A new combination of cyclohexylhydrazine and IBX for oxidative generation of cyclohexyl free radical and related synthesis of parvaquone

Article abstract of DOI:10.1016/j.tetlet.2017.04.006

The present paper demonstrates a single-step and straightforward synthesis of parvaquone through intermediacy of cyclohexyl radical generated from novel combination of cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-naphthoquinone. Formation of cyclohexyl free radical using this new combination was reaffirmed by cyclohexylation of readily available 2-amino-1,4-naphthoquinone.

Full text of DOI:10.1016/j.tetlet.2017.04.006

Accepted Manuscript
A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation
of Cyclohexyl Free Radical and Related Synthesis of Parvaquone
Pravin C. Patil, Krishnacharya G. Akamanchi
PII:
S0040-4039(17)30429-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.006
TETL 48798
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 March 2017
29 March 2017
2 April 2017
Please cite this article as: Patil, P.C., Akamanchi, K.G., A New Combination of Cyclohexylhydrazine and IBX for
Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.006
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Graphical Abstract
A New Combination of Cyclohexylhydrazine and IBX Leave this area blank for abstract info.
for Oxidative Generation of Cyclohexyl Free Radical
and Related Synthesis of Parvaquone
Pravin C Patil* and Krishnacharya G Akamanchi
NH2
O
O
HN
•
•
•
Novel, simple and mild transformation
Satisfactory yield of 60% in single step
Free from transition metals and hazardous peroxides
IBX, ACN
+
OH
2.5 h, rt. 60%
OH
O
Lawson
O
Parvaquone, 1
Cyclohexylhydrazine

1
Tetrahedron Letters
journal homepage: www.els evier.com
A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free
Radical and Related Synthesis of Parvaquone
*
Pravin C. Patila and Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai-400 019.
aPresent address: 2320 S Brook Street, Department of Chemistry, University of Louisville, Louisville, KY-40217, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The present paper demonstrate a single-step and straightforward synthesis of parvaquone
through intermediacy of cyclohexyl radical generated from novel combination of
cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-
naphthoquinone. Formation of cyclohexyl free radical using this new combination was
reaffirmed by cyclohexylation of readily available 2-amino-1, 4-naphthoquinone.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Parvaquone
Oxidation
Cyclohexylhydrazine
IBX
Quinones,
including
1,4-benzoquinones
and
1,4-
is caused due to parasite Theileria parva.9 According to the study
done, there is annual loss of 1.1 million cattle and more than 250
million are at risk due to lack of effective treatment of
Theileriosis.9a
naphthoquinones are ubiquitous in nature and essentially
contributed into wide range of pharmaceutical and natural
products.1 Specifically, hydroxylated naphthoquinones are
precisely known to have remarkable biological activities such as
These
cyclohexylated
naphthoquinone
drugs
are
antifungal,
anti-inflammatory,
antiallergic,
antiplatelet,
Hydroxylated
predominantly synthesized through trapping of corresponding
cyclohexyl free radicals by related naphthoquinones
antibacterial, antibiotic and apoptosis.2
naphthoquinones bearing alicyclic rings at 2 or 3 positions are
widely used for suppression of trophozoites in ducks, chickens
and monkeys infected with blood induced malaria.3 For example,
2-cyclohexyl-3-hydroxy-1,4-naphthoquinone
(marketed as Clexon), 1) and
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione
(atovaquone, 2) are leading members of this class due to their
clinically useful antiprotozoal activities.4-8 (Fig. 1).
counterparts.10-11 Parvaquone
1
was synthesized through
generation of cyclohexyl free radical A in the presence of
2-hydroxy-1, 4-naphthoquinone 3 by using various approaches
10
(parvaquone
trans-2-[4-(4-
(Scheme 1).3,
First report on cyclohexyl radical mediated
synthesis of parvaquone was disclosed by Fieser and Leffler
while generating cyclohexyl free radical thermally from
cyclohexanecarboperoxoic acid 4 in the presence of lawson 3 to
afford 1 in 45% yield3 (Scheme 1, path a). Later on, Amini and
Huyser demonstrated synthesis of 1 in 53% yield through
generating cyclohexyl free radical from cyclohexane 5 by using
tert-butyl peroxide as radical initiator in the process10a(Scheme 1,
path b).
Cl
O
O
O
O
OH
OH
OH
(i), path a
O
O
O
Atovaquone, 2 (antimalarial)
Parvaquone, 1 (antiprotozoal)
4
O
OH
(ii), path b
O
3
Fig. 1. Clinically used alicyclic hydroxylated naphthoquinone drugs.
Atovaquone 2 has been used for Pneumocystis carinii
OH
5
OH
O
A
O
1
pneumonia (PCP),
a
parasitic lung infection of
(iv), path d
immunocompromised patients.5 Additionally, it has been also
used in the treatment of malaria,6 toxoplasmosis7 and babesiosis.8
On the other hand, parvaquone is gaining remarkable importance
towards controlling a devastating cattle disease, Theileriosis
(East Coast Fever) in central and eastern African countries which
6
Reagents and conditions: (i) HOAc, 100 °C, 45%. (ii) (CH3)3COOC(CH3)3, 125 °C, 53%.
(iii) Cu(OTf)2, TBHP, 80 °C, 6 h, 72%. (iv) AgNO3/(NH4)2S2O8, ACN/H2O, 65-70 °C, 25%.
Scheme 1. Various approaches for cyclohexyl radical mediated synthesis
of parvaquone 1.

