Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions via Vicarious Nucleophilic Substitution of Hydrogen

Article abstract of DOI:10.1021/jo970726m

Rhone-Poulenc Polska Ltd., ul. Grzybowska 80/82, 00-844 Warszawa, Poland Garbo- and heterocyclic nitroarenes react with anions of tert-butyl and cumyl hydroperoxides in the presence of strong bases to form substituted o- and p-nitrophenols. The reaction usually proceeds in high yields and is of practical value as a method of synthesis and manufacturing of nitrophenols. Orientation of the hydroxylation can be controlled to a substantial extent by selection of the proper conditions. Basic mechanistic features of this process were clarified.

Full text of DOI:10.1021/jo970726m

J . Org. Chem. 1998, 63, 4199-4208
4199
Hyd r oxyla tion of Nitr oa r en es w ith Alk yl Hyd r op er oxid e An ion s
via Vica r iou s Nu cleop h ilic Su bstitu tion of Hyd r ogen
Mieczysław Makosza* and Krzysztof Sienkiewicz†
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw, Poland
Received April 23, 1997
Carbo- and heterocyclic nitroarenes react with anions of tert-butyl and cumyl hydroperoxides in
the presence of strong bases to form substituted o- and p-nitrophenols. The reaction usually proceeds
in high yields and is of practical value as a method of synthesis and manufacturing of nitrophenols.
Orientation of the hydroxylation can be controlled to a substantial extent by selection of the proper
conditions. Basic mechanistic features of this process were clarified.
In tr od u ction
VNS reaction with nitroarenes to produce nitrophenols
as shown in eq 2.
Vicarious Nucleophilic Substitution of hydrogen (VNS)
allows the direct introduction of substituents onto elec-
trophilic aromatic rings.1 A variety of carbo- and het-
erocyclic nitroarenes, as well as some electrophilic het-
erocycles lacking a nitro group, undergo this process with
carbanions that contain a leaving group X at the carban-
ionic center. The reaction proceeds according to the
addition-elimination scheme shown in eq 1.2
Although alkyl hydroperoxides are rather strong OH-
acids, the corresponding anions exhibit relatively high
nucleophilicity, due to the so-called R-effect.8 The nu-
cleophilic reactivity of anions of alkyl hydroperoxides is
exemplified in their well-documented reactions with
alkylating agents which give unsymmetrical dialkyl
peroxides.9 More relevant to the subject of this paper
are reactions of these anions with electrophilic alkenes.
The formation of oxiranes by the nucleophilic addition
of alkyl hydroperoxide anions, followed by intramolecular
SN2 type substitution of an RO group,10 resembles the
reactions of R-halo carbanions in related cyclopropanation
reactions. Moreover, it was reported that the anion of
tert-butyl hydroperoxide reacts with nitroalkenes to yield
nitroketones.11 This reaction appears to be analogous to
the aliphatic VNS process described recently by us.12
There were also reports on the reactions of alkyl hydro-
peroxide anions with polynitroarenes. Formation of the
corresponding σ-adducts was confirmed by spectroscopy,13
and the kinetic study of nucleophilic aromatic substitu-
tion (SNAr) of halogen in halonitroarenes by hydroper-
oxide anion demonstrates its high reactivity.14
The amination of a nitroarene with hydroxylamine3
apparently proceeds by a similar mechanism, although
a hydride shift has been proposed for the transformation
of the σH adduct into products.4 Recently, more efficient
amination processes were described and use such ami-
nation agents as aminotriazoles,5 O-methyl hydroxyl-
amine,6a and N,N,N-trimethylhydrazinium iodide.6b No
mechanistic proposals has been made for these processes,
but they seem to follow a general VNS mechanism,
namely nucleophilic addition followed by base-induced
â-elimination. This mechanism was shown to operate in
the amination of nitroarenes with sulfenamides.7 Since
anions of alkyl hydroperoxides (ROOH) can be considered
to be nucleophiles that bear a leaving group (RO) at the
anionic center, like R-halocarbanions and anions of
sulfenamides, etc., they can be expected to undergo the
(8) Edwards, J . O.; Pearson, R. G. J . Am. Chem. Soc. 1962, 84, 16.
Molsaac, I. E., J r.; Subbaraman, L. R.; Subbaraman, J .; Mulhausen,
H. A.; Behrman, E. J . J . Org. Chem. 1972, 37, 1037. Dixon, J . E.;
Bruice, T. C. J . Am. Chem. Soc. 1971, 93, 6592. Buncel, E.; Wilson,
H.; Chuaqui, C. J . Am. Chem. Soc. 1982, 104, 4896.
(9) Bourgeois, M.-J .; Montaudon, E.; Maillard, B. Synthesis 1989,
700. Baj, S. Pol. J . Chem. 1994, 68, 1559.
† Present address: Rhoˆne-Poulenc Polska Ltd., ul. Grzybowska 80/
82, 00-844 Warszawa, Poland.
(1) Makosza, M.; Winiarski, J . Acc. Chem. Res. 1987, 20, 282.
Makosza, M. Chimia 1994, 48, 499. Makosza, M. Usp. Khimii 1989,
58, 1289.
(2) Makosza, M.; Glinka, T. J . Org. Chem. 1983, 48, 3860.
(3) Meisenheimer, J .; Patzig, E. Ber. Deutch. Chem. Ges. 1906, 39,
2533. Price, C. C.; Voong, S.-T. Organic Syntheses; Wiley: New York,
1955; Coll. Vol. 3, p 664.
(4) Gitis, S. S.; Glaz, A. I.; Grigoriev, B. B.; Kaminsky, A. Y.;
Martynienko, A. S.; Saukov, P. I. Zh. Org. Khim. 1967, 3, 1617.
(5) Katritzky, A. R.; Laurenzo, K. S. J . Org. Chem. 1986, 51, 5039.
Ibid. 1988, 53, 3978.
(10) Yang, N. C.; Finnegan, R. A. J . Am. Chem. Soc. 1958, 80, 5845.
Payne, G. B. J . Org. Chem. 1960, 25, 275. Meth-Cohn, O.; Moore, C.;
Taljaard, H. C. J . Chem. Soc., Perkin Trans. 1 1988, 2663.
(11) Gautier, E. C. L.; McKillop, A.; Taylor, R. J . K. Tetrahedron
Lett. 1994, 35, 8759. Ashwell, M. A.; J ackson, R. F. W. Synthesis 1988,
229.
(12) Makosza, M.; Kwast, A. Chem. Comm. 1984, 1619. Tetrahedron
1991, 47, 5001.
(6) (a) Seko, S.; Kawamura, N. J . Org. Chem. 1996, 61, 442. (b)
Pagoria, P. F.; Mitchell, A. R.; Schmidt, R. D. J . Org. Chem. 1996, 61,
2934.
(13) Kropf, H.; Ball, M.; Siegfriedt, K. H.; Wagner, S. J . Chem. Res.
(S) 1981, 339; (M) 1981, 4001.
(14) Ritchie, C. D.; Sawada, M. J . Am. Chem. Soc. 1977, 99, 3754.
Heller, R. A.; Weiler, R. Can. J . Chem. 1987, 65, 251.
(7) Makosza, M.; Białecki, M. J . Org. Chem. 1992, 57, 4784.
S0022-3263(97)00726-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

4200 J . Org. Chem., Vol. 63, No. 13, 1998
Makosza et al.
