Synthesis of 3h-quinazolin-4-ones and 4h-3,1-benzoxazin-4-ones via benzylic oxidation and oxidative dehydrogenation using potassium iodide-tert-butyl hydroperoxide

Article abstract of DOI:10.1002/adsc.201000580

A simple and elegant method for benzylic activation was demonstrated employing the potassium iodide/tert-butyl hydrogen peroxide catalytic system. This methodology was further extended for the synthesis of biologically important heterocycles namely, 3H-quinazolin-4-ones and 4H-3,1-benzoxazin-4-ones including mecloqualone and etaqualone which are important quinazolinone-based drugs used for the treatment of insomnia in good yields.

Full text of DOI:10.1002/adsc.201000580

FULL PAPERS
DOI: 10.1002/adsc.201000580
Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-ones
via Benzylic Oxidation and Oxidative Dehydrogenation using
Potassium Iodide-tert-Butyl Hydroperoxide
R. Arun Kumar,a,b C. Uma Maheswari,a,b Satheesh Ghantasala,a C. Jyothi,a
and K. Rajender Reddya,*
a
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 607,
India
Fax : (+91)-040-2716-0921; e-mail: rajender@iict.res.inrajenderkallu@yahoo.com
R. Arun Kumar and C. Uma Maheswari shall be considered as equal first authors.
b
Received: July 22, 2010; Revised: November 10, 2010; Published online: February 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000580.
Abstract: A simple and elegant method for benzylic zin-4-ones including mecloqualone and etaqualone
activation was demonstrated employing the potassi- which are important quinazolinone-based drugs used
um iodide/tert-butyl hydrogen peroxide catalytic for the treatment of insomnia in good yields.
system. This methodology was further extended for
the synthesis of biologically important heterocycles Keywords: 4H-3,1-benzoxazin-4-ones; oxidation; per-
namely, 3H-quinazolin-4-ones and 4H-3,1-benzoxa- oxides; potassium iodide; 3H-quinazolin-4-ones
Introduction
which on subsequent addition to an amine yields the
desired product.[11] Other synthetic routes include the
3H-Quinazolin-4-ones and 4H-3,1-benzoxazin-4-ones microwave-assisted three-component methodology
(Figure 1) are core structural subunits that exist in a from anthranilic acids,[12] solvent-free synthesis from
number of bioactive natural products.[1] 3H-Quinazo- isatoic anhydride and orthoester with primary amine
lin-4-ones exhibit a broad spectrum of biological and employing silica-sulphuric acid (SSA)[13a] and a solid-
pharmaceutical activities including antihypertensive,[2] phase traceless synthesis.[13b] Recently, Alper and co-
antidiabetic,[3] anti-inflammatory,[4] antibacterial,[5] an- worker reported the synthesis of quinazolin-4-(3H)-
ticonvulsant,[6] antitumor,[7] central nervous system ones through palladium (Pd)-catalyzed cyclocarbony-
(CNS) depressant[8] and diuretic[9] activities. Along lation of o-iodoanilines with imidoyl chlorides and
similar lines, 2-substituted-4H-3,1-benzoxazin-4-ones carbon monoxide.[14] Similarly, several methods have
compounds act as chymotrypsin inactivators,[10a] inhib- been reported for the synthesis of 2-substituted-4H-
itors of human leukocyte elastase[10b,c] and serine pro- 3,1-benzoxazin-4-ones, primarily from anthralinic acid
tease.[10d]
or its derivatives. Other notable methods include oxi-
Conventional methods for the preparation of 3H- dation of 2-substituted indoles and 2-phenylindolenin-
quinazolin-4-ones employ the coupling of 2-amino- 3-one, electrochemical cyclization of o-trichloroace-
benzoic acid or its derivatives with acyl chloride or
tylanilides, rearrangement of 2-phenylisatogen, etc.[15]
ACHTUNGTRENNUNG
carboxylic acid anhydride to give benzoxazinone Another strategy was through the Pd-catalyzed car-
bonylation of o-iodoanilines with unsaturated ha-
AHCTUNGTRENNUNG
lides,[16a] triflates,[16b] or acid chlorides[16c] in the pres-
ence of CO. However, in terms of substrate scope,
yields and the reaction conditions, these methods
suffer from one or more drawbacks.
