.0
0.5
0.5
0.5
0.5
0.5
EDCb
Tolueneb
EtOH
THF
5
6
1,4-Dioxane
DMF
7
8c
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9d
10
11
12
13
14
15
16
17
18
19
NaHCO3
KHCO3
NaOH
8.0
KOH
10.0
aReaction conditions: the compound III was in solvents/base aqueous solution mixture (1:1.1, v/v) at 80 °C; Added Bu4NBr as phase transfer
b
catalyst; cThe reaction was at 60 °C; dThe reaction was at 100 °C; eIsolated yield

Vol. 27, No. 9 (2015)
An Improved Synthetic Method of Phenazine-1-carboxylic Acid 3359
TABLE-3
EFFECTS OF REACTION CONDITIONSa ON THE YIELD OF THE COMPOUND I
Content by HPLCb
Entry
Bromo sources
n(II):n(AIBN):n(NBS/Br2)
Yield (%)c
I (%)
14.3
36.5
65.9
100.0
–
II (%)
1
2
3
4
5
6
7
8
NBS
NBS
NBS
NBS
NBS
–
1:0.1:0.1
1:0.1:0.2
1:0.1:0.3
1:0.1:0.4
1:0.1:0.4
1:0.1:0.0
1:1.0:0.4
1:1.0:0.4
76.7
63.5
19.8
0
–
–
9.6
29.4
58.7
98.2
0d
–
–
–
0
Br2
Br2
–
–
Trace
0d
aReaction conditions: the compound II, azobisisobutyronitrile (AIBN) and NBS/Br2 were under O2 atmosphere in anhydrous MeCN at 80 °C;
bHPLC; cIsolated yield; dThe reaction was carried out under N2.
atmosphere, which was an efficient, green and non-metal
process.
Conclusion
In summary, an improved synthetic method to phenazine-
Different equivalent of NBS in 0.1 equivalent of azobisiso-
butyro-nitrile was studied and the results were summarized in
Table-3. The yield of I was improved by increasing the
equivalent of NBS from 0.1 to 0.4 and I was obtained in 98 %
yield with the addition of 0.4 equivalent NBS (entries 1-4).
No reaction occurred when conducting the reaction in N2
atmosphere or in the absence of bromo sources showed the
necessity of both NBS and molecular oxygen (entries 5-6).
Furthermore, Br2 was examined instead of NBS in O2 or N2
and gave bad performances (entry 7-8), which demonstrated
that O2 was the oxidant and NBS/Br2 provided the bromo
radical in the reaction.
Based on these results, a possible mechanism was proposed
as shown in Scheme-III. Firstly, the radical species II-1 was
generated by abstraction of one hydrogen radical with a bromo
radical, formed under the initiation of azobisisobutyronitrile
from NBS. Then, II-1 trapped O2 to afford II-2, which subse-
quently transformed to I via hydroperoxide II-3.
1-carboxylic acid was successfully developed in 66 % yield
with the employment of commercially aviable reagents. The
method involved condensation, bromination, hydrolyzation
and oxidation. The intermediate IV was obtained in one-pot
which is advantageous in workup and reaction time.An improved
protocol was also established for the formation of I by treat-
ment with molecular oxygen in the presence of NBS, in mild,
green and metals-free reaction condition.
ACKNOWLEDGEMENTS
The authors acknowledge the National Key Technology
R&D Program of the Ministry of Science and Technology
(2011BAE06A07-04), the Technology R&D Program of
Jiangsu Province (BE2012363), the Postgraduate Innovation
fund of Jiangsu province (2013, CXZZ13_0459; 2013, CXLX-
13_399) P.R. China.
REFERENCES
1. Y. Hosoya, H. Adachi, H. Nakamura, Y. Nishimura, H. Naganawa, Y.
Okami and T. Takeuchi, Tetrahedron Lett., 37, 9227 (1996).
2. L.S. Thomashow, Curr. Opin. Biotechnol., 7, 343 (1996).
3. M. McDonald, B. Wilkinson, C.W. Van’t Land, U. Mocek, S. Lee and
H.G. Floss, J. Am. Chem. Soc., 121, 5619 (1999).