Ta ble 1
Finally, the second step of the VNS reaction of ni-
troarenes with anions of alkyl hydroperoxides, namely
â-elimination of the alcohol from the σ-adduct, is feasible
since it is analogous to the base-catalyzed decomposition
of secondary alkyl peroxides by an E2 elimination
pathway, which yields ketones and alcohols.15 Indeed,
the VNS hydroxylation of nitroarenes with alkyl hydro-
peroxide anions does occur satisfactorily as reported in
our preliminary communication.16 Similar observations
were made by a German group.17 This paper presents a
full account of our studies on the nucleophilic hydroxy-
lation of nitroarenes with alkyl hydroperoxide anions.
ratio
ROOH
base (mol)
time (min)
yield, %
(4a :4b:4c)a
1
2
1
1
NaOH (10)
KOH (10)
60
60
15
15
15
40
15
73
80
87
0:100:0
0:100:0
3:94:3
t-BuOK (2.5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (2.5)
t-BuOK (2.5)
80
76
14:76:10
25:59:16
2:95:3
Resu lts a n d Discu ssion
2
1c
1d
41(82)b
66
Rea ction Con d ition s. Because of their availability
and stability, tert-butyl hydroperoxide t-BuOOH 1, cumene
hydroperoxide PhMe2COOH 2, and triphenylmethyl hy-
droperoxide Ph3COOH 3 were selected as reagents for
the hydroxylations of nitroarenes. Preliminary studies
indicated that powdered KOH or NaOH or t-BuOK in
liquid NH3 assured the best yields of nitrophenols. The
choice of alkyl hydroperoxide and the base was often a
crucial determinant of the course of the reaction, as
exemplified for 3-chloronitrobenzene 4 (Table 1). In the
presence of an insoluble base such as NaOH or KOH, the
hydroxylation occurs regioselectively at position 4 giving
p-nitrophenol derivative 4b in high yield. On the other
hand, in the presence of t-BuOK mixtures of o- and
p-nitrochlorophenols 4a -c were produced, the ortho
hydroxylation being favored when 2 and t-BuOK were
in high concentration. This effect on the orientation can
be attributed to the faster elimination of more acidic
phenyldimethyl carbinol than tert-butyl alcohol and will
be discussed later. Although the VNS hydroxylation can
also be performed in DMF, the use of this solvent is
limited, by a more complicated workup procedure. The
reaction also proceeds in THF; however, this solvent is
less convenient and the previously reported preference
for ortho substitution in the VNS reactions of chlorocar-
banions in THF18 was not observed in the current
hydroxylation.
1:99:0
a
Ratio 4b:(4a + 4c) based on isolated products; 4a :4c from 1H
NMR. Calculated on consumed 4. c Reaction in THF at -25 °C.
Reaction in DMF at -25 °C.
b
d
Ta ble 2
Z
substrate no.
product no.
yield, %
H
Me
OMe
F
Cl
5
6
7
5ba
6ba
7ba
8b
31(86)b
18(78)b
24(73)b
76
8
4
4b
84
Br
CF3
9
9b
82
10
11
12
13
14
15
16
10b
11b
12b
13b
14ba
17
86
85
87
90
SO2Me
CN
NO2
COPh
CHO
CO2Me
74
28(54)b
90
17c
aReaction time: 3 h. Calculated on consumed substrate. c The
same result was obtained with t-BuOK.
b
Hyd r oxyla tion of Nitr oben zen e a n d Its Mon osu b-
stitu ted Der iva tives. Hydroxylation of nitrobenzene
5 and a range of its 3-substituted analogues (4, 6-14)
with cumene hydroperoxide 2 (Tables 1 and 2) occurs
selectively at the position para to the nitro group when
carried out in the presence of KOH in NH3. Nitrobenzene
itself shows moderate electrophilic activity, thus its
reaction is slow. Nevertheless, the yield of p-nitrophenol
5b was high, based on on consumed substrate 5. Similar
low reactivity was observed for less electrophilic 3-sub-
stituted nitrobenzenes 6 and 7, deactivated by electron-
donating methyl and methoxy groups. More electrophilic
nitrobenzene derivatives, substituted in the meta-position
with electron-withdrawing groups, such as halogens, CF3,
SO2CH3, COPh, CN, and NO2, easily underwent the VNS
hydroxylation giving corresponding p-nitrophenols regi-
oselectively and in high yields. Interestingly, for the
efficient conversion of 3-nitrobenzophenone 14 a longer
reaction time was required. Lower susceptibility of
ketone 14 to the VNS hydroxylation is apparently due
to a competing, reversible addition of the alkyl hydrop-
eroxide anion to the carbonyl group. The reaction of
3-nitrobenzaldehyde 15 and methyl 3-nitrobenzoate 16
with the anion of 2 did not result in VNS hydroxylation,
but rather an addition to the carbonyl group. Thus,
under the applied reaction conditions, aldehyde 15 was
slowly oxidized to 3-nitrobenzoic acid 17.19 The same
carboxylic acid 17 was obtained from methyl ester 16,
apparently due to transesterification with the alkyl
hydroperoxide anion, followed by base-induced decom-
position of the peroxy ester. A similar reaction of methyl
3-nitrobenzoate 16 was observed in the VNS amination
where an attack of the sulfenamide anion on the ester
group gave primarily the acylated sulfenamide.7
(15) Kornblum, N.; de la Mare, H. E. J . Am. Chem. Soc. 1951, 73,
880. Bell, R. P.; McDougall, A. O. J . Chem. Soc. 1958, 1697.
(16) Makosza, M.; Sienkiewicz, K. Polish Patent Appl. Nr PL 273927,
J uly 1988; European Patent Appl. Nr EP 352.563, J an 1990; J . Org.
Chem. 1990, 55, 4979.
(17) Mattersteig, G.; Pritzkov, W.; Voerckel. V. J . Prakt. Chem. 1990,
332, 569. Brose, T.; Holzscheiter, F.; Mattersteig, G.; Pritzkow, W.;
Voerckel, V. J . Prakt. Chem. 1992, 334, 497.
(18) Makosza, M.; Glinka, T.; Kinowski, A. Tetrahedron 1984, 37,
1863.
(19) Maruyama, K. Bull. Chem. Soc. J pn. 1960, 33, 1516. Ibid. 1961,
34, 102, 105.

Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions
J . Org. Chem., Vol. 63, No. 13, 1998 4201
Ta ble 3
Ta ble 4
position
of OH
substr
no.
position
of OH product no. yield, %
Z
substr ROOH
product no. yield, %
3-Z 4-X
NO2
NO2 Cl
NO2 Cl
base (mol)
4-Cl
18
18
2a,b
1e
4
2
4
2
4
2
4
2
4
4
2
4
2
2
4
2
1
4
2
2
4
4
6
5bc
18a
5bc
18a
5bc
19a
5bc
20a
5bc
5bc
22a
5bc
23a
24a
5bc
25a
25bc
26a
5a c
5a c
28a
29a
29b
36(72)d
27(34)d
27(34)d
73
7
80
F
30a
31
31
t-BuOK(5)
t-BuOK(2.5)
NaOH(10)
4
6
6
4
6
4
6
2
6
4
13bb
31a
63
83
79
1
62
50
86
57
12
13
4-Cl
4-Cl
4-Br
4-I
31a
18
19
20
2
2
2
13bb
32a
CN Cl
CN Cl
CF3 Cl
32
32
33
34
t-BuOK(2.5)
NaOH(10)
t-BuOK(2.5)
t-BuOK(2.5)
12bb
33a
3
62
Cl
Cl
34a
traces
74
34b
4-F
21
22
2
4bb
4-OMe
2b
4(17)d
5(21)d
80
a
b
2 used instead of 1. SNAr of halogen.
4-CF3
4-SO2Ph
23
24
1e
1
33
38
41
7
37
37
51
25a in a moderate yield, along with a small amount of
4-cyanophenol 25b, which resulted from the substitution
of the nitro group. In the reactions of a few ortho-
substituted nitrobenzenes 26-29 similar diversity was
observed (Table 3), namely competing and dominating
formation of o-nitrophenol 5a via SNAr of the halogen in
o-chloro- and o-fluoronitrobenzenes 26 and 27, but low
reactivity of o-nitroanisole 28 and high yield of the VNS
hydroxylation of o-(trifluoromethyl)nitrobenzene 29.