For the last few years we have been focussing on
catalytic oxidative organic transformations using non-
transition metals, particularly with halogens and their
derivatives. In this regard, we have reported previous-
Figure 1. Basic structures of 3H-quinazolin-4-ones and 4H-
3,1-benzoxazin-4-ones.
Adv. Synth. Catal. 2011, 353, 401 – 410
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
401

R. Arun Kumar et al.
FULL PAPERS
ly that the combination of a catalytic amount of po- Results and Discussion
tassium iodide (KI) in the presence of 70% tert-butyl
hydroperoxide in water (TBHP) as the external oxi- Benzylic Oxidation using KI/TBHP
dant is effective for various oxidative transforma-
tions.[17] Recently, we have also demonstrated the con- During our earlier investigation on the selective oxi-
struction of heterocycles like 2-quinazolines and 4H- dation of aromatic amines to nitro compounds with
benzo[d]ACHTUNGTRENNUNG[1,3]oxazines via cross-dehydrogenative cou-
pling using commercially available NaOCl.[18] Herein,
we wish to report a new strategy for the synthesis of
3H-quinazolin-4-ones and 4H-3,1-benzoxazin-4-ones
via benzylic oxidation using potassium iodide/tert-
butyl hydrogen peroxide (KI-TBHP).
Scheme 1. Oxidation of 2-aminofluorene to 2-nitro-9-fluore-
none using KI-TBHP.
Table 1. Optimization studies for benzylic oxidation.[a]
[a]
Reaction conditions: diphenylmethane (1 mmol), catalyst, oxidant, CH3CN (3 mL),
21 h.
[b]
Conversions based on GC with respect to diphenylmethane.
402
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 401 – 410

Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-ones via Benzylic Oxidation
Table 2. Screening of solvents for benzylic oxidation.[a]
the KI-TBHP system,[17b] the reaction with 2-amino-
fluorene resulted in the formation of 2-nitro-9-fluore-
none, which provided us the initial clue for benzylic
oxidation with our catalytic system (Scheme 1).
Initially, we focused our attention on the benzylic
oxidation of alkylarenes to yield their corresponding
carbonyl compounds. Diphenylmethane was chosen
as the model substrate for optimization studies. First,
the role of the catalyst was ascertained by doing back-
ground experiments. No product was observed with
20 mol% of KI. A very low product conversion was
observed with 70% aqueous TBHP at room tempera-
ture and CH3CN as solvent (Table 1, entries 1 and 2).
Under similar reaction conditions, use of 20 mol% of
KI and 3.0 equivalents of oxidant afforded 78% of
oxidized product (Table 1, entry 3), which clearly es-
tablished the role of the catalyst for the benzylic oxi-
dation. Furthermore, screening of various oxidants,
such as hydrogen peroxide (30% v/v solution of
H2O2), NaOCl (approx 4% w/v of available chlorine),
urea hydrogen peroxide (UHP) and m-chloroperben-
zoic acid (mCPBA) (3 equivalents of oxidants are
[a]
[b]
Reaction conditions: diphenylmethane (1 mmol), solvent
(3 mL), 21 h.
Conversions based on GC with respect to diphenylme-
thane.
taken in all these cases) could not improve the prod- NH3, CH3CN and water. Although the maximum con-
uct conversion. The reaction did not proceed, when it version was observed in water, owing to its limitation
was performed only with molecular iodine (I2) with respect to substrate solubility, CH3CN was
(Table 1, entry 10). Similarly, no improvement was ob- chosen as the solvent of choice for further studies.
served on variation of the catalyst and oxidant ratio Thus, 20 mol% of KI in conjunction with 3 mmol of
(KI:TBHP varied from 0.1:2.0, 0.2:3.0 and 0.2:3.8). TBHP as oxidant in CH3CN at room temperature
Hence, further solvent variations were carried out at proved to be the best reaction conditions (Table 1,
room temperature (Table 2). The yields were low with entry 3).
