Pinacol rearrangement of 3,4-dihydro-3,4-dihydroxyquinolin-2(1H)-ones: An alternative pathway to viridicatin alkaloids and their analogs

Article abstract of DOI:10.1002/hlca.201300074

3-Alkyl/aryl-3-hydroxyquinoline-2,4-diones were reduced with NaBH ₄ to give cis-3-alkyl/aryl-3,4-dihydro-3,4-dihydroxyquinolin-2(1H)- ones. These compounds were subjected to pinacol rearrangement by treatment with concentrated H₂SO

Full text of DOI:10.1002/hlca.201300074

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Pinacol Rearrangement of 3,4-Dihydro-3,4-dihydroxyquinolin-2(1H)-ones:
An Alternative Pathway to Viridicatin Alkaloids and Their Analogs
by Ondrˇej Rudolfa), Michal Rouchala), Antonꢀn Lycˇkab)c), and Antonꢀn Kla´sek*a)
a) Department of Chemistry, Faculty of Technology, Tomas Bata University, CZ-762 72 Zlꢀn
(e-mail: klasek@ft.utb.cz)
b) Research Institute for Organic Syntheses (VUOS), Rybitvꢀ 296, CZ-533 54 Pardubice 20
c
´
´
´
´
) University of Hradec Kralove, Faculty of Science, CZ-500 03 Hradec Kralove 3
ˇ
ˇ
Dedicated to Prof. Vojeslav Sterba on the occasion of his 90th birthday
3-Alkyl/aryl-3-hydroxyquinoline-2,4-diones were reduced with NaBH4 to give cis-3-alkyl/aryl-3,4-
dihydro-3,4-dihydroxyquinolin-2(1H)-ones. These compounds were subjected to pinacol rearrangement
by treatment with concentrated H2SO4, resulting in 4-alkyl/aryl-3-hydroxyquinolin-2(1H)-ones. When a
benzyl (Bn) group was present in position 3 of the starting compound, its elimination occurred during the
rearrangement, and the corresponding 3-hydroxyquinolin-2(1H)-one was formed. The reaction
1
mechanisms are discussed for all transformations. All compounds were characterized by IR, H- and
13C-NMR spectroscopy, as well as mass spectrometry.
Introduction. – 3-Hydroxyquinoline-2,4-diones 2 are known as metabolites of
some Pseudomonas species [1][2]. These compounds are available by several
pathways: the photooxidation of 4-hydroxyquinolin-2(1H)-ones 1 [3], the oxidation
of 4-hydroxyquinolin-2(1H)-ones with peroxy acids [1][4], or the reaction of the
quinisatines and/or their hydrates and aminals with phenols [5][6]. We studied, the
reaction of 2 with ethyl (triphenylphosphoranylidene)acetate to give (E)-4-[(ethoxy-
carbonyl)methylidene]-3-hydroxy-1,2,3,4-tetrahydroquinolin-2-ones and 2,3a,4,5-tet-
rahydrofuro[2,3-c]quinoline-2,4-diones was studied [7][8]. The same reaction with
3,5,8-trisubstituted starting compounds afforded, via a molecular rearrangement of 2,
1,3-dihydro-3-phenylacetoxy-2H-indol-2-ones [9]. 3-Acyloxy-1,3-dihydro-2H-indole-2-
ones and isomeric 4-acyl-1,4-dihydro-3,1-benzoxazin-2-ones were obtained by the
double rearrangement of 2 in boiling xylene in the presence of 4-(dimethylamino)-
pyridine (DMAP) or Ph3P as a catalyst [10], or by the thermally induced rearrange-
ment of 2 in boiling cyclohexylbenzene [11]. The rearrangement of compounds 2 also
proceeded in aqueous KOH with the formation of 2-hydroxyindoxyls and/or
dioxindoles [12].
Our results revealed that 3-hydroxyquinoline-2,4-diones 2 are very reactive
compounds, prone to the molecular rearrangements that result in the formation of
new heterocyclic compounds. The chemistry of 2 inspired us to attempt at their
reduction to the corresponding diols, which should also be suitable compounds to study
molecular rearrangements. Herein, we report the validity of that presumption, and that
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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novel and interesting compounds, including quinoline alkaloids, can be prepared in this
way.