4. D. Haas, C. Blumer and C. Keel, Curr. Opin. Biotechnol., 11, 290 (2000).
5. C. Pathirana, P.R. Jensen, R. Dwight and W. Fenical, J. Org. Chem., 57,
740 (1992).
OH
HC
N
O2
N
II-1
6. G.R. Rewcastle, W.A. Denny and B.C. Baguley, J. Med. Chem., 30, 843
(1987).
7. E.G.Ahuja, P. Janning, M. Mentel,A. Graebsch, R. Breinbauer, W. Hiller,
B. Costisella, L.S. Thomashow, D.V. Mavrodi and W. Blankenfeldt, J. Am.
Chem. Soc., 130, 17053 (2008).
8. S.M. Delaney, D.V. Mavrodi, R.F. Bonsall and L.S. Thomashow, J.
Bacteriol., 183, 318 (2001).
9. A. Sato, S. Takahashi, T. Ogita, M. Sugano and K. Kodama, Annu.
Rep. Snakyo Res. Lab., 47, 1 (1995).
CH2OH
N
O
OH
O
N
II
N
HBr
N
II-2
10. N. Imamura, M. Nishijima, T. Takadera, K. Adachi, M. Sakai and H.
Sano, J. Antibiot., 50, 8 (1997).
AIBN
NBS
Br
11. S. Fotso, D.A. Santosa, R. Saraswati, J.Yang, T. Mahmud, T.M. Zabriskie
and P.J. Proteau, J. Nat. Prod., 73, 472 (2010).
12. M.S. Abdelfattah, T. Kazufumi and M. Ishibashi, J. Nat. Prod., 73,
1999 (2010).
HO
O
O
OH
HO
13. J.Y. Lee, S.S. Moon and B.K. Hwang, Pest Manage. Sci., 59, 872 (2003).
14. J.M. Turner and A.J. Messenger, Adv. Microb. Physiol., 27, 211 (1986).
15. J.B. Laursen and J. Nielsen, Chem. Rev., 104, 1663 (2004).
16. D.V. Mavrodi, W. Blankenfeldt and A.M.L.S. Thomashow, Annu. Rev.
Phytopathol., 44, 417 (2006).
N
N
N
I
N
H2O
II-3
17. W.T. Clark and J. Sperry, Synlett, 23, 2827 (2012).
Scheme-III: Possible mechanism for the oxidation reaction from II to I

3360 Zhan et al.
Asian J. Chem.
18. H.B. Hu, Y.Q. Xu, F. Chen, X.H. Zhang and B.K. Hur, J. Microbiol.
Biotechnol., 15, 86 (2005).
19. L.S. Thomashow, D.M. Weller, R.F. Bonsall and L.S. Pierson, Appl.
Environ. Microbiol., 56, 908 (1990).
20. D.V. Mavrodi, V.N. Ksenzenko, R.F. Bonsall, R.J. Cook, A.M. Boronin
and L.S. Thomashow, J. Bacteriol., 180, 2541 (1998).
21. J.F. Parsons, F.H. Song, L. Parsons, K. Calabrese, E. Eisenstein and
J.E. Ladner, Biochemistry, 43, 12427 (2004).
22. X.L. Du, Y.Q. Li, W.P. Zhou, Q. Zhou, H.M. Liu and Y.Q. Xu, Appl.
Microbiol. Biotechnol., 97, 7767 (2013).
30. M.Z. Wang, H. Xu, S.J. Yu, Q. Feng, S.H. Wang and Z.M. Li, J. Agric.
Food Chem., 58, 3651 (2010); Y. Omote, T. Hirama and T. Komatsu,
Bull. Chem. Soc. Jpn., 47, 1957 (1974); L.T. Yu, X.G. Zhou, D. Wu
and H.F. Xiang, J. Organomet. Chem., 705, 75 (2012); I.J. Pachter and
M.C. Kloetzel, J. Am. Chem. Soc., 73, 4958 (1951); I.J. Pachter and
M.C. Kloetzel, J. Am. Chem. Soc., 74, 971 (1952); D.B. Paul, Aust. J.
Chem., 25, 2283 (1972).