CH2Cl2, THF, EtOAc, toluene, MeOH. Moderate to
The general applicability of this method was evalu-
good conversions are observed with t-BuOH, aqueous ated for structurally diverse alkylarenes (Scheme 2).
Scheme 2. Benzylic oxidation of alkylarenes catalyzed by KI-TBHP.
Adv. Synth. Catal. 2011, 353, 401 – 410
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
403

R. Arun Kumar et al.
FULL PAPERS
The reaction proceeds smoothly producing the re-
quired carbonyl compounds in moderate to excellent
yields. In the case of indan, the reaction was slow and
42% of 1-indanone (Scheme 2, 2c) was formed after
48 h. We have also observed the hydroxy derivative,
i.e., 1-indanol as minor product, which was deter-
mined by GC and confirmed by GC-MS. In the case
of 9,10-dihydroanthracene, the dicarbonyl product,
9,10-anthracenedione was formed with 6 equivalents
of oxidant (Scheme 2, 2e). When oxygen is present in
the ring adjacent to the benzylic position, as in the
case of 1,3-dihydroisobenzofuran and isochroman, the
desired products were obtained in excellent yields
after shorter reaction times (Scheme 2, 2g, 2h). For
fluorene derivatives, the reactivity depends on the
substituent present. Thus fluorene gave the required
fluorenone
almost
quantitatively
within
9 h
(Scheme 2, 2j), whereas when electron-withdrawing
bromine or acetyl groups are present on the aromatic
ring, the reaction was found to be slow (Scheme 2, 2k,
2l). In the case of N-heterocycles, instead of benzylic
oxidation, the reaction proceeds to aromatization of
the heterocyclic ring (Scheme 2, 2m–o).
Scheme 3. Synthesis of 3H-quinazolin-4-ones and 4H-3,1-
benzoxazin-4-ones via benzylic oxidation.
One-Pot Synthesis of 3H-Quinazolin-4-ones via
Benzylic Oxidation and Oxidative Dehydrogenation
À
The higher activity of the benzylic C H bond adja- coupling partner, i.e., N-(2-aminobenzyl)aniline (5a)
cent to a heteroatom like oxygen and nitrogen as well was synthesized from 2-nitrobenzaldehyde (3) via re-
as our earlier work on the synthesis of 2-quinazolines ductive amination to yield 4a followed by further re-
and 4H-benzo[d]ACHTUNGTRENUNG
[1,3]oxazines via cross-dehyderoge- duction.[19] Initial studies were performed by treating
native coupling prompted us to explore the KI-TBHP 5a with benzaldeyhde in ethanol to yield the cyclic
system for the synthesis of 3H-quinazolin-4-ones and product 6a which, on further treatment with KI/
4H-3,1-benzoxazin-4-ones (Scheme 3). For this we TBHP, resulted in the desired product 8a along with
have synthesized substituted N-(2-aminobenzyl)- 4-tert-butylperoxy-2,3-diphenylquinazoline (7a) as the
ACHTUNGTRENNUNGamines as the starting material, presuming that ben- major product. The product 7a was isolated and char-
1
zylic oxidation will take over the aromatization of the acterized by H NMR. The formation of 7a was rather
condensed cyclic product. obvious, considering the literature precedents for this
A schematic representation for the synthesis of 3H- intermediate in oxidative iminium ion formation from
quinazolin-4-ones is given in Scheme 4. The initial tertiary amine with TBHP as the oxidant.[20,21] How-
Scheme 4. Synthesis of 2,3-diphenyl-3H-quinazolin-4-one using the KI/TBHP catalytic system.
404
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 401 – 410

Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-ones via Benzylic Oxidation
Table 3. Synthesis of 2,3-substituted-3H-quinazolin-4-ones using KI/TBHP.