Results and Discussion. – We have found only two examples of the reduction of 3-
hydroxyquinoline-2,4-diones 2 in the literature. Podesva et al. [13] prepared 6-chloro-
3,4-dihydro-3,4-dihydroxy-1-methyl-3-phenylquinolin-2(1H)-one by the reduction of
the corresponding 3-hydroxyquinoline-2,4-dione with NaBH4, and Kappe et al. [5]
prepared 3,4-dihydro-3,4-dihydroxy-3-(pyridin-2-yl)methylquinolin-2(1H)-one by the
hydrogenation of the corresponding 3-hydroxyquinoline-2,4-dione in the presence of a
Pd/C catalyst. In both cases, the configuration of the product was not described. For our
experiments, we chose NaBH4 as the reducing agent. The starting 3-hydroxyquinoline-
2,4-diones 2a – 2i were prepared by oxidation of the corresponding 4-hydroxyquinolin-
2(1H)-ones 1 with AcOOH according to a well-known protocol [7]. To determine the
influence of the R2 substituent on the transformation of compounds 2, we chose Bu, Ph,
and Bn groups. The H-atom, and the Me and Ph groups were selected as the R1
substituent.
The results of the reduction of compounds 2 with NaBH4 are compiled in Table 1. In
principle, four stereoisomers, i.e., two pairs of diastereoisomers, trans-3 and cis-3,
should form from the reduction (Scheme 1). However, all the reduction products 3a – 3i
Scheme 1

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Table 1. The Results of the Reduction of Compounds 2a – 2i
Entry
Starting compound
R1
R2
Product (Yield [%])a)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
Me
Me
Me
Ph
Ph
Ph
Bu
Ph
Bn
Bu
Ph
Bn
Bu
Ph
Bn
cis-3a (79)
cis-3b (88)
cis-3c (74)
cis-3d (64)
cis-3e (77)
cis-3f (75)
cis-3g (83)
cis-3h (93)
cis-3i (83)
a) The yields of pure recrystallized compounds are given.
exhibited only one TLC spot in several solvent systems. In the NMR spectra of the
reaction products (Table 2), only one set of signals was observed, indicating that the
reaction proceeded with high diastereoselectivity to give only one of the possible two
diastereoisomers.
The assignment of the 1H- and 13C-NMR chemical shifts of compounds 3 followed
from the analysis of 1D- and 2D-NMR (COSY, NOESY, HMQC, and gs-HMBC)
experiments. The differentiation of the resonance of the OH group was based on the
presenece of a 3J(C(4)H,C(4)OH) coupling, with a value of 4.8 ꢀ 0.5 Hz in the
1H-NMR spectra, while the OH group at C(3) appeared as a singlet. The NOESY
spectra of compounds 3 were recorded with the aim of determining the mutual
orientation of the substituents at C(3) and C(4). The results strongly supported a
through-space proximity of both OH groups, as well as the proximity of HꢁC(4) with
suitable H-atoms of the R2 substituent due to the appearance of appropriate cross-
peaks in the NOESY spectra. However, because the compounds 3 were not completely
rigid, the dynamic behavior of the substituents on C(3) and C(4) (certain rotamers)
resulted in some additional cross-peaks. The 1H and 13C chemical shifts of compounds 3
are collected in Table 2.
Thus, it was possible to differentiate between the possible diastereoisomers trans
and cis with NMR spectra. However, we decided to prepare a cyclic carbonate of one of
the reaction products by its reaction with triphosgene (¼ bis(trichloromethyl)
carbonate). From cis-3d, carbonate 4d was prepared, which is convincingly indicative
of the cis-configuration of the OH groups in 3d. In the 1H-NMR spectrum of 4d, no OH
group signals appeared, while a new resonance was detected in the 13C-NMR spectrum
of this compound, ascribed to a C(3)ꢁOꢁC(¼O)ꢁOꢁC(4) fragment, resonating at
153.2 ppm (Table 2).