Disu b st it u t ed Nit r ob en zen e Der iva t ives (Ta b le
4). Most interesting is the comparison of the reaction of
2,4-dinitrofluorobenzene (Sanger’s reagent 30) and its
chloro analogue 31 with anions of 1 and 2. In the case
of 30 the only result was substitution of the very labile
fluorine, whereas in 2,4-dinitrochlorobenzene 31 the
selective VNS process at position 6 dominated even when
NaOH was used as the base. In 4-chloro-3-cyano- and
4-chloro-3-trifluoromethyl derivatives of nitrobenzene 32
and 33, the VNS hydroxylation gave practical results only
when it was carried out in the presence of t-BuOK.
Interestingly, in 3,4-dichloronitrobenzene 34 the substi-
tution of hydrogen at the more crowded position 2 was
the major process, although replacement of the chlorine
also occurred to some extent. These results, when
compared to those obtained with 4-chloronitrobenzene 18
(Table 3), show that introduction of an additional electron-
withdrawing group at the meta-position strongly pro-
motes the VNS reaction over chlorine substitution.
Nitr on a p h th a len es (Ta ble 5). A bicyclic aromatic
ring system provides additional stabilization of the
anionic σ-adducts; hence, nitronaphthalene derivatives
readily enter into the VNS reaction with R-chloro car-
banions1,21 and sulfenamides.7 Good reactivity of ni-
tronaphthalenes in the VNS reaction was also observed
in the hydroxylation of 1-nitronaphthalene 35. The
reaction proceeded efficiently giving the expected 2- and
4-hydroxy derivatives in high yields. It should be stressed
that the orientation of the hydroxylation is dependent
on the kind of base used; thus, 2- or 4-hydroxy-1-
nitronaphthalenes can be obtained in high yield and
selectivity. These results are of significant practical
importance and will be discussed together with mecha-
nistic questions. A similar but weaker effect of conditions
4-CN
2-Cl
25
26
2e
2f
2-F
27
28
29
2
2-OMe
2-CF3
2b
1e
8(47)d
88
1
KOH was used instead of t-BuOK. bReaction time: 1 h. c SNAr
a
d
of halogen, OMe, SO2Ph, or NO2 group. Calculated on consumed
substrate. e 2.5 equiv of t-BuOK was used. f In the presence of
NaOH only SNAr was observed.
The conditions for selective para-hydroxylation of
3-substituted nitrobenzene derivatives appeared unsuit-
able in the reactions of para- and ortho-substituted
nitrobenzenes with 1 and 2 where the competitive SNAr
process could play a substantial role (Table 3). For
example, the reaction of 4-chloronitrobenzene 18 with 2
and KOH gave 4-nitrophenol 5b as the sole product,
formed by substitution of the halogen, followed by a
spontaneous decomposition of the unstable nitroaryl
cumyl peroxide.13,20 The desired VNS hydroxylation of
4-halonitrobenzenes 18, 19, and 20 (hal ) Cl, Br, I) was
achieved when 2 was used in the presence of an excess
of t-BuOK in high concentration. However, with 4-fluo-
ronitrobenzene 21, which is very reactive in the SNAr of
halogen process, substitution of fluorine took place. The
reaction of p-methoxynitrobenzene 22 yielded small
amounts of ortho-hydroxylated product 22a and 4-nitro-
phenol 5b formed apparently by SNAr of the methoxy
group. Thus 22, similar to 21, showed preference for the
SNAr reaction, although due to the electron-donating
character of the MeO group its overall reactivity was low.
Surprisingly, nitrobenzene derivatives substituted at the
para position with electron-withdrawing groups, in spite
of the expected enhanced electrophilic character of the
ring, reacted in diverse ways. Thus, 4-(trifluorometh-
yl)nitrobenzene 23 smoothly gave the expected o-hydroxy
derivative 23a , while in the reaction of nitrosulfone 24
substitution of the phenylsulfonyl group competed to a
significant extent with the VNS process. Hydroxylation
of 4-cyanonitrobenzene 25 furnished the expected phenol
(20) Kropf, H.; Ball, M. Lieb. Ann. Chem. 1976, 2331. Kropf, H.;
Amirabadi, H. M. Synthesis 1981, 397.
(21) Makosza, M.; Danikiewicz, W.; Wojciechowski, K. Lieb. Ann.
Chem. 1987, 711.

4202 J . Org. Chem., Vol. 63, No. 13, 1998
Makosza et al.
Ta ble 5
Ta ble 7
position substr
position
position of
NO2,Z,X
position
of OH product no. yield, %
of NO2
no.
base (mol)
of OH
product no. yield, %
substr
basea
8
44
44
45
t-BuOK (2.5)
NaOH (10)
t-BuOH (2.5)
7
5
5
44a
44b
45a
67
79
86
1-NO2
35
t-BuOK
2
4
2
4
2
4
2
4
2
4
2
4
2
4
2
4
1
35a
35b
35a
35b
36a
36b
36a
36b
37a
37b
37a
37b
38a
38b
39a
35b
40a
81
4
traces
88
81
5
22
61
85
traces
32
44
63
2
85
traces
84
6
1-NO2
35
36
36
37
37
38
39
40
NaOH
As expected, nitroquinolines reacted similarly to ni-
tronaphthalenes. Hydroxylation of 8-nitroquinoline 44
could be directed by the reaction conditions to give
selectively the 7- or 5-hydroxy derivative, and 6-nitro-
quinoline 45 reacted solely at position 5 (Table 7). In
the reaction of 2-nitrothiophene 46 (eq 3), hydroxylation
at position 3 proceded almost quantitatively; however,
1,5-diNO2
1,5-diNO2
1-NO2-5-Br
1-NO2-5-Br
1-NO2-4-OMe
1-NO2-4-Cl
t-BuOK
NaOH
t-BuOK
NaOH
t-BuOK
t-BuOK
t-BuOK
2-NO2
a
t-BuOK, 2.5 mol; NaOH, 10 mol.
Ta ble 6
the product 2-nitro-3-hydroxythiophene 46b decomposed
upon attempted purification. It was finally isolated as
a stable, crystalline tetrabutylammonium salt 46a using
an ion-pair extraction procedure. Some efforts were also
made to perform the hydroxylation of electrophilic het-
eroarenes lacking a nitro group but previously shown to
react with carbanions along the VNS pathway.23 For
example, acridine did not react with alkyl hydroperoxide
anions, while 4-cyanoisoquinoline 4724 entered the VNS
hydroxylation, albeit producing a moderate yield (eq 4).
substr
no.
position
of OH
X
product no.
yield, %
4-OEt
6-OMe
6-Cl
41
42
43
6
2
2
41a
42a
43a
78
75
64
on the orientation was observed in the reaction of 1,5-
dinitronaphthalene 36 and 1-nitro-5-bromonaphthalene
37. The hydroxylation can be directed to the ortho-
position under properly selected conditions, whereas the
selective substitution of para-hydrogen was somewhat
impeded, apparently by steric hindrance by substituents
in position 5. The high reactivity of nitronaphthalenes
was also evidenced in the reactions of 4-methoxy- and
4-chloro-1-nitronaphthalenes 38 and 39 where the sub-
stitution of hydrogen at position 2 was the dominant
process. Finally, 2-nitronaphthalene 40 reacted exclu-
sively at position 1 as already observed in other VNS
reactions.1,21
Ar om a tic Heter ocycles. Nitro derivatives of pyri-
dine, quinoline, and other aromatic heterocycles react
readily with carbanions in the VNS process.1,22 These
heteroaromatic compounds were also highly reactive
toward alkyl hydroperoxide anions. For example, hy-
droxylation of 4-ethoxy-3-nitropyridine 41 occured ef-
ficiently at position 6 whereas 6-substituted 3-nitropy-
ridines 42 and 43 reacted exclusively at position 2 (Table
6). All hydroxynitropyridines were isolated in their
pyridone forms. It should be stressed that in 3-nitro-6-
chloropyridine 43, VNS of hydrogen was the exclusive
process and that SNAr substitution of the very labile
halogen was not observed.