[a]
Yields refer to the isolated yield of pure products.
Acetaldehyde was dropped slowly into the solution of N-(2-aminobenzyl)substituted amines in ethanol at 08C.
[b]
ACHTUNGTRENNUNGever, when 7a was further treated with piperidine, the 8a–8e). On the other hand, reactions with o-substitut-
desired product 8a was obtained in quantitative yield ed N-(2-aminobenzyl)aniline resulted in lower yields,
via Kornblum-type decomposition which was finally which may be due to the steric influence (Table 3, 8f,
1
confirmed by H NMR and ESI-MS.[22]
8g). With aliphatic N-(2- aminobenzyl)amines, the
Further reactions were performed in one-pot with- yields were good irrespective of the aldehyde variant
out isolating the peroxy ether intermediates 7. Vari- (Table 3, 8i and 8j). Some of these molecules possess
ous N-(2-aminobenzyl)-substituted amines were cou- biological importance and were used in quinazoli-
pled with structurally diverse aromatic and aliphatic none-based drugs. For example, mecloqualone (8g)
aldehydes to obtain 2,3-substituted 3H-quinazolin-4- and etaqualone (8h) have sedative, hypnotic and anx-
ones (Table 3). When N-(2-aminobenzyl)aniline was iolytic properties, and are used for the treatment of
taken as the amine variant along with various substi- insomnia. Similarly NPS 53574 (8l) is found to be
tuted benzaldehydes and aliphatic aldehydes, there potent calcium receptor antagonist.
was no appreciable change in terms of yields (Table 3,
Adv. Synth. Catal. 2011, 353, 401 – 410
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
405

R. Arun Kumar et al.
FULL PAPERS
Synthesis of Benzo[d]
Oxidation and Oxidative Dehydrogenation
[1,3]oxazin-4-ones via Benzylic
With the optimized reaction condition in hand, we
have performed the reactions with pre-synthesized 2-
substituted 4H-benzo[d]
The above strategy was further applied for the synthe- Irrespective of the electronic nature of the substrates,
sis of 2-phenylbenzo[d][1,3]oxazin-4-one using 2-ami- all the oxidized products 12a–e were obtained in mod-
ACHTUNGTNER[NUNG 1,3]oxazines 11a–e (Table 5).
AHCTUNGTRENNUNG
nobenzyl alcohol as the coupling partner. Under simi- erate to good yields.
lar reaction conditions, treatment of 2-aminobenzyl
alcohol with benzaldehyde yielded the cyclized prod-
uct which, on further oxidation with KI/TBHP, result- Mechanistic Considerations
ed in 2-phenylbenzo[d]ACTHNUTRGNE[NUG 1,3]oxazin-4-one (12a) in a
trace amount along with undesired products. So, in- Although the exact mechansim is not clear right now,
stead of performing the reaction in one pot, we have a possible pathway involving three key steps for the
synthesized 2-phenyl-4H-benzo[d]ACTHNUTRGNEUG[N 1,3]oxazine (11a) formation of 3H-quinazolin-4-ones is shown in
by our earlier reported method[18] which, on further Scheme 6. The first step involves the oxidation of KI
treatment with KI/TBHP at room temperature, result- with TBHP to molecular iodine and potassium hy-
ed in the desired product 12a along with the cleaved droxide, which subsequently oxidizes the cyclic com-
product 13a (Scheme 5).