The ESI-MS experiments of compounds cis-3 were carried out in the positive-ion
mode. Typically, signals at m/z corresponding to [M þ H]þ, as well as [M þ Na]þ and
[M þ K]þ were observed for all of the examined structures (except the [M þ H]þ ion for
cis-3b). These signals were accompanied by several types of higher associates, namely
the singly charged Naþ adduct of the dimer [2M þ Na]þ and the doubly charged Ca2þ
adduct of the trimer [3M þ Ca]2þ. In addition, the doubly charged Ca2þ adduct of the
dimer [2M þ Ca]2þ was determined in the first-order ESI mass spectra of cis-3c, cis-3f,

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and cis-3i bearing a Bn group at C(3). The fragmentation (MS/MS) of the [M þ H]þ ion
under collision-induced dissociation (CID) conditions led in all cases to the loss of a
H2O molecule. Further fragmentation (MS3) of the [M þ H ꢁ H2O]þ ion was
considerably affected by the R2 substituent at C(3). In the MS3 of compounds cis-3a,
cis-3d, and cis-3g (R2 ¼ Bu), three signals originating from consecutive losses of CO
and two CH2¼CH2 molecules were observed. When a Ph group was present at C(3)
(cis-3b, cis-3e, and cis-3h), only the loss of CO (m/z 28) occurred. Finally, in the MS3 of
compounds cis-3c, cis-3f, and cis-3i (R2 ¼ Bn), two signals, assigned to [M þ H ꢁ
H2O ꢁ CO]þ and Bnþ (m/z 91), were observed.
Only two compounds 3 were reported in the literature [5][13], but neither their
configuration nor biological activity were. However, from Penicilium janczewskii, two
diastereoisomeric alkaloids were isolated, differing from cis-3b only by the presence of
the 4-methoxyphenyl group at C(4) and the H-atom at C(3). These alkaloids showed
low-to-moderate cytotoxic activities against various human tumor cell lines, but
significantly stronger cytotoxicities against SKOV-3 cells (human ovary adenocarcino-
ma) [14].
Compounds cis-3 are vicinal diols that are easily liable to the pinacol rearrangement
[15 – 17] under acid catalysis. To perform the rearrangement of compounds cis-3, we
used concentrated H2SO4.
The rearrangement of diols cis-3a, cis-3b, cis-3d, cis-3e, cis-3g, and cis-3h took place
quickly and, with the exception of cis-3g, only a single product was obtained (Table 3).
The IR spectrum of the products exhibited strong absorption bands characteristic
of a OH group in the region of 3251 – 3436 cmꢁ1, and an amide group in the region of
1643 – 1685 cmꢁ1, but it did not exhibit any absorption bands in the aldehyde or ketone
region.
Table 3. The Results of the Rearrangement of Compounds cis-3
Entry
Starting compound
R1
R2
Product (Yield [%])a)
1
2
3
4
5
6
7
8
9
cis-3a
cis-3b
cis-3c
cis-3d
cis-3e
cis-3f
cis-3g
cis-3h
cis-3i
H
H
H
Me
Me
Me
Ph
Ph
Ph
Bu
Ph
Bn
Bu
Ph
Bn
Bu
Ph
Bn
5a (71)
5b (85)
6c (59)
5d (72)
5e (93)
6f (63)
5g (61), 1g (9)b)
5h (65)
6i (58)
a) The yields of pure recrystallized compounds. b) Identical in all respects to the authentic sample.
Four compounds may be produced during the rearrangement of compounds cis-3
(Scheme 2). The structures A, B, and 1 can be excluded, because they are not in
accordance with the IR spectra of the products. The remaining structure 5 is, therefore,
plausible as the structure of the products of the pinacol rearrangement of compounds
cis-3. This result indicates that the elimination of H2O from C(4) of the protonated cis-3
results in the formation of a secondary carbocation securing the aromatic ring, which

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Scheme 2
contributes to the delocalization of the positive charge (benzylic cation). The following
1,2-shift of the alkyl or aryl group from C(3) provides a tertiary carbocation which,
after the deprotonation, gives compound 5. It is interesting that also compounds cis-3b,
3e, and 3h with Ph substituents at C(3), which should be able to create a carbocation at
C(3), also react to give products 5. From this viewpoint, it is surprising that the isomeric
side product 1g was isolated in addition to 5g from the reaction of cis-3g with H2SO4.