The reported results indicate that cumene hydroper-
oxide 2 is in some cases a more efficient hydroxylation
agent than 1 because higher acidity assures faster
elimination of phenyldimethyl carbinol than tert-butyl
alcohol from the respective σH adducts. This effect
appears to be more important than the somewhat larger
steric demands of 2 than 1. We expected that the
elimination should be particularly facile for the σH
adducts of the anion 3- to nitroarenes because of the high
acidity of Ph3COH. Examples presented in Table 8 show
however that the bulkiness of 3- hinders its reactions
(both VNS and SNAr) in positions ortho to the NO2 group.
Mech a n ism a n d Or ien ta tion . In our previous pa-
pers it was shown that the VNS reaction proceeds via
nucleophilic addition of R-halo carbanions to nitroaro-
matic rings followed by a base-induced â-elimination of
(23) Makosza, M.; Golin´ski, J .; Rykowski, A. Tetrahedron Lett. 1983,
3277.
(24) Owczarczyk, Z. Ph.D. Thesis, IChO-PAN, 1988.
(22) Makosza, M. Synthesis 1991, 103. Makosza, M.; Kwast, E.
Tetrahedron 1995, 51, 8339.

Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions
J . Org. Chem., Vol. 63, No. 13, 1998 4203
Ta ble 8
Ta ble 9
substr
no.
position
of OH
Z
Z′
product no.
yield, %
4-Cl
18
26
48
4c
2
H
4-Cl
2-Cl
H
2,3-Cl2
2,3-Cl2
3-Cl
5b
24(7)a,b
19(73)a,b
58(37)a,b
3(37)a,b
66(28)a
4(19)a
18a
26a
5a
48b
48a
4b
2-Cl
4
2c
4
2,3-Cl2
6
2c
9(18)a
Results when 2 was used. Data from Table 3. c SNAr of Cl.
a
b
a
a
HX from the σH adducts.1,2 This general mechanistic
picture was formulated on the basis of the effect of
strength and base concentration on the reaction rate,
estimated via intramolecular competition between VNS
of hydrogen and SNAr of halogen in p-fluoronitrobenzene
and some other halonitroarenes. An excess of strong base
assured domination of the former process whereas, when
carbanions were in low concentration without the pres-
ence of an additional base, substitution of fluorine was
the main process.1,2 In our preliminary communication
an analogous â-elimination mechanism was suggested for
the VNS hydroxylation on the basis of similar competitive
experiments.16
PH
PX
substr
no. ROOH base (mol)
(18a or 31a ) (5b or 13b)
% yield
X
Z
% yield
Cl
Cl
Cl
Cl
Cl
Cl NO2
Cl NO2
Cl NO2
H
18
18
18
18
18
31
31
31
21
30
2
NaOH (10)
2- K+ (2.5)
0
0
36(50)b
50(53)b
27(79)b
16(88)b
7
H
H
H
H
1
1
2
1
t-BuOK (2.5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (2.5)
1- K+ (1)
NaOH (10)
t-BuOK (5)
t-BuOK (5)
27
47
73
83
50
79
0
0
20(78)
1
1
2
2
F
F
H
NO2
74
63
0
a
b
Yields of isolated products. Conversion.
Here mechanistic features of this reaction will be
discussed on the basis of the competition between SNAr
of halogen and VNS of hydrogen, the kinetic isotope effect
in this reaction, and its orientation pattern.
The overall rate of the hydroxylation can be described
by eq 5. According to this equation the rate-limiting step
Although we have not undertaken kinetic examination
of the VNS hydroxylation, we believe that reliable
mechanistic conclusions can be drawn from the results
and observations made in the synthetic studies and
semiquantitative competitive experiments discussed in
terms of these kinetic considerations.
Com p etition of VNS ver su s SNAr of Ha logen
(Ta ble 9). Effect of a base on the rate of VNS can be
estimated from its competition with SNAr of halogen
because under given conditions of temperature, solvent,
and counterion, the rate of the latter process should not
be affected by the base concentration.25 Thus the in-
tramolecular competition between SNAr of halogen and
VNS of hydrogen can serve as a simple probe to evaluate
an effect of base on the overall rate of the latter process.
The ratio of products from VNS of hydrogen (PH) and
substitution of halogen (PX) will depend on the strength
and concentration of a base, provided that the elimination
is a kinetically important step in the VNS reaction,
namely PH/PX ) k1kE[B]/k-1kx. As the relation of the
elimination rate kE[B] to k-1 is growing, the influence of
the base on this competition will decrease until the
constant value of PH/PX ) k1/kx. Results obtained with
4-chloronitrobenzene 18 (Table 9) fit satisfactorily the
mechanistic concept of the VNS hydroxylation. When the
reaction was carried out in the presence of NaOH,
exclusive substitution of chlorine took place. A similar
result was obtained when the reaction was performed
with an excess of potassium salt of 2, when t-BuOK was
absent. Apparently a weak base sodium salt of 2 operat-
ing in these two experiments (NaOH is practically
insoluble in the reaction medium) was responsible for the
may vary depending on the value of the partitioning
factor k-1/kE[B]. When k-1/kE[B] . 1, eq 5 can be
simplified to kobs ) (k1/k-1)kE[B]. Here, equilibrium of
the σH-adduct formation is established and the subse-
quent elimination is the rate-limiting step; hence, the
overall reaction rate depends linearly on the base con-
centration. This situation is likely to occur for moder-
ately electrophilic nitroarenes which form short-lived,
easily dissociating σH-adducts, and/or for a slow elimina-
tion step caused by low strength and concentration of
base and by steric hindrance. On the other hand, when
k-1/kE[B] , 1, eq 5 is reduced to kobs ) k1. Here the
elimination step is a fast and kinetically less important
process. This situation is expected for stable, slowly
dissociating σ-adducts as well as for fast elimination
driven by a high concentration of a strong base.
Between these two border cases there is a range of
intermediate situations, namely k-1/kE[B] ≈ 1. In these
cases the influence of the base concentration on the
overall reaction rate will be nonlinear and smaller than
for the case k-1/kE[B] . 1, and the rate-limiting step
cannot be clearly defined and may vary depending on the
reaction conditions.
(25) Miller, J . Aromatic Nucleophilic Substitution, Elsevier, 1968.
Terrier, F. Nucleophilic Aromatic Displacement, Verlag Chemie,
Weinheim, 1991.

4204 J . Org. Chem., Vol. 63, No. 13, 1998
Makosza et al.
Sch em e 1
slow rate of elimination and consequently overall VNS
reaction, and thus SNAr of Cl dominated.
On the other hand, when the reaction was carried out
with an excess of t-BuOK the VNS process was favored.
These results indicate that the VNS reaction rate is
efficiently accelerated by base; thus, it proceeds via a
base-induced elimination from the σH adduct, and the
elimination is the rate-limiting step at least in the range
of base concentrations used in these experiments. More-
over, the greater extent of hydrogen substitution of 18
observed in the experiments with 2 can be explained as
an effect of faster elimination of phenyldimethylcarbinol
which is more acidic than tert-butyl alcohol eliminated
in the reaction with 1. This suggests an E2 character to
the elimination because its rate depends on the kind and
concentration of base and the kind of leaving group.
Results of these competitive experiments also indicate
that the addition to the chloronitrobenzene ring at
positions occupied by hydrogen proceeds faster than at
those occupied by chlorine (k1 > kCl). Surprisingly, with
1-chloro-2,4-dinitrobenzene 31, the VNS hydroxylation
almost completely dominated chlorine substitution, re-
gardless of the reaction conditions. Hydrogen substitu-
tion was the primary process even when the potassium
salt of hydroperoxide 1, a much weaker base, was used
without an excess, so the elimination was a slow process.
This is perhaps due to the high stability of the σH-adduct
derived from the highly electrophilic dinitroarene which
is formed faster than the σX-adduct and dissociates more
slowly than the subsequent â-elimination.