Experiments for optimization of the conditions for the second step. Finally, the intermediates react with
the construction of 2-penylbenzo[d][1,3]oxazin-4-one one equivalent of TBHP to form the product 7, which
(12a) from 2-phenyl-4H-benzo[d][1,3]oxazine (11a) was isolated and well characterized. The following ex-
pound 6 to hypothetical intermediates In1 and In2 in
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
with different solvents and oxidants are given in periments have been carried out to establish the
Table 4. Control runs showed that the catalyst was above proposed mechanism.
crucial for this oxidative transformation (Table 4, en-
To prove that TBHP oxidizes KI to iodine, a blank
tries 1–3). Screening of various solvents, such as THF, reaction with 0.2 mmol of KI in the presence of
1,4-dioxane, DCM, DMSO and DMF did not improve 3 equivalents of TBHP in water as well as CH3CN
the yield of the desired product (Table 4, entries 4–8). was performed, where we could observe an immedi-
When the reaction was examined with different oxi- ate change in colour (dark brown solution). The liber-
dants such as H2O2, urea hydrogen peroxide, ation of iodine was further confirmed by addition of
mCPBA, TBHP in decane and NaOCl, the yields starch solution which instantaneously changed to
were negligible (Table 4, entries 9–13). There was no bluish black. The liberation of iodine occurs very rap-
significant improvement in yield of the desired prod- idly (within 1 min) which is much faster than the time
uct when molecular iodine was used as the catalyst scale of our reaction. Apart from the formation of I2
(Table 4, entry 15). When the reaction was carried out and KOH in the first step, the involvement of other
with iodine (I2) as an oxidant, it did not proceed species such as t-BuOI cannot be ruled out. It has
(Table 4, entry 16). There was a dramatic decrease in been reported that under alkaline conditions iodine
the yield when a lesser amount of oxidant was em- participates in multiple equilibria, in which hypoio-
ployed (Table 4, entry 17). From these optimization dous acid is one of the possible intermediates.[23]
A
studies it is clear that 0.2 equivalents of KI as catalyst, similar intermediate was also proposed under acidic
3.8 equivalents of TBHP as oxidant in 3 mL of conditions with NaI and H2O2 in the a-iodination of
CH3CN under reflux conditions proved to be the best ketones.[24]
(Table 4, entry 14).
Regarding the second step, we have performed two
experiments, one with cyclic product 6 in the presence
Scheme 5. Synthesis of 2-phenylbenzo[d]ACTHNUGTRNEUNG[1,3]oxazin-4-ones using KI/TBHP.
406
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 401 – 410

Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-ones via Benzylic Oxidation
Table 4. Optimization of the reaction conditions for construction of 2-subsitituted
benzo[d]
ACHTUNGTRENNUNG
[a]
Reaction conditions: 11a (1 mmol), catalyst (0.2 equiv.), oxidant (3.8 equiv.), sol-
vent (3 mL).
Conversion based on GC with respect to 11a.
Reaction was carried out at 808C for 6 h.
3 equiv. of TBHP were used.
[b]
[c]
[d]
Adv. Synth. Catal. 2011, 353, 401 – 410
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
407

R. Arun Kumar et al.
FULL PAPERS
Table 5. Synthesis of 2-subsitituted benzo[d]ACTHNURTGNEU[GN 1,3]oxazin-4-
to occur through benzylic tert-amine oxidation in the
presence of I2 and base,[20] which upon nucleophilic
capture yield 7.[21] Treatment of 7 with piperidine
yields the desired product 8 through a Kornblum-type
decomposition.[22]
ones using KI/TBHP.[a]
To investigate the possibility for the generation of
any radical type of intermediates, the reaction was
performed by adapting the earlier reported proce-
dure.[25] To a solution of N-(2-aminobenzyl)aniline
(5a) (3 mmol) in 12 mL of ethanol, benzaldehyde
(3 mmol) was added and stirred at room temperature
for 5 h. To the same solution KI (0.6 mmol) was
added and the reaction vessel was sealed with a
septum, allowing inclusion of air. An empty balloon
was added to capture any oxygen generated during
the course of the reaction. To the reaction mixture
70% TBHP in H2O (2.1 mL, 5 equivalents) was added
in one portion via syringe and stirred at room temper-
ature for 6 h. There was no inflation of the balloon
suggesting that there is no oxygen evolution, implying
that there is no formation of radical intermediates,
i.e., tert-butylperoxy radical, which is known to dimer-
ize to di-tert-butyl tetraoxide which in turn releases
oxygen.[25]
In similar lines, the conversion of 11 to 12 occurs
via oxidation followed by ring cleavage to yield In3,
which is equilibrium with In4. The intermediate In3
1
was isolated and characterized by H NMR and ESI-
mass spectral analysis.