The NMR data of compounds 5 are compiled in Table 4. In the case of compounds cis-
3c, cis-3f, and cis-3i, the products of molecular rearrangement did not exhibit the Bn
signals in their NMR spectra and were identified as debenzylated compounds 6. The
formation of 6 can be explained as the result of the stabilization of the intermediate
carbocation by removal of the Bn group (Scheme 2). The NMR data of compounds 6
are given in Table 4.
In the positive-ion-mode first-order ESI-MS of compounds 5, we observed five
significant peaks for each structure. These peaks were assigned to the [M þ H]þ ion,
Naþ and Kþ adducts of the molecular ion, Naþ adduct of the dimer, and doubly charged
Ca2þ adduct of the trimer [3M þ Ca]2þ. In the first-order ESI-MS of compounds 6, the
peaks mentioned above were accompanied by those of two additional ions, namely of
the Kþ adduct of the dimer [2M þ K]þ and a peak at m/z corresponding to the doubly
charged Ca2þ adduct of the tetramer [4M þ Ca]2þ. Moreover, in the case of compounds
6c and 6f, the [3M þ K]þ ion peak was also detected. It should be noted that the peak at
m/z 91 (Bnþ), which was formed during the fragmentation (MS3) of compounds cis-3c,
cis-3f, and cis-3i, and was also observed at low intensity in the first-order MS of these

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structures (see Exper. Part), was completely absent in the ESI-MS of compounds 6.
These results were in accordance with other structural analyses, indicating that
structures 6c, 6f, and 6i are debenzylated products due to the rearrangement of
corresponding compounds cis-3.
In nature, compounds 5 bearing a Ph group at C(4) occur frequently as secondary
metabolites of fungi belonging to the genus Penicillium [18]. Two of the well-known
quinolin-2-ones of fungal origin are viridicatin (5b) and viridicatol (viridicatin bearing
a OH group at C(3) of the Ph substituent). These compounds showed significant
biological activities [19], e.g., inhibition of the glycine binding site associated with the
NMDA receptor [20], inhibition of human immunodeficiency virus (HIV) induced by
tumor necrosis factor (TNF-a) [21], and antibacterial activities owing to their action as
maxi-K channel openers [22]. Additionally, compounds 6 exhibit biological activities,
e.g., 6c causes reduction of lymphocyte MT-4 cells, and inhibits activity of reverse
transcriptase ribonuclease H of HIV-1 and d-amino acid oxidase [23], and 6f inhibits
activity of d-amino acid oxidase [23]. 3-Butyl derivatives 5a, 5d, and 5g have not been
described in the literature yet, but a 4-Me analog of 5a exhibited biological effects
similar to those of compounds 6c and 6f [23].
4-Alkyl/aryl-3-hydroxyquinolin-2(1H)-ones or their 4-unsubstituted analogs were
most frequently prepared by the reaction of isatins with aryldiazomethanes or
diazoalkanes [24 – 26], or by Friedlꢀnder-type condensations [27]. The best hitherto
known method for the preparation of 4-arylquinolin-2(1H)-one derivatives appears to
be the Knoevenagel condensation of cyanoacetanilides with aromatic aldehydes,
followed by oxidative cyclization [19].
Conclusions. – In summary, we have demonstrated an efficient approach to the
synthesis of 4-alkyl/aryl-3-hydroxyquinolin-2(1H)-ones 5 or 6, starting from the easily
accessible 3-hydroxyquinoline-2,4-diones 2. The NaBH4 reduction of 2 proceeds with
high diastereoselectivity to give cis-3,4-dihydro-3,4-dihydroxyquinolin-2(1H)-ones, cis-
3, as the sole products. The subsequent pinacol rearrangement of cis-3 to 5 or 6 opens
the way to prepare a broad-spectrum of both 4-alkyl- or 4-aryl substituted compounds 5
and 4-unsubstituted compounds 6. The described transformations are very interesting
from the viewpoint of theory and, owing to the simple reaction protocol, open a path to
the synthesis of new compounds of types 3, 5, and 6. Because compounds 3, 5, and 6
exhibit significant biological activities, the new compounds described in this article
could also be interesting structures for studies in this direction.
