V. K. Tandon, H. K. Maurya / Tetrahedron Letters 50 (2009) 5896–5902
5897
Table 2
Organic solvent usage is often an integral part of chemical or
Reaction of 2,3-dichloro-1,4-naphthoquinone (1a) with morpholine (2i)35
manufacturing processes of amino and mercapto derivatives of
quinone since more than a century28 for miscellaneous applica-
tions.8–27 Different organic solvents such as EtOH,19–25 MeOH,29
C6H6, CHCl3, CH2Cl2, DMF, DMSO, ether, THF, AcOEt, and tolu-
ene12,30 have been used for the synthesis of amino and mercapto
derivatives of quinone.
O
O
O
HN
N
Cl
Cl
O
2i
Cl
H2O
O
O
In connection with our studies on the reactivity of quinone with
nucleophiles ‘on water’, we first explored the preparation of 2-anili-
no-3-chloro-1,4-naphthoquinone (3a) from 2,3-dichloro-1,4-naph-
thoquinone (1a) by the nucleophilic substitution reaction with
aniline (2a) synthesized by Lien et al.12 as depicted in Figure 1.
The typical reaction conditions involve heating 1a with aniline
(2a) in benzene at 50 °C for 30 min to afford product 3a in 81%
yield. Sarhana et al.31 reported 73% yield by change of nonpolar
solvent to polar solvent MeOH. However use of excess of absolute
ethanol at room temperature for 1 h afforded 90% yield of 3a. In
contrast, when a mixture of 1a and 2a is stirred ‘on water’ the reac-
tion is complete within 50 min at ambient temperature and 15 min
at 50 °C leading to the formation of 3a in 100% yield as shown in
Table 1. Here, we find that water alone is the medium of choice.
The reactions are completed in shorter times than in other protic
and nonprotic solvents and the pure product precipitates and can
be isolated by simple filtration. Bhattacharyya32 has reported the
synthesis of 2-chloro-3-(4-morpholino)-1,4-naphthoquinone (3n)
by refluxing a solution of 2,3-dichloro-1,4-naphthoquinone (1a)
and morpholine (2i) in ethanol and using anhydrous K2CO3 as base
in 16 h under an atmosphere of nitrogen. The corresponding reac-
tion of 2,3-dichloro-1,4-naphthoquinone (1a) and morpholine (2i)
‘on water’ is complete within 30 min at 50 °C (Table 2). The nucle-
ophilic substitution of aniline (2a) with 2,3-dichloro-1,4-naphtho-
quinone (1a) demonstrates that ‘on water’ method consists of
simply heating the reactants with stirring. It is pertinent to note
that both solid reactants can also be utilized, as reaction of 1a with
1a
3n
Solvent
b
t
Yield (%)
EtOH
On H2O
K2CO3
—
16 h
30 min
6832
98
Thiols also respond effectively to conditions of aqueous suspen-
sion compared to reaction in organic solvents. We have explored
the reaction of 1a with ethyl thioglycolate (2n) to achieve the
nucleophilic substitution reaction in excess of absolute ethanol
by prolonged vigorous refluxing at 80–90 °C for 8–10 h to afford
the product 3v in 95–97% yield.21 In contrast, the reaction per-
formed ‘on water’ was complete in 2 h at 50 °C and afforded the
product 3v in 100% yield. On the basis of the above results we have
performed reactions of different quinones (1) with thiophenol (2l),
5-(4-nitrophenyl)-1,3,4-oxadiazole-2-thiol (2m), ethyl thioglyco-
late (2n), diethyl 2-mercaptosuccinate (2o), and ethane-1,2-dithiol
(2p) affording 3(l–p) in good to excellent yields (Table 5).
Wang and co-workers33 reported palladium-catalyzed amina-
tion of 2,3-dichloro-1,4-naphthoquione with nitro-substituted
arylamines in presence of t-BuONa as a base which is entirely
different to the nucleophilic substitution carried out by us ‘on
water’. The palladium-catalyzed amination involves oxidative
addition followed by transmetalation and reductive elimination.33
In order to explore the reactivity of thiophenol with 2-anilino-3-
chloro-1,4-naphthoquinone (3a), we observed that the reaction
with thiophenol (2l) ‘on water’ afforded 98% yield of 3s in an hour
without using any catalyst or base at room temperature. On further
study of rate acceleration for reactions on H2O, we attempted to
explore reaction of methyl amine (2d) with 3v ‘on water’ at 50 °C
using Et3N as base. This resulted in the formation of 3-hydroxy-
4-methyl-4H-naphtho[2,3-b][1,4] thiazine-5,10-dione (3f) in
shorter duration of time.21 The mechanism of formation of 3f in-
volves nucleophilic displacement followed by intramolecular
nucleophilic addition–elimination and cyclization.21
The nucleophilic addition reactions depicted in Tables 3 and 4
proceed by mechanism outlined in Figure 2. The mechanism of oxi-
dation proceeds by redox process of 1,4-quinones which is well
documented in literature.27 Reoxidation with remaining starting
material leads to excellent yields of the nucleophilic substitution
product as depicted in Figure 2. Oxygen in the media presumably
accelerates the process of oxidation since no quinol intermediate
is left in the reaction mixture.
p-hydroxy aniline (2b), L-alanine ethyl ester (2f), glycine (2e), 5-(4-
nitrophenyl)-1,3,4-oxadiazole-2-thiol (2m), and 2-phenylacet-
amide (2k) (Table 3) afforded excellent results, showing that
vigorous stirring promotes the reaction, most likely by increasing
the area of surface contact between the organic and aqueous
phases.
Change in amount of water does not alter the observed rate
acceleration till sufficient water is present for clear phase separa-
tion or filtration. In cases where clear phase separation does not
occur, such as in small-scale reactions, liquid extraction or evapo-
ration of water and purification may be necessary as shown in
workup process (W) in Table 3. We have found that the high reac-
tivity of quinones (1) ‘on water’ is not limited to these nucleophilic
substitutions with primary andsecondary aminogroups containing
reactants.
Table 1
Thus a variety of nucleophilic substitution (Fig. 1) and addition
reactions (Fig. 2) of quinones 1 with a variety of aromatic amines
(2a and b), primary aliphatic amines (2c and d), amino acid (2e),
ester of amino acid (2f), heterocyclic amines (2g–i), hydrazine
(2j), amide (2k) (Table 3), and thiols (2l–p) (Table 5) can be effi-
ciently carried out in aqueous suspension with the most dramatic
effects observed for the second nucleophilic substitution of 2l with
thiophenol without using any base and formation of product 3s in
aqueous suspension. In absence of water, the rate of completion of
reaction is extremely slow especially with nucleophiles having
high boiling point. As with nucleophilic substitution reactions,
the ‘on water’ protocol provides the best of conditions in terms
of efficiency, safety, and convenience, even when rate accelerations
are not large. Thus a variety of nucleophilic substitution and addi-
tion reactions can be efficiently carried out in aqueous suspension,
Comparison of water versus organic solvents for a typical nucleophilic substitution
reaction of 2,3-dichloro-1,4-naphthoquinone (1a) with aniline (2a)35
O
O
O
H2N
H
N
Cl
Cl
2a
Cl
H2O
O
1a
3a
Solvent
T (°C)
t
Yield (%)
Benzene
MeOH
EtOH
50–60
—
rt
30 min
—
1 h
8112
7331
90
On H2O
On H2O
rt
50
50 min
15 min
100
100