2
Tetrahedron Letters
Recently, Lee and coworkers also described synthesis of 1
We inferred that the formation of nitrogen gas during the course
through generation of cyclohexyl radical from cyclohexane in
of reaction might be due to oxidation of 8 by IBX.
presences of tert-butyl hydroperoxide and copper (II) triflate at
0
80 C provided 1 in 72% yield after 6 h 10b (Scheme 1, path c).
Khambay and Batty contributed by demonstrating new method
through
generating
cyclohexyl
free
radical
from
cyclohexanecarboxylic acid 6 using a combination of silver
nitrate/ammonium persulfate to provide 1 in 25% yield10c
(Scheme 1, path d).
Aforementioned synthetic methods retain their disadvantages
of affording low yields due to formation of by-product,10c
10a
requirement of high temperature,3,
uses of hazardous
peroxides10a and expensive catalyst such as AgNO3. Besides
free radical based methods, there are few reports available for the
synthesis of 112a and its derivatives12bcomprising multistep
approaches. Use of Grignard reagents, cryogenic reaction
conditions and requirement of special handling for reagents
restricted these processes from being generalized.12 A step
forward towards overcoming these problems was our latest
development of transition metals free, simple and efficient four
steps process by using cheaply and commercially available raw
materials such as 1-naphthol and cyclohexanol under mild
conditions.13
10c
Scheme 2. IBX mediated oxidative arylation and cyclohexylation of 3.
After completion of reaction, crude product was isolated and
purified by using column chromatography. Spectral
characterization data of the isolated pure product confirmed the
formation of parvaquone, 1 in satisfactory yield of 60% (Scheme
2, path b).
To reaffirm the formation of cyclohexyl free radical using this
Recently, we have disclosed novel combination of
arylhydrazine and IBX for oxidative generation of aryl free
radical and subsequently trapping by differently substituted
naphthoquinones14 and anilines15 resulting in new methods for C-
and N-arylations, respectively. On the same lines as IBX
mediated oxidative free radical arylation of naphthoquinones
(Scheme 2, path a) and considering the potential of 3 to trap
cyclohexyl free radical (Scheme 1, path a-d), we envisaged that if
cyclohexyl free radical gets formed by combination of
cyclohexylhydrazine 8 and IBX, it would be trapped by 3
ultimately leading to a novel route for synthesis of parvaquone 1
(Scheme 2, path b). To attest this hypothesis we choose 3 and 8
as starting materials. Requirement of 8 was fulfilled by
synthesizing it using literature procedure. 16
new combination of cyclohexylhydrazine
8
and IBX,
cyclohexylation of readily available 2-amino-1, 4-
naphthoquinone 10 was attempted. Thus when the reaction was
performed using 10 as substrate under the same reaction
conditions expected product 2-amino-3-cyclohexyl-1, 4-
naphthoquinone, 11 was isolated in satisfactory yield of 58%
(Scheme 3).
NH2
O
O
HN
IBX, ACN
2.5 h, rt
+
NH2
NH2
O
O
10
8
11, 58% yield
Scheme 3. IBX mediated synthesis of 2-amino-3-cyclohexyl-1, 4-
naphthoquinone, 11.
When to a mixture of 3 and IBX in acetonitrile was added
dropwise 8 at room temperature, immediately evolution of
nitrogen gas in the form of bubbles was observed.
OH
O
I
O
NH2
O
HN
H
N
OH
OH
N
I
O
H
O
OH
O
8
1
B
O
HO
I
H2O
O
D
O
IBA
N
NH
O
H
12
O
OH
OH
I
O
O
O
O
E
O
HO
OH
HO
OH
O
HO
N
I
I
SET
3
N
O
O
O
C
D
A
N2
Scheme 4: Cyclohexyl radical mediated postulated mechanism for formation of 1.