O. R., M. R., and A. K. thank TBU in Zlꢁn for financial support (internal grant No. IGA/FT/2012/
015, funded from the resources of specific university research). The authors are grateful to Mrs. H.
´
Gerzˇova (Faculty of Technology, Tomas Bata University in Zlꢀn) for technical help.
Experimental Part
1. General. TLC: Alugramꢃ-SIL-G/UV254 foils (MachereyꢁNagel); elution with benzene/AcOEt 4 :1,
CHCl3/EtOH 9 :1 and/or 19 :1, CHCl3/AcOEt 7:3, and THF/AcOH 4 :1. Column chromatography (CC):
silica gel (SiO2; Merck, grade 60, 70 – 230 mesh); elution with CHCl3, then CHCl3/EtOH 99 :1 ! 8 :2 or
benzene, and then benzene/AcOEt 99 :1 ! 8 :2. M.p.: Kofler block or Gallencamp apparatus. IR Spectra:
Nicolet iS10 spectrophotometer; KBr; in cmꢁ1. NMR Spectra: Bruker Avance spectrometer at 500.13

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(1H) and 125.76 MHz (13C), and Bruker Avance II 400 spectrometer at 400.13 (1H) and 100.56 (13C);
(D6)DMSO soln.; d in ppm rel. to Me4Si as internal standard; J in Hz; manufacturerꢄs software for all 2D
experiments (gradient-selected gs-COSY, gs-NOESY, gs-HMQC, and gs-HMBC). EI-MS (pos.):
Shimadzu QP-2010 instrument within m/z 50 – 600, using direct inlet probe (DI); analysis of samples in
CH2Cl2 (30 mg/ml), 10 ml of the soln. was evaporated in DI cuvette at 50; ion-source temp., 2008; the
energy of electrons, 70 eV; only signals exceeding rel. abundance of 5% are listed. ESI-MS (pos. as well
as neg.): amaZon X ion-trap mass spectrometer (Bruker Daltonics, DE-Bremen) equipped with an ESI
source; individual samples infused into the ion source as MeOH/H2O 1:1 (v/v) solns. via a syringe pump
at a constant flow rate of 4 ml/min; other instrumental conditions: m/z range, 50 – 1500; electrospray
voltage, ꢀ 4.2 kV; drying gas temp., 220; drying gas flow, 6.0 dm3/min; nebulizer pressure, 55.16 kPa; cap.
exit, ꢀ 140 V; N2 used as nebulizing as well as drying gas. Elemental analysis (C, H, N): Flash EA 1112
elemental analyzer (Thermo Fisher Scientific).
2. General Procedure for the Preparation of Compounds cis-3 (¼(3R*,4R*)-3). NaBH4 (85 mg,
2.5 mmol) was added in four portions during 5 min to the stirred soln. of compound 2 (2 mmol) in MeOH
(10 ml) at r.t. After 20 min, crushed ice (up to 20 g), conc. HCl (0.25 ml), and H2O (4 ml) were added
successively to the mixture under cooling with crushed ice. Deposited product was filtered off, washed
with H2O, and recrystallized from an appropriate solvent. In the case of cis-3i, the deposited product was
of a gummy character; therefore, the mixture was extracted with CHCl3. The dried (Na2SO4) extract was
evaporated to dryness, and the residue was recrystallized from the benzene/hexane mixture. The yields
are given in Table 1, for NMR spectra of compounds cis-3, see Table 2.
cis-3-Butyl-3,4-dihydro-3,4-dihydroxyquinolin-2(1H)-one (cis-3a). Prepared from 2a in 79% yield.
White solid. M.p. 160 – 1708 and then 176 – 1908 (MeOH). IR: 3434, 3218, 3072, 2950, 2927, 2869, 1673,
1637, 1596, 1486, 1436, 1386, 1238, 1226, 1162, 1126, 1079, 1058, 873, 848, 761, 694, 671, 518. EI-MS: 235 (7,
Mþ), 132 (21), 123 (8), 122 (100), 94 (12), 93 (9), 77 (12), 57 (7). ESI-MS (pos.): 493.3 (24, [2 M þ
Na]þ), 372.8 (87, [3 M þ Ca]2þ), 274.2 (11, [M þ K]þ), 258.2 (100, [M þ Na]þ), 236.2 (13, [M þ H]þ),
218.2 (15, [M þ H ꢁ H2O]þ). Anal. calc. for C13H17NO3 (235.28): C 66.36, H 7.28, N 5.95; found: C 66.42,
H 7.27, N 5.95.
cis-3,4-Dihydro-3,4-dihydroxy-3-phenylquinolin-2(1H)-one (cis-3b). Prepared from 2b in 88% yield.