Conclusions
In summary, we have demonstrated an elegant and
À
simple method for benzylic C H oxidation using KI/
TBHP as the catalytic system. By employing the same
catalytic oxidation strategy, we have demonstrated
the construction of biologically important heterocy-
cles, namely, 3H-quinazolin-4-ones and 4H-3,1-ben-
zoxazin-4-ones, including mecloqualone and etaqu-
alone which are important quinazolinone-based drugs
used for the treatment of insomnia. Further research
on the application of this methodology for the synthe-
sis of biologically important molecules having 3H-qui-
nazolin-4-ones and 4H-3,1-benzoxazin-4-ones as a
core structure is ongoing in our laboratory.
[a]
Reaction conditions: 11a–e (1 mmol), KI (0.2 mmol),
TBHP (3.8 equiv.), CH3CN (3 mL), 808C, 6 h. Yields
refer to the isolated yield of pure products.
of three equivalents of I2 and KOH and the second
one with I2 and KOH with cyclic product 6 in the
presence of TBHP. In the former case we could not
observe any product, however, in the later case we
have observed a small amount of 7 along with some
undesired products. This clearly indicates the unstable
nature of intermediates In1 and In2 which require the
presence of TBHP for the formation of product 7.
Experimental Section
General Procedure for Benzylic Oxidation of
Alkylarenes
To a solution of alkylarene (1.0 mmol), potassium iodide
(0.20 mmol) in 3 mL of CH3CN, was added a solution of
70% aqueous TBHP (3.0 mmol) dropwise over a period of
Similar to iminium ion, In2 intermediates are known 30 min and stirred at room temperature. Progress of the re-
408
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 401 – 410

Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-ones via Benzylic Oxidation
Scheme 6. Plausible mechanism for the formation of 3H-quinazolin-4-ones and 2-subsitituted-benzo[d]ACHTUNTRGNEUNG[1,3]oxazin-4-ones.
action was monitored by TLC and the reaction mixture was
quenched after the stipulated time with saturated aqueous
Na2S2O3, washed with brine, extracted with ethyl acetate
and dried over anhydrous Na2SO4. Removal of the solvent
under vacuum afforded the crude product, which was puri-
fied by column chromatography using hexane/ethyl acetate
General Procedure for Synthesis of 2-Substituted
Benzo[d][1,3]oxazin-4-ones via Benzylic Oxidation
using KI/TBHP
AHCTUNGTRENNUNG
To
a solution of 2-substituted 4H-benzo[d]ACHTNUTGNUER[NG 1,3]oxazine
(1 mmol) in 3 mL of CH3CN, KI (0.2 mmol) and 0.5 mL of
70% TBHP in H2O (3.8 equivalents) were added dropwise
for 5 min. Then the reaction mixture was refluxed for 6 h
and allowed to cool to room temperature. The solvent was
evaporated under reduced pressure. The residue was mixed
with water and extracted with ethyl acetate. The extract was
washed with brine, dried over Na2SO4 and solvent was re-
moved by rotary evaporation. The product was isolated by
column chromatography using hexane/ethyl acetate mixture
1
mixture and was analyzed by H NMR, 13C NMR, GC and
GC-MS.
General Procedure for the One-Pot Synthesis of
Substituted Quinazoline-4(3H)-ones via Benzylic
Oxidation and Oxidative Dehydrogenation using KI/
TBHP
1
as eluent and was analyzed by H NMR, 13C NMR, IR, ESI-
MS and ESI-HR-MS.