3
In our previous studies on arylation of naphthoquinones it has
been proved, through radical trapping experiments, that the
combination of arylhydrazine and IBX generates aryl free
radicals.14-15 On the same lines we postulate cyclohexyl free
radical mediated mechanism for the reaction leading to formation
of 1 (Scheme 4). Attack of cyclohexylhydrazine on electrophilic
iodine of IBX would form intermediate B which on redox
decomposition may form cyclohexyldiazine 12 and
o-iodosobenzoic acid (IBA). Further highly nucleophilic 12
would attack on another molecule of IBX forming an
intermediate C. Intermediate C on oxidative extrusion of
nitrogen would leave behind two free radical species A and D by
single electron transfer mechanism demonstrated by Nicolaou et
al.17 Cyclohexyl free radical A would then attack on unsubstituted
electrophilic position of corresponding quinoid ring of 3 to form
1 after removal of water molecule presumed through interaction
of free radical intermediates E and D. Observance of evolution of
nitrogen gas during the course of reaction and recovery of IBA as
a by-product are found supportive toward the postulated radical
mediated mechanism.
In conclusion, we have established a novel protocol for
generation of cyclohexyl free radical alongside a new, mild, and
single step method for synthesis of parvaquone. This new method
could be considered as competent alternative to the previously
reported free radical based methods as it circumvent toxic
transition metals, hazardous peroxides, high temperature and
longer reaction time. We believe that the developed method
could be considered as valuable entry not only for parvaquone
but also toward exploration of synthesis of other similar
molecules through combination of appropriate hydrazines and
IBX. A free radical mediated mechanism is postulated for the
reaction based on observations and previously established IBX
chemistry.
TLC (using mobile phase, hexane: ethyl acetate/5:95). After
satisfactory TLC, water (20 mL) was added to the reaction
mixture and acetonitrile was evaporated using rotary evaporator.
To the residue obtained was added dichloromethane (30 mL).
Oganic layer was separated and washed with saturated sodium
bicarbonate solution followed by saturated solution of sodium
sulphite. Separated organic layer was dried over anhydrous
sodium sulphate and evaporated to obtain crude 1 which was
further purified by column chromatography (mobile phase -
hexane: ethyl acetate/5:95) to afford 1 as yellow solid, (0.88 g,
60% yield); mp 136-138 °C (lit.18 135-136°C); FT-IR (KBr):
3585, 3513, 3071, 2926, 2853, 1666, 1604, 1590 cm-1; 1H NMR
(300 MHz; CDCl3): δ 1H NMR (400 MHz, CDCl3): δ 8.17-7.96 (m,
2H), 7.82-7.59 (m, 2H), 7.34 (s, 1H, OH), 3.22-2.85 (m, 1H), 1.85-
1.12 (m, 10H) ppm; 13C NMR (75 MHz; CDCl3): δ 184.5, 181.9,
152.8, 135.1, 134.9, 132.7, 129.2, 127.9, 126.9, 125.9, 35.1, 29.2,
26.7, 25.9.
Synthesis of 2-amino-3-cyclohexyl-1,4-naphthoquinone (11):
Above mentioned procedure for synthesis of 1 was similarly
followed for synthesis of 11 by using 10 (1.0 g, 5.77 mmol), IBX
(3.87 g, 13.8 mmol) and cyclohexylhydrazine (0.79 g, 6.92
mmol) to provide 11 as orange red solid, (0.85 g, 58% yield); mp
125-128 °C; FT-IR (KBr): 3466, 3372, 3071, 2926, 2853, 1666,
1604, 1575, 1446, 1384 and 1282 cm-1; H NMR (300 MHz;
1
CDCl3): δ 8.05-7.98 (dd, J = 21 Hz, 2H), 7.67-7.58 (dd, J = 27
Hz, 2H), 5.24 (s, broad, 2H), 2.78 (m, 1H), 1.93-1.34 (m, 10H);
13C NMR (75 MHz; CDCl3): δ 182.6, 181.8, 144.3, 134.0, 133.2,
131.6, 129.9, 126.0, 125.3, 120.4, 36.4, 29.0, 26.8, 25.8; Anal.
Calcd for C16H17NO2: C, 75.33; H, 6.68; N, 5.45; Found: C,
75.29; H, 6.66; N, 5.49.
References and notes
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Acknowledgements: We are thankful to TEQIP (Technical
Education Quality Improvement Program) for providing financial
support to this work.
Supplementary Material: 1H NMR for compound 1 and 1H, 13C
NMR spectra for compound 11 are can be found, in the online
version at http://dx.doi.org/j.tetlet.
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Note: *Corresponding author: Pravin C Patil. Tel: +91-22-3361102.
Email: pravinchem@gmail.com.
Experimental
General Methods: Commercial grade solvents and reagents were
used without further purification. Silica gel-G plates (Merck)
were used for TLC analysis. Column chromatography was
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resonance (1H and l3C NMR) spectra were recorded with Bruker
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Typical procedure and characterization data for compound 1
and 10:
Synthesis
of
2-cyclohexyl-3-hydroxy-1,4-naphthoquinone
(parvaquone) (1): To a solution of 3 (1.0 g, 5.74 mmol) in
acetonitrile (20 mL) was added IBX (3.80 g, 13.6 mmol) in one
lot and stirred for 5 min at room temperature. To this was added
dropwise a solution of 8 (0.78 g, 6.8 mmol) dissolved in 10 mL
of acetonitrile over the course of 20 min. During the addition of 8
exotherm (up to 35 °C) was observed with evolution of nitrogen
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Highlights
•
•
•
•
New method of generating cyclohexyl radical by using IBX and cyclohexylhydrazine.
Parvaquone synthesized in 60% yield using metal, hazardous peroxide free conditions.
Described method has advantages of single step and mild reaction conditions.
The mechanism for cyclohexyl radical mediated synthesis of parvaquone is postulated.