Ta ble 10
ROOH
base (mol)
yield, %
PH/PD (KIE)
1
2
NaOH (10)
NaOH (10)
77
75
83
76
74
7.0 ( 0.3
7.1 ( 0.4
1- K+ (2.5)
6.0 ( 0.2
1
2
t-BuOK (2.5)
t-BuOK (2.5)
0.98 ( 0.01
0.96 ( 0.02
In the VNS reaction of R-chlorocarbanions, 4-fluoroni-
trobenzene was the suitable model compound in which
VNS and SNAr processes occurred simultaneously, and
the competition between these reactions was governed
by the concentration of base, whereas in 4-chloroni-
trobenzene the SNAr of chlorine was hardly observed.1,2
This indicates that addition of carbanions to nitroaro-
matic rings occurs faster at positions bearing hydrogen
than at those bearing fluorine.2 Even in 2,4-dinitrofluo-
robenzene 30, VNS of hydrogen with R-chloro carbanions
proceeds faster than SNAr of fluorine.26 On the other
hand, attempts at VNS hydroxylations of 4-fluoroni-
trobenzene 21 and 2,4-dinitrofluorobenzene 30 with 1
and 2 resulted exclusively in SNAr of fluorine, even under
conditions strongly favoring the elimination step, namely
when hydroperoxide 2 and t-BuOK were in high concen-
tration. Thus one can conclude that alkyl hydroperoxide
anions add to nitroarenes in positions occupied with
hydrogen faster than in positions occupied with Cl, Br
and I, but not F. The tendency of O-nucleophiles to add
to nitroaromatic rings at positions bearing F is known.27
Finally, a comment on the course of the SNAr reaction
of halogen with alkyl hydroperoxide anions, which is not
a simple process (Scheme 1) is warranted. Nitroaryl
alkyl peroxides initially formed in this reaction are
known to be unstable and to decompose rapidly, probably
via a homolytic pathway.13,20 The formation of substan-
tial amounts of 2-tert-butoxy-4-nitrophenol 49 is a strong
piece of evidence supporting the homolytic dissociation
pathway of the initial SNAr product. Since formation of
49 is suppressed when excess t-BuOK is present in the
reaction mixture (Table 3), one can suppose that the
intermediate nitrophenoxide radical is converted into the
nitrophenoxide anion via electron transfer from t-BuO-
anion, rather than during hydrogen abstraction from the
solvent.
Kin etic Isotop ic Effect (Ta ble 10). The kinetic
isotope effect in the VNS hydroxylation was studied using
1-deutero-2,4-dinitrobenzene 13D as a model compound
in which competition between substitution of 1-D and 5-H
was observed. The value of the kinetic isotope effect,
KIE, was measured as the ratio of the H vs D substitution
products (PH/PD) and was estimated via mass spectrom-
etry. The deuterated dinitrobenzene 13D was prepared
via diazotization of 2,4-dinitroaniline in D2SO4 followed
by reduction of the diazonium salt with deuterohypo-
phosphoric acid.2 Its isotopic purity was 96.4% as
established by MS measurements. In separate experi-
ments when 13D was treated with t-BuOK in NH3 and
also when it was subjected to hydroxylation with 0.5
equiv of 1, it was shown that loss of the label in the
recovered substrate was negligible and within the ex-
perimental error: 2.1% and 2.5%, respectively. The value
of KIE in the VNS hydroxylation of 13D was greatly
affected by the reaction conditions (Table 10). These
results fit well the general mechanistic scheme of the
VNS process.
For the hydroxylation carried out in the presence of
NaOH with both of the alkyl peroxides 1 and 2 a
significant value of KIE ≈ 7 was observed. A similar
value of KIE = 6 was observed when t-BuOOK, generated
by treatment of 1 with an equimolar amount of t-BuOK,
was used in the reaction. Obviously under these condi-
tions the rate constant of the elimination with a weak
base has a small value; hence, it was a slow process
(26) Makosza, M.; Stalewski, J . Lieb. Ann. Chem. 1991, 605.
(27) Bordwell, F. G.; Hughes, D. L. J . Am. Chem. Soc. 1986, 108,
5991.

Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions
J . Org. Chem., Vol. 63, No. 13, 1998 4205
Ta ble 11
ratioa
substr
X
R
no.
ROOH
base (mol)
yield, %
2-OH
4-OH
6-OH
8a
0
8
63
12a
0
3
5
13
8b
100
92
8c
0
0
0
12c
0
11
18
43
29b
1
H
H
H
F
F
F
8
8
8
2
1
2
KOH (10)
t-BuOK (2.5)
t-BuOK (5)
76
83
72
37
12b
100
86
77
44
29a
99
64
H
H
H
H
CN
CN
CN
CN
12
12
12
12
2
1
1
2
KOH (10)
87
86
84
77
t-BuOK (2.5)
t-BuOK (5)
t-BuOK (5)
CF3
CF3
H
H
29
29
1
2
t-BuOK (2.5)
t-BuOK (5)
89
72
-
-
36
a
Ratio: 12b(12a +12c) based on isolated products, 12a :12c from 1H NMR.
determining the overall reaction rate. On the other hand,
when the reaction of 1 and 2 were each carried out in
the presence of an excess of t-BuOK, there was no
difference in the rate of substitution of H and D, so the
value of KIE was ∼1. These results suggest that the
elimination effected by a weak base, namely, the alkyl
hydroperoxide anion, is the rate-determining step. The
significant value of KIE agrees with the supposition that
the elimination is of E2 character. On the other hand,
disappearance of KIE when the reaction is carried out
with an excess of t-BuOK, a strong, soluble base, can be
rationalized by a high rate of elimination with the strong
(Po/Pp) can be estimated from simple transformations of
eq 5. Assuming the fast elimination step at both the
ortho and para positions k-1/kE[B] , 1, the ratio of the
products will be determined by the kinetic preferences
in the addition step, namely the rate of formation of
para
isomeric σ-adducts, Po/Pp ≈ k1ortho/k1
. In contrast,
when the elimination is the slow, rate-limiting step k-1
/
kE[B] . 1, the value Po/Pp ) (k1kE/k-1) )
ortho/(k1kE/k-1
para
will depend on the relative stability of the isomeric σH-
adducts as well as the corresponding rate constants of
the elimination. In this respect the effect of t-BuOK
concentration on the orientation of hydroxylation in
3-chloronitrobenzene 4 (Table 1), 3-fluoronitrobenzene 8,
and 3-cyanonitrobenzene 12 (Table 11) is informative.
Following this reasoning, the substantial extent and even
domination of the ortho-hydroxylation under the fast
elimination conditions observed for 3-fluoro- and 3-cy-
anonitrobenzene 8 and 12 (Table 11) and especially for
nitronaphthalenes (Table 12) indicates that for these
nitroarenes formation of σH-adducts at the ortho positions
base and its high concentration which assures that k-1
/
kE(H,D)[B] , 1. Thus the observed ratio of products PH
and PD reflects the ratio of σH and σD adducts initially
formed (no equilibration can occur because of the rapid
consumption of each of them). Alternatively, a situation
when the rate constants kE for the elimination of ROD
and ROH induced by a strong base become similar
because of an early, unsymmetrical transition state, thus
the value kE(H)/kE(D) ≈ 1 hence PH ≈ PD, cannot be
excluded. Since the secondary KIE for the nucleophilic
addition has a small value, it can be neglected in these
semiquantitative experiments. This change of the KIE
value depending on the reaction conditions, namely
strength and concentration of base, is compatible with
the conclusion from the competition between replacement
of chlorine and hydrogen in the structurally related and
similarly electrophilic 1-chloro-2,4-dinitrobenzene 31.