To
a solution of N-(2-aminobenzyl)-substituted amines
(1 mmol) in 4 mL of ethanol, aldehyde (1 mmol) was added
and stirred at room temperature for 5 h. To the same solu-
tion, KI (0.2 mmol) and 0.66 mL of 70% TBHP in H2O
(5 equiv.) was added dropwise for 5 min and stirred at room
temperature for 6 h. The solvent was removed under re-
duced pressure. The residue was treated with 0.5 mL of pi-
peridine. The mixture was heated to 508C for 15 min, al-
lowed to cool to room temperature and stirred overnight.
The residue was mixed with water and extracted with ethyl
acetate. The extract was washed with brine, dried over
Acknowledgements
R.A.K., C.U.M. and S.G. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi for the award of Re-
search Fellowships.
Na2SO4 and solvent was removed by rotary evaporation. References
The product was isolated by column chromatography using
hexane/ethyl acetate mixture as eluent and was analyzed by
[1] a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem.
Rev. 2003, 103, 893; b) S. Johne, in: Supplements to the
1H NMR, 13C NMR, IR, ESI-MS and ESI-HR-MS.
Adv. Synth. Catal. 2011, 353, 401 – 410
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
409

R. Arun Kumar et al.
FULL PAPERS
2nd Edition of Roddꢀs Chemistry of Carbon Com-
pounds, (Ed.: M. F. Ansell), Elsevier, Amsterdam,
1995, Vol. IV I/J, p 223.
J. McKenna, W. C. Shieh, O. Repic, J. Org. Chem. 2004,
69, 6474.
[12] a) J. F. Liu, J. Lee, A. M. Dalton, G. Bi, L. Yu, C. M.
Baldino, E. McElory, M. Brown, Tetrahedron Lett.
2005, 46, 1241; b) A. Dandia, R. Singh, P. Sarawgi, Org.
Prep. Proced. Int. 2005, 37, 397.
[2] a) H. J. Hess, T. H. Cronin, A. Scriabine, J. Med. Chem.
1968, 11, 130; b) M. Ishikawa, Y. Eguchi, Heterocycles
1981, 16, 31.
[3] M. S. Malamas, J. Millen, J. Med. Chem. 1991, 34, 1492.
[4] a) G. Leszkovsky, L. Tardos, Chem. Abstr. 1965, 62,
16821; b) S. Saxena, M. Verma, A. K. Saxena, K.
Shanker, Indian J. Pharm. Sci. 1991, 53, 48.
[5] P. P. Kung, M. D. Casper, K. L. Cook, L. Wilson-Lin-
gard, L. M. Risen, T. A. Vickers, R. Ranken, L. B.
Blyn, R. Wyatt, P. D. Cook, J. Ecker, J. Med. Chem.
1999, 42, 4705.
[13] a) P. Salehi, M. Dabiri, M. A. Zolfigol, M. Baghbanza-
deh, Tetrahedron Lett. 2005, 46, 7051; b) D. J. R.
ˇ
OꢁMahony, V. Krchnꢂk, Tetrahedron Lett. 2002, 43, 939.
[14] Z. Zheng, H. Alper, Org. Lett. 2008, 10, 829.
[15] G. M. J. Coppola, J. Heterocycl. Chem. 1999, 36, 563,
and references cited therein.
[16] a) S. Cacchi, G. Fabrizi, F. Marinelli, Synlett 1996, 997;
b) R. C. Larock, C. A. Fellows, J. Org. Chem. 1980, 45,
363; c) C. Larksarp, H. Alper Org. Lett. 1999, 1, 1619.
[17] a) K. R. Reddy, C. U. Maheswari, M. Venkateshwar,
M. L. Kantam, Eur. J. Org. Chem. 2008, 3619; b) K. R.
Reddy, C. U. Maheswari, M. Venkateshwar, M. L.
Kantam, Adv. Synth. Catal. 2009, 351, 93; c) K. R.
Reddy, C. U. Maheswari, M. Venkateshwar, M. L.
Kantam, Tetrahedron Lett. 2009, 50, 2050; d) K. R.
Reddy, M. Venkateshwar, C. U. Uma Maheswari, S.
Prashanthi, Synth. Commun. 2010, 40, 186.