White solid. M.p. 236 – 2428 (EtOH). IR: 3432, 3355, 3199, 3062, 1671, 1637, 1594, 1488, 1448, 1432, 1374,
1332, 1270, 1238, 1203, 1176, 1099, 1079, 1045, 1024, 971, 943, 914, 873, 846, 794, 767, 750, 709, 692, 674,
570, 536. EI-MS: 255 (7, Mþ), 132 (10), 123 (8), 122 (100), 94 (13), 93 (9), 77 (37), 71 (6), 57 (6), 51 (9).
ESI-MS (pos): 533.2 (14, [2M þ Na]þ), 294.2 (85, [M þ K]þ), 278.2 (100, [M þ Na]þ), 238.2 (7, [M þ H ꢁ
H2O]þ). Anal. calc. for C15H13NO3 (255.27): C 70.58, H 5.13, N 5.49; found: C 70.64, H 5.15, N 5.45.
cis-3-Benzyl-3,4-dihydro-3,4-dihydroxyquinolin-2(1H)-one (cis-3c). Prepared from 2c in 74% yield.
White solid. M.p. 230 – 2338 (MeOH). IR: 3419, 3303, 3218, 2915, 1666, 1633, 1596, 1488, 1454, 1432,
1394, 1299, 1282, 1241, 1207, 1112, 1070, 1022, 944, 916, 877, 848, 833, 761, 738, 721, 696, 671, 659, 632, 586,
503. EI-MS: 269 (21, Mþ), 251 (20), 178 (17), 177 (5), 161 (10), 160 (24), 149 (7), 133 (10), 132 (69), 123
(8), 122 (100), 121 (8), 120 (6), 105 (7), 104 (12), 94 (14), 93 (20), 92 (16), 91 (65), 78 (8), 77 (30), 76
(5), 65 (24), 51 (11). ESI-MS (pos.): 561.2 (5, [2M þ Na]þ), 423.7 (9, [3M þ Ca]2þ), 308.2 (48, [M þ K]þ),
292.2 (100, [M þ Na]þ), 289.2 (43, [2M þ Ca]2þ), 270.2 (19, [M þ H]þ), 252.2 (4, [M þ H ꢁ H2O]þ), 91.3
(3, [Bn]þ). Anal. calc. for C16H15NO3 (269.30): C 71.36, H 5.61, N 5.20; found: C 71.27, H 5.63, N 5.18.
cis-3-Butyl-3,4-dihydro-3,4-dihydroxy-1-methylquinolin-2(1H)-one (cis-3d). Prepared from 2d in
64% yield. White solid. M.p. 100 – 1038 (benzene/hexane). IR: 3457, 3394, 2950, 2925, 2857, 1666, 1604,
1477, 1359, 1288, 1178, 1132, 1110, 1079, 1047, 943, 842, 755, 696, 640, 609, 553. EI-MS: 249 (10, Mþ), 164
(30), 147 (13), 146 (100), 136 (35), 135 (8), 118 (32), 106 (16), 91 (14), 77 (12), 57 (6), 41 (9). ESI-MS
(pos.): 537.3 (5, [2M þ K]þ), 521.3 (22, [2M þ Na]þ), 393.8 (100, [3M þ Ca]2þ), 288.2 (10, [M þ K]þ),
272.2 (50, [M þ Na]þ), 250.2 (8, [M þ H]þ), 232.2 (4, [M þ H ꢁ H2O]þ). Anal. calc. for C14H19NO3
(249.31): C 67.45, H 7.68, N 5.62; found: C 67.53, H 7.70, N 5.68.