Or ien t a t ion of t h e VNS H yd r oxyla t ion (Ta b les
11-13). As already mentioned, the orientation of the
VHS hydroxylation is strongly affected by the reaction
conditions. A general trend emerged: in the reactions
performed with NaOH or KOH a highly selective para-
hydroxylation usually occurred while when excess t-
BuOK was used, a competing ortho-substitution process
ortho
para
proceeds faster than at the para position k1
> k1
.
para
Obviously, the exact values of k1ortho/k1
can not be
extracted from these results, as it is not certain whether
the border case of the fast elimination is already operat-
ing. On the other hand, para-hydroxylation generally
observed under the slow elimination conditions suggests
para
higher stability of the para σ-adducts; (k1/k-1
)
> (k1/
para
k-1
)
ortho hence k-1
, k-1ortho. Faster elimination from
para ortho
the less sterically hindered para σ-adduct kE
> kE
should also be considered; however, it is difficult to
separate these two effects. Some kinetic data available
for substituted 1,3-dinitrobenzenes indicate that anionic
σ-adducts at positions ortho to the nitro groups are
formed faster and also decompose faster than isomeric
para adducts.28 It appears that this is the case for the
majority of nitroarenes.
took place and, for certain nitroarenes, prevailed.
A
The ortho:para hydroxylation ratio depends also on the
temperature of the process. For example, in the reaction
of 1-nitronaphthalene 35, the extent of para hydroxyla-
tion increases with the increase of temperature (Table
13). This effect can be due to faster equilibration of the
σ-adducts, hence the tendency toward thermodynamic
control at higher temperatures.
reasonable explanation for this phenomenon can also be
associated with the change of the value of the partitioning
factor k-1/kE[B], depending on the reaction conditions.
Kinetic analysis of the competition between ortho and
para hydrogen substitution (Po/Pp) is rather complicated.
However, for the border values of k-1/kE[B] the ratios of

4206 J . Org. Chem., Vol. 63, No. 13, 1998
Makosza et al.
Ta ble 12
NH3 was dried by passing through KOH pellets tube prior to
its condensation; DMF (puriss. p.a.) was kept over molecular
sieves (4A); THF was distilled over sodium-benzophenone.
TLC: silica gel 60F254 (Merck). Flash chromatography: silica
gel 60 (230-400 mesh, Merck) and hexane-ethyl acetate or
chloroform or chloroform-methanol. Melting points (mp) are
not corrected, literature mp are quoted from Beilstein’s Hand-
buch der Organischen Chemie (unless otherwise stated).
NMR: in acetone-d6 unless otherwise stated, chemical shifts
δ in ppm in relation to internal standard TMS. Satisfactory
elemental analyses (C, H, N) were obtained for all products.
Rea ction s of Alk yl Hyd r op er oxid es w ith Nitr oa r en es
in Liqu id Am m on ia . Gen er a l P r oced u r e. To a stirred
solution of t-BuOK (2.5 or 5.0 equiv) or suspension of powdered
NaOH (10 equiv) or KOH (10 equiv) in liquid NH3 (ca. 10 mL)
was added dropwise a solution of nitroarene (3 mmol) and alkyl
hydroperoxide (3.3 mmol) in dry THF (3 mL). The reaction
was conducted under reflux at ca. -33 °C over 15 min for
t-BuOK, or 1 h for NaOH or KOH (unless otherwise stated,
see tables for details). Then solid NH4Cl was added, ammonia
evaporated, and the reaction mixture treated with 1 N HCl
(20 mL) and extracted with CH2Cl2 (3 × 15 mL). Combined
organic extracts were washed with 0.5 N NaOH (3 × 10 mL),
alkaline solution of nitrophenolates was acidified with 6 N HCl
and extracted with CH2Cl2 (3 × 15 mL), and the organic phase
was dried (Na2SO4) and evaporated. In most cases the residue
was subjected to flash chromatography to give pure products.
Certain products were purified by recrystallization; 41a , 42a ,
44a from ethanol; 43a , 44b, 45a from aqueous acetone; 47a
from acetone-heptane.
yield, %
2-OH 4-OH
(ib)
88
substr
X
no. “i”
ROOH
base (mol)
(ia )
H
H
H
H
NO2
NO2
NO2
NO2
Br
35
35
35
35
36
36
36
36
37
37
37
1
2
1
2
1
2
1
2
1
2
1
NaOH (10)
NaOH (10)
t-BuOK (2.5)
t-BuOK (2.5)
NaOH (10)
NaOH (10)
t-BuOK (2.5)
t-BuOK (2.5)
NaOH (10)a
NaOH (10)a
t-BuOK (2.5)
traces
5
81
4
81
79
22
64
81
81
32
61
85
4
61
30
5
4
44
19
traces
Br
Br
a
Reaction time: 3 h.
Ta ble 13
Rea ction s in THF or DMF of Nitr oa r en es 4 a n d 35. A
solution of nitroarene (3 mmol) and hydroperoxide 1 (0.300 g,
3.3 mmol) in THF or DMF (3 mL) was added dropwise to
t-BuOK (0.840 g, 7.5 mmol) in THF or DMF (10 mL). The
resulting mixture was stirred for 15 min at the temperature
given in the Tables 1 and 13, and then the reaction mixture
was diluted with 1 N HCl (40 mL) and the products were
isolated following the General Procedure.
yield, %
solv
temp, °C
35a
35b
NH3
NH3
DMF
DMF
DMF
-65
-33
-25
0
86
81
76
61
50
1
4
7
22
40
25
Rea ction s of P ota ssiu m Sa lts of Hyd r op er oxid es 1 or
2 a n d Nitr oa r en es 13D, 18, 21, a n d 31. To a cold (ca. -50
°C) solution of t-BuOK (3 or 7.5 mmol) in liquid NH3 (10 mL)
was added an equimolar amount of hydroperoxide 1 or 2. The
reaction mixture was allowed to warm up to the reflux
temperature, and then a solution of nitroarene (3 mmol) in
THF (3 mL) was added and the mixture stirred over 1 h.
Products were isolated according to the General Procedure.
Am m on iu m Sa lt 46a . Hydroxylation of 2-nitrothiophene
46 (3 mmol) with hydroperoxide 1 and t-BuOK in liquid NH3
was performed as given in General Procedure. After the
ammonia was evaporated, the residue was diluted with water
(20 mL) and treated with tetrabutylammonium hydrogen
sulfate (1.02 g, 3 mmol), and the mixture was shaken vigor-
ously over a few min and then extracted with CH2Cl2 (3 × 15
mL). Combined organic solutions were dried (Na2SO4) and
evaporated to give the crude salt 46a which was recrystallized
from hexane-ethyl acetate.
Con clu sion s
Hydroxylation of nitroarenes with tert-butyl and cumene
hydroperoxides 1 and 2 by vicarious nucleophilic substi-
tution is a general process of wide scope. Available data
suggests that it proceeds via nucleophilic addition of the
alkyl hydroperoxide anion to nitroarenes followed by
base-induced â-elimination of the alcohol. It appears that
the elimination proceeds according to an E2 type mech-
anism and that there is a full range of relations between
the rates of the addition and elimination processes.
Exp er im en ta l Section
4a : mp 70-71 °C (water) (lit. mp 70-71 °C). 1H NMR δ
7.13 (dd, 1H, J ) 8.6, 8.2), 7.86 (dd, 1H, J ) 8.2, 1.6), 8.13
(dd, 1H, J ) 8.6, 1.6).
Gen er a l. tert-Butyl hydroperoxide 1 (80% in t-Bu2O2) and
triphenylmethyl hydroperoxide 3 (pure grade) were purchased
from Aldrich. Cumene hydroperoxide 2 (90%, technical grade)
was used without purification. Commercially available start-
ing nitroarenes were purified when necessary. The following
substrates were prepared: 3-nitrophenyl methyl sulfone 11,29
4-nitrophenyl phenyl sulfone 24,30 1-bromo-5-nitronaphthalene
37,31 1-methoxy-4-nitronaphthalene 38,32 1-chloro-4-nitronaph-
thalene 39,33 and 4-cyanoisoquinoline 47.34 Solvents: gaseous
4b: mp 111-112 °C (water) (lit. mp 111 °C). 1H NMR δ
7.23 (d, 1H, J ) 9.0), 8.12 (dd, 1H, J ) 9.0, 2.8), 8.26 (d, 1H,
J ) 2.8).