31. G.W. Rewcastle and W.A. Denny, Synth. Commun., 17, 1171 (1987).
32. Y. Li, S.H. Yu, Y. Guan, C. Lu, L.L. Liu and T.L. Rong, China Patent
CN 103373967 (2013).
23. J.W. Kloepper, R. Lifshitz and R.M. Zablotowicz, Trends Biotechnol.,
7, 39 (1989).
33. H.J. Zhu, X.L. Zhu, G.K. He and G.L. Song, China Patent CN
201210058409X (2013).
24. B.R. Glick, Can. J. Microbiol., 41, 109 (1995).
25. B.R. Glick, C.B. Jacobson, M.M.K. Schwarze and J.J. Pasternak, Can.
J. Microbiol., 40, 911 (1994).
26. B.T. Glick, D.M. Karaturovíc and P.C. Newell, Can. J. Microbiol., 41,
533 (1995).
27. X.Q. Huang, D.H. Zhu, Y.H. Ge, H. Hu, X. Zhang and Y. Xu, FEMS
Microbiol. Lett., 232, 197 (2004).
28. U. Hollstein, J. Heterocycl. Chem., 5, 299 (1968); J.S. Morley, J. Chem.
Soc., 4008 (1952); G. Gaertner, A. Gray and F.G. Holliman, Tetrahe-
dron, 18, 1105 (1962); S.R. Challand, R.B. Herbert and F.G. Holliman,
J. Chem. Soc. D, 1423 (1970); B. Cross, P.J. Williams and R.E. Woodall,
J. Chem. Soc., 2085 (1971).
29. T. Emoto, N. Kubosaki, Y. Yamagiwa and T. Kamikawa, Tetrahedron
Lett., 41, 355 (2000); T. Horaguchi, T. Oyanagi, E.C. Creencia, K.
Tanemura and T. Suzuki, J. Heterocycl. Chem., 41, 1 (2004); M. Tietze,
A. Iglesias, E. Merisor, J. Conrad, I. Klaiber and U. Beifuss, Org. Lett.,
7, 1549 (2005); E.G. Ahuja, P. Janning, M. Mentel, A. Graebsch, R.
Breinbauer, W. Hiller, B. Costisella, L.S. Thomashow, D.V. Mavrodi
and W. Blankenfeldt, J. Am. Chem. Soc., 130, 17053 (2008).
34. I. Yosioka and K. Ueda, Chem. Pharm. Bull. (Tokyo), 12, 1247 (1964).
35. J.G. Millar, A.C. Oehlschlager and J.W. Wong, J. Org. Chem., 48, 4404
(1983); M. Zhao, J. Li, Z. Song, R. Desmond, D.M. Tschaen, E.J.J.
Grabowski and P.J. Reider, Tetrahedron Lett., 39, 5323 (1998); P.H.J.
Carlsen, T. Katsuki, V.S. Martin and K.B. Sharpless, J. Org. Chem.,
46, 3936 (1981); L.M. Berkowitz and P.N. Rylander, J. Am. Chem. Soc.,
80, 6682 (1958); R.S. Varma and M.E. Hogan, Tetrahedron Lett., 33,
7719 (1992).
36. I.A.Ansari and R. Gree, Org. Lett., 4, 1507 (2002); P. Gamez, P.G.Aubel,
W.L. Driessen and J. Reedijk, J. Chem. Soc. Rev., 30, 376 (2001); R. Liu,
C. Dong, X. Liang, X. Wang and X. Hu, J. Org. Chem., 70, 729 (2005).
37. S. Ohta, T. Tachi and M. Okamoto, Synthesis, 291 (1983).
38. X. Wang and D.Z. Wang, Tetrahedron, 67, 3406 (2011).
39. J. Wang, C. Liu, J. Yuan and A. Lei, New J. Chem., 37, 1700 (2013).
40. K. Kuwabara and A. Itoh, Synthesis, 1949 (2006).
41. S.I. Hirashima, S. Hashimoto, Y. Masaki and A. Itoh, Tetrahedron, 62,
7887 (2006).
42. S.I. Hirashima and A. Itoh, Synthesis, 1757 (2006).
43. T. Sugai and A. Itoh, Tetrahedron Lett., 48, 9096 (2007).