cis-3,4-Dihydro-3,4-dihydroxy-1-methyl-3-phenylquinolin-2(1H)-one (cis-3e). Prepared from 2e in
77% yield. White solid. M.p. 198 – 2008 (benzene). IR: 3475, 3399, 1660, 1606, 1592, 1467, 1380, 1290,
1213, 1110, 1074, 1047, 1025, 970, 850, 790, 755, 742, 703, 680, 649, 624, 576. EI-MS: 269 (11, Mþ), 165 (7),
164 (43), 147 (8), 146 (78), 137 (9), 136 (100), 135 (11), 119 (6), 118 (68), 117 (6), 107 (8), 106 (38), 105
(38), 93 (8), 91 (24), 78 (12), 77 (68), 65 (7), 51 (17). ESI-MS (pos.): 561.2 (18, [2M þ Na]þ), 423.7 (68,

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[3M þ Ca]2þ), 308.2 (17, [M þ K]þ), 292.2 (100, [M þ Na]þ), 270.2 (5, [M þ H]þ), 252.2 (24, [M þ H ꢁ
H2O]þ), 224.2 (23, [252 ꢁ CO]þ). Anal. calc. for C16H15NO3 (269.29): C 71.36, H 5.61, N 5.20; found:
C 71.50, H 5.59, N 5.18).
cis-3-Benzyl-3,4-dihydro-3,4-dihydroxy-1-methylquinolin-2(1H)-one (cis-3f). Prepared from 2f in
75% yield. White solid. M.p. 144 – 1478 (benzene). IR: 3396, 3021, 1643, 1604, 1473, 1415, 1380, 1305,
1213, 1157, 1122, 1066, 1045, 1006, 916, 873, 786, 754, 732, 698, 673, 646, 584. EI-MS: 283 (21, Mþ), 265 (9),
236 (17), 192 (39), 191 (5), 175 (9), 174 (45), 164 (15), 147 (14), 146 (100), 136 (17), 135 (7), 118 (30),
106 (18), 91 (63), 78 (7), 77 (22), 65 (16), 51 (9). ESI-MS (pos.): 589.2 (7, [2M þ Na]þ), 444.7 (20, [3M þ
Ca]2þ), 322.2 (30, [M þ K]þ), 306.2 (100, [M þ Na]þ), 303.2 (58, [2M þ Ca]2þ), 284.2 (23, [M þ H]þ), 91.3
(4, [Bn]þ). Anal. calc. for C17H17NO3 (283.32): C 72.07, H 6.05, N 4.94; found: C 72.03, H 6.05), N 4.98.
cis-3-Butyl-3,4-dihydro-3,4-dihydroxy-1-phenylquinolin-2(1H)-one (cis-3g). Prepared from 2g in
83% yield. White solid. M.p. 165 – 1698 (benzene/hexane). IR: 3475, 3440, 3062, 2954, 1677, 1604, 1492,
1459, 1346, 1299, 1282, 1265, 1186, 1147, 1079, 1058, 1004, 944, 871, 856, 763, 696, 646, 559. EI-MS: 311 (16,
Mþ), 238 (9), 237 (7), 227 (6), 226 (42), 209 (17), 208 (100), 198 (24), 197 (18), 196 (11), 181 (12), 180
(80), 168 (25), 167 (14), 93 (6), 77 (22), 65 (6), 57 (16), 51 (9), 43 (11), 41 (17). ESI-MS (pos.): 645.3 (12,
[2M þ Na]þ), 627.3 (9, [2M þ Na ꢁ H2O]þ), 486.8 (40, [3M þ Ca]2þ), 677.8 (16, [2M þ Ca ꢁ H2O]2þ),
350.2 (19, [M þ K]þ), 234.3 (100, [M þ Na]þ), 216.2 (32, [M þ Na ꢁ H2O]þ), 312.3 (19, [M þ H]þ), 294.3
(77, [M þ H ꢁ H2O]þ), 266.3 (4, [294 ꢁ CO]þ). Anal. calc. for C19H21NO3 (311.38): C 73.29, H 6.80, N
4.50; found: C 73.35, H 6.79, N 4.30.