4c: mp 87-89 °C (water) (lit. mp 70-71 °C). 1H NMR δ
7.25 (d, 1H, J ) 9.0), 7.70 (dd, 1H, J ) 9.0, 2.7), 8.10 (d, 1H,
J ) 2.7).
5a : mp 43-44 °C (hexane) (lit. mp 45 °C). Compared with
an authentic sample (TLC).
(28) Buncel, E.; Crampton, M. R.; Strauss, M. J .; Terrier, F. Electron
Deficient Aromatic - and Heteroaromatic - Base Interactions; Elsevier;
Amsterdam, 1984. Buncel, E.; Dust, J . M.; Terrier, F. Chem. Rev. 1995,
95, 2261.
(29) Twist, R. F.; Smiles, S. J . Chem. Soc. 1925, 1249.
(30) Waldom, W. R.; Reid, E. E. J . Am. Chem. Soc. 1923, 45, 2405.
(31) Lock, G. Monatsh. Chem. 1950, 81, 850.
5b: mp 112-114 °C (water) (lit. mp 45 °C). Compared with
an authentic sample (TLC).
6b: mp 92-94 °C (water) (lit. mp 95 °C). 1H NMR δ 2.30
(s, 3H), 7.01 (d, 1H, J ) 8.8), 7.99 (dd, 1H, J ) 8.8, 2.9), 8.06
(d, 1H, J ) 2.9).
(32) Alcan, P. G. E.; Wells, P. R. Austr. J . Chem. 1965, 18, 1391.
(33) Hodgson, H. H.; Walker, J . J . Chem. Soc. 1933, 1620.
(34) Tyson, E. T. J . Am. Chem. Soc. 1939, 61, 183.

Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions
J . Org. Chem., Vol. 63, No. 13, 1998 4207
7b: mp 101-103 °C (water) (lit. mp 103-104 °C). 1H NMR
δ 4.00 (s, 3H), 7.02 (d, 1H, J ) 8.6), 7.80 (d, 1H, J ) 2.6), 7.85
(dd, 1H, J ) 8.6, 2.6).
29b: mp 69-72 °C (hexane) (lit.36 mp 71-73 °C). 1H NMR
δ 7.38 (dm, 1H, J ) ∼8), 7.50 (dm, 1H, J ) ∼8), 7.66 (tm, 1H,
J ) ∼8).
8a : mp 90-92 °C (hexane) (lit. mp 91-92 °C). 1H NMR
(DMSO-d6) δ 7.01 (td, 1H, J ) 8.4, 5.0), 7.60 (ddd, 1H, J )
10.6, 8.4, 1.6), 7.74 (dt, 1H, J ) 8.4, 1.6).
31a : mp 90-91 °C (water) (lit. mp 92 °C). 1H NMR δ 7.54
(s, 1H), 8.84 (s, 1H).
32a : mp 125-127 °C (ethanol-water). 1H NMR δ 7.56 (s,
1H), 8.71 (s, 1H). IR: 2230.
33a : mp 53-54 °C (benzene-hexane). 1H NMR δ 7.53 (s,
1H), 8.46 (s, 1H).
34a : mp 66-67 °C (ethanol-water). 1H NMR δ 7.35 (d,
1H, J ) 9.3), 8.16 (d, 1H, J ) 9.3).
34b: mp 67.5-68 °C (ethanol-water) (lit.37 mp 68 °C). 1H
NMR δ 7.48 (s, 1H), 8.29 (s, 1H).
8b: mp 118-120 °C (water). 1H NMR (DMSO-d6) δ 7.14
(t, 1H, J ) 8.9), 8.01 (ddd, 1H, J ) 8.9, 2.7, 1.2), 8.10 (dt, 1H,
J ) 11.1, 2.7).
9b: mp 112-114 °C (water) (lit. mp 113-114 °C). 1H NMR
δ 7.21 (d, 1H, J ) 9.0), 8.15 (dd, 1H, J ) 9.0, 2.7), 8.40 (d, 1H,
J ) 2.7).
10b: mp 135-136 °C (benzene-hexane) (lit.35 mp 134-135
°C). 1H NMR δ 7.32 (d, 1H, J ) 9.1), 8.37 (dd, 1H, J ) 9.1,
2.8), 8.42 (d, 1H, J ) 2.8).
35a : mp 102-104 °C (ethanol) (lit. mp 103 °C) identical
with an authentic sample (TLC).
11b: mp 167-169 °C (water). 1H NMR δ 3.33 (s, 3H), 7.34
(d, 1H, J ) 9.1), 8.41 (dd, 1H, J ) 9.1, 2.9), 8.66 (d, 1H, J )
2.9).
35b: mp 163-164 °C (water) (lit. mp 164 °C) identical with
an authentic sample (TLC).
12a : mp 130-132 °C (ethanol) (lit. mp 132-133 °C). 1H
NMR δ 7.31 (dd, 1H, J ) 8.6, 7.7), 8.15 (dd, 1H, J ) 7.7, 1.7),
8.47 (dd, 1H, J ) 8.6, 1.7). IR: 2240.
36a : mp 190 °C, dec (ethanol-water) (lit. mp 187 °C, dec).
1H NMR δ 7.66 (d, 1H, J ) 9.6), 7.84 (dd, 1H, J ) 8.6, 7.7),
8.03 (ddd, 1H, J ) 8.6, 1.0, 0.9), 8.17 (dd, 1H, J ) 7.7, 1.0),
8.46 (dd, 1H, J ) 9.6, 0.9).
36b: mp 233 °C, dec (ethanol-water) (lit. mp 235 °C, dec).
1H NMR δ 7.19 (d, 1H, J ) 8.7), 7.82 (dd, 1H, J ) 7.5, 1.1),
7.90 (dd, 1H, J ) 8.8, 7.5), 8.49 (d, 1H, J ) 8.7), 8.82 (dd, 1H,
J ) 8.8, 1.1);
37a : mp 126-127 °C (ethanol-water). 1H NMR δ 7.56 (d,
1H, J ) 9.4), 7.57 (dd, 1H, J ) 8.6, 7.5), 7.75 (ddd, 1H, J )
8.6, 1.0, 0.9), 7.83 (dd, 1H, J ) 7.5, 1.0), 8.33 (dd, 1H, J ) 9.4,
0.9).
37b: mp 201-203 °C, dec (ethanol-water). 1H NMR δ 7.15
(d, 1H, J ) 8.7), 7.57 (dd, 1H, J ) 8.6, 7.5), 7.96 (dd, 1H, J )
7.5, 1.1), 8.26 (d, 1H, J ) 8.7), 8.57 (dd, 1H, J ) 8.6, 1.1).
38a : mp 121-123 °C (ethanol). 1H NMR δ 4.20 (s, 3H),
6.75 (s, 1H), 7.52-7.57 (m, 1H), 7.77-7.81 (m, 1H), 8.26-8.29
(m, 1H), 8.87-8.89 (m, 1H).
39a : mp 127-128 °C (ethanol). 1H NMR δ 7.59 (s, 1H),
7.65 (ddd, 1H, J ) 8.5, 6.9, 1.2), 7.78 (ddd, 1H, J ) 8.5, 6.9,
1.1), 7.88 (ddd, 1H, J ) 8.5, 1.1, 0.7), 8.27 (ddd, 1H, J ) 8.5,
1.2, 0.7).
12b: mp 193-194 °C (ethanol) (lit. mp 194 °C). 1H NMR δ
7.32 (d, 1H, J ) 9.2), 8.39 (dd, 1H, J ) 9.2, 2.8), 8.57 (d, 1H,
J ) 2.8). IR: 2240.
12c: mp 140-142 °C (ethanol) (lit. mp 143-145 °C). 1H
NMR δ 7.41 (d, 1H, J ) 8.7), 8.04 (dd, 1H, J ) 8.7, 2.1), 8.56
(d, 1H, J ) 2.1). IR: 2230.