[6] A. Mannscherck, H. Koller, G. Stuhler, M. A. Davis, J.
Traber, Eur. J. Med. Chem. 1984, 19, 381.
[7] a) J. Felter, T. Czuppo, G. Hornyak, A. Feller, Tetrahe-
dron 1991, 47, 9393; b) L. A. Sorbera, J. Bolos, N. Ser-
radell, M. Bayes, Drugs Future 2006, 31, 778.
[8] a) M. L. Gujral, P. N. Saxena, R. S. Tiwari, Indian J.
Med. Res.1955, 43, 637; b) B. L. Chenard, A. R. Rein-
hold, W. M. Welch, European Patent Application EP
0884310A1, 1998.
[9] E. Cohen, B. Klarberg, J. R. Vaughan, J. Am. Chem.
[18] C. U. Maheswari, G. S. Kumar, M. Venkateshwar, R. A.
Kumar, M. L. Kantam, K. R. Reddy, Adv. Synth. Catal.
2010, 352, 341.
Soc. 1960, 82, 2731.
[10] a) L. Hedstrom, A. R. Moorman, J. Dobbs, R. H.
Abeles, Biochemistry 1984, 23, 1753; b) R. L. Stein,
A. M. Strimpler, B. R. Viscarello, R. A. Wildonger,
R. C. Mauger, D. A. Trainor, Biochemistry 1987, 26,
4126; c) A. Krantz, R. W. Spencer, T. F. Tam, T. J. Liak,
L. J. Copp, E. M. Thomas, S. P. Rafferty, J. Med. Chem.
1990, 33, 464; d) S. J. Hays, B. W. Caprathe, J. L. Gil-
more, N. Amin, M. R. Emmerling, W. Michael, R. Na-
dimpali, R. Nath, K. J. Raser, D. Stafford, D. Watson,
K. Wang, J. C. Jaen, J. Med. Chem. 1998, 41, 1060.
[11] a) E. C. Taylor, R. I. Knopf, A. L. Borror, J. Am.
Chem. Soc. 1960, 82, 3152; b) T. G. Jackson, S. R.
Morris, R. H. Turner, J. Chem. Soc. (C) 1968, 13, 1592;
c) L. A. Errede, J. Org. Chem. 1976, 41, 1763; d) H.
Kotsuki, H. Sakai, H. Morimoto, H. Suenaga, Synlett
1999, 1993; e) B. L. Chenard, W. M. Welch, J. F. Blake,
T. W. Butler, A. Reinhold, F. E. Ewing, F. S. Menniti,
M. J. Pagnozzi, J. Med. Chem. 2001, 44, 1710; f) S. Xue,
[19] F. Ishikawa, Y. Watanabe, J. Saegusa, Chem. Pharm.
Bull. 1980, 28, 1357.
[20] N. J. Leonard, G. W. Leubner, J. Am. Chem. Soc. 1949,
71, 3408.
[21] a) A. J. Cattino, J. M. Nichols, B. J. Nettles, M. P. Doyle,
J. Am. Chem. Soc. 2006, 128, 5648; b) Z. Li, C. J. Li, J.
Am. Chem. Soc. 2005, 127, 3672.
[22] N. Kornblum, H. E. DeLaMare, J. Am. Chem. Soc.
1951, 73, 880.
[23] S. Yamada, D. Morizono, K. Yamamoto, Tetrahedron
Lett. 1992, 33, 4329.
[24] J. Barluenga, M. M-Arias, F. G. Bobes, A. Ballesteros,
J. M. Gonzꢂlez , Chem. Commun. 2004, 2616.
[25] a) A. J. Catino, R. E. Forslund, M. P. Doyle, J. Am.
Chem. Soc. 2004, 126, 13622; b) P. D. Bartlett, P.
Gunther, J. Am. Chem. Soc. 1966, 88, 3288; c) P. D.
Bartlett, G. Guaraldi, J. Am. Chem. Soc. 1967, 89, 4799.
410
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 401 – 410