cis-3,4-Dihydro-3,4-dihydroxy-1,3-diphenylquinolin-2(1H)-one (cis-3h). Prepared from 2h in 93%
yield. White solid. M.p. 197 – 2008 (benzene/hexane). IR: 3469, 3311, 2852, 1675, 1606, 1494, 1459, 1347,
1267, 1184, 1120, 1074, 1027, 1000, 944, 854, 761, 725, 700, 688, 649, 588. EI-MS: 331 (13, Mþ), 303 (5), 227
(7), 226 (43), 209 (11), 208 (66), 199 (8), 198 (56), 197 (30), 196 (17), 181 (15), 180 (100), 169 (7), 168
(44), 167 (19), 152 (8), 106 (9), 105 (45), 93 (9), 78 (9), 77 (78), 65 (10), 51 (23). ESI-MS (pos.): 685.3 (7,
[2M þ Na]þ), 516.8 (6, [3M þ Ca]2þ), 370.2 (33, [M þ K]þ), 354.2 (100, [M þ Na]þ), 332.3 (3, [M þ H]þ),
314.3 (6, [M þ H ꢁ H2O]þ), 286.3 (5, [314 ꢁ CO]þ). Anal. calc. for C21H17NO3 (331.36): C 76.12, H 5.17,
N 4.23; found: C 76.26, H 5.28), N 3.95.
cis-3-Benzyl-3,4-dihydro-3,4-dihydroxy-1-phenylquinolin-2(1H)-one (cis-3i). Prepared from 2i in
83% yield. White solid. M.p. 148 – 1528 (benzene/hexane). IR: 3461, 3062, 1687, 1602, 1494, 1459, 1351,
1299, 1236, 1199, 1128, 1108, 1022, 960, 875, 862, 761, 730, 696, 647, 599. EI-MS: 346 (8), 345 (32, Mþ), 327
(7), 298 (20), 255 (8), 254 (49), 237 (10), 236 (48), 226 (29), 209 (18), 208 (100), 198 (15), 197 (16), 196
(13), 181 (13), 180 (97), 179 (8), 168 (31), 167 (19), 152 (10), 105 (15), 92 (12), 91 (55), 78 (7), 77 (38),
66 (6), 65 (21), 51 (16). ESI-MS (pos.): 713.2 (5, [2M þ Na]þ), 537.8 (7, [3M þ Ca]2þ), 384.2 (43, [M þ
K]þ), 368.2 (100, [M þ Na]þ), 365.2 (41, [2M þ Ca]2þ), 346.3 (10, [M þ H]þ), 328.3 (5, [M þ H ꢁ H2O]þ),
91.3 (3, [Bn]þ). Anal. calc. for C22H19NO3 (345.39): C 76.50, H 5.54, N 4.06; found: C 76.54, H 5.55, N
3.88.
3. Synthesis of 3a-Butyl-5,9b-dihydro-5-methyl[1,3]dioxolo[4,5-c]quinoline-2,4(3aH)-dione (4d).
Triphosgene (¼ bis(trichloromethyl) carbonate; 43 mg, 0.073 mmol) was added at r.t. in several portions
during 1 h to the well-stirred soln. of cis-3d (99 mg, 0.4 mmol), Et3N (0.138 ml, 0.1 mmol), and DMAP
(¼4-(dimethylamino)pyridine; 20 mg, 0.18 mmol) in benzene (10 ml). The soln was stirred at r.t. for 1 h
and then heated at reflux for 4 h. After cooling, the soln was filtered, and the filtrate was evaporated to
dryness. H2O (15 ml) was added to the residue, and the suspension was extracted with benzene (3 ꢂ
20 ml). Collected extracts were dried (Na2SO4), evaporated, and the residue was separated by CC
(SiO2). Compound 4d was obtained in 34% yield. White solid. M.p. 150 – 1518 (benzene/hexane). IR:
2956, 2871, 1818, 1700, 1616, 1585, 1496, 1465, 1379, 1344, 1232, 1188, 1165, 1109, 1070, 1008, 979, 935, 918,
777, 763, 679, 638, 532. NMR Spectra: see Table 2. EI-MS: 276 (10), 275 (60, Mþ), 247 (11), 205 (15), 203
(11), 189 (8), 188 (15), 175 (33), 174 (19), 161 (10), 160 (43), 149 (23), 148 (10), 147 (51), 135 (15), 134
(16), 133 (8), 132 (23), 130 (13), 125 (10), 120 (13), 119 (31