13b: mp 112-114 °C (ethanol) (lit. mp 113-114 °C). 1H
NMR δ 7.23 (d, 1H, J ) 9.3), 8.33 (dd, 1H, J ) 9.3, 2.8), 8.85
(d, 1H, J ) 2.8).
14b: mp 120-122 °C (ethanol) (lit. mp 119-121 °C). 1H
NMR δ 7.29 (d, 1H, J ) 8.7), 7.60-7.90 (m, 5H), 8.45 (dd, 1H,
J ) 8.7, 2.8), 8.52 (d, 1H, J ) 2.8). IR: 1630.
17: mp 140-142 °C (water), identical with an authentic
sample.
18a : mp 37-39 °C (water) (lit. mp 39 °C). 1H NMR δ 7.13
(dd, 1H, J ) 9.1, 2.3), 7.27 (d, 1H, J ) 2.3), 8.14 (d, 1H, J )
9.1).
19a : mp 40-42 °C (hexane) (lit. mp 42 °C). 1H NMR δ 7.28
(dd, 1H, J ) 9.0, 2.1), 7.44 (d, 1H, J ) 2.1), 8.05 (d, 1H, J )
9.0).
20a : mp 94-96° (hexane) (lit. mp 96 °C). 1H NMR δ 7.48
(dd, 1H, J ) 8.8, 1.8), 7.65 (d, 1H, J ) 1.8), 7.85 (d, 1H, J )
8.8).
40a : mp 128-129 °C (ethanol) (lit. mp 128 °C) identical
with an authentic sample (TLC).
41a : mp 207-209 °C (ethanol). 1H NMR (DMSO-d6) δ 1.40
(t, 3H, J ) 7.0), 4.13 (q, 2H, J ) 7.0), 5.80 (s, 1H), 8.38 (s,
1H). IR: 1660.
22a : mp 93-95° (ethanol) (lit. mp 96 °C). 1H NMR δ 3.96
(s, 3H), 6.66 (m, 1H, J ) 9.9, 2.6), 6.66 (m, 1H, J ) 2.6), 8.08
(m, 1H, J ) 9.9);
42a : mp 177-179 °C (ethanol) (lit.38 mp 172-173 °C). 1H
NMR (DMSO-d6) δ 3.92 (s, 3H), 6.26 (d, 1H, J ) 9.0), 8.36 (d,
1H, J ) 9.0). IR: 1680.
43a : mp 189-191 °C, dec (acetone). 1H NMR (DMSO-d6)
δ 7.09 (d, 1H, J ) 8.4), 8.44 (d, 1H, J ) 8.4). IR: 1670.
44a : mp 250-251 °C, dec (ethanol) (lit. mp 255 °C, dec).
1H NMR δ 7.47 (dd, 1H, J ) 8.3, 4.4), 7.50 (d, 1H, J ) 9.1),
8.02 (d, 1H, J ) 9.1), 8.37 (dd, 1H, J ) 8.3, 1.7), 8.85 (dd, 1H,
J ) 4.4, 1.7).
44b: mp 261-263 °C, dec (acetone-water) (lit.39 mp 261
°C, dec). 1H NMR (DMSO-d6) δ 6.88 (d, 1H, J ) 8.8), 7.67
(dd, 1H, J ) 8.5, 4.5), 8.26 (d, 1H, J ) 8.8), 8.71 (dd, 1H, J )
8.5, 1.8), 9.01 (dd, 1H, J ) 4.5, 1.8).
23a : oil. 1H NMR δ 7.25 (dd, 1H, J ) 8.9, 1.9), 7.47 (d, 1H,
J ) 1.9), 8.25 (d, 1H, J ) 8.9).
24a : mp 141-143 °C (ethanol). 1H NMR δ 7.60 (dd, 1H, J
) 8.7, 2.0), 7.65-7.77 (m, 4H), 8.04-8.08 (m, 2H), 8.27 (d, 1H,
J ) 8.7).
25a : mp 119-121 °C (ethanol) (lit. mp 121 °C). 1H NMR δ
7.47 (dd, 1H, J ) 8.6, 1.7), 7.66 (d, 1H, J ) 1.7), 8.24 (d, 1H,
J ) 8.6). IR: 2240.
25b: mp 109-112 °C (hexane) (lit. mp 113 °C). 1H NMR
(AA′XX′ system) δ 6.98-7.01 (m, 2H), 7.59-7.62 (m, 2H). IR:
2220.
26a : mp 120-122 °C (water) (lit. mp 121-122 °C). 1H NMR
δ 6.99 (dd, 1H, J ) 9.0, 2.6), 7.08 (d, 1H, J ) 2.6), 8.01 (d, 1H,
J ) 9.0).
28a : mp 142-144 °C (ethanol) (lit. mp 144 °C). 1H NMR δ
3.93 (s, 3H), 6.54 (dd, 1H, J ) 9.0, 2.4), 6.68 (d, 1H, J ) 2.4),
7.88 (d, 1H, J ) 9.0).
29a : mp 77-79 °C (benzene-hexane) (lit. mp 78,5-79 °C).
1H NMR δ 7.29 (dd, 1H, J ) 8.9, 2.6), 7.35 (d, 1H, J ) 2.6),
8.08 (d, 1H, J ) 8.9).
45a : mp > 255 °C, dec (acetone-water) (lit.40 mp > 250
°C, dec). 1H NMR (DMSO-d6) δ 7.47 (dd, 1H, J ) 9.5, 0.7),
7.69 (dd, 1H, J ) 8.4, 4.4), 8.25 (d, 1H, J ) 9.5), 8.84 (ddd,
1H, J ) 8.4, 1.7, 0.7), 9.06 (dd, 1H, J ) 4.4, 1.7).
(36) Smith, M. A.; Applegate, V. C.; J ohnson, B. G. H. J . Chem. Eng.
Data. 1961, 6, 607.
(37) Acheson, R. M.; Taylor, N. F. J . Chem. Soc. 1956, 4727.
(38) Katritzky, A. R.; Tarhan, H. O.; Tarhan, S. J . Chem. Soc. (B)
1970, 114.
(39) Fuson, R. C.; Bauman, R. A.; Howard, E.; Marell, E. N. J . Org.
Chem. 1947, 12, 794.
(40) Lebenstedt, E.; Schumack, W. Arch. Pharm. 1975, 308, 977.
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27, 4660.

4208 J . Org. Chem., Vol. 63, No. 13, 1998
Makosza et al.
46a : mp 121-123 °C (hexane-ethyl acetate). 1H NMR δ
0.94-1.90 (m, 28H), 3.41-3.49 (m, 8H), 6.09 (d, 1H, J ) 6.2),
7.19 (d, 1H, J ) 6.2).
48a : mp 74-75 °C (hexane) (lit. mp 76 °C). 1H NMR δ 7.19
(d, 1H, J ) 9.1), 7.60 (d, 1H, J ) 9.1).
48b: mp 152-154 °C (heptane-diethyl ether) (lit.42 154 °C).
49: oil. 1H NMR δ 1.45 (s, 9H), 7.07 (d, 1H, J ) 8.8), 7.90
(dd, 1H, J ) 8.8, 2.7), 7.92 (d, 1H, J ) 2.7).
46b: dec without melting. 1H NMR δ 6.90 (d, 1H, J ) 5.9),
7.87 (d, 1H, J ) 5.9).
47a : mp 259-261 °C (acetone-heptane) (lit.41 mp 257 °C).
1H NMR δ 7.66-7.70 (m, 1H), 7.79-7.82 (m, 1H), 7.91-7.95
(m, 1H), 8.09 (s, 1H), 8.33-8.36 (m, 1H). IR: 2220, 1690.
J O970726M
(42) Harada, H.; Matsushita, Y.; Yodo, M.; Nakamura, M.; Yonetani,
Y. Chem. Pharm. Bull. 1987, 35, 3215.
(41) Eiden, F.; Nagar, B. S. Arch. Pharm. 1964, 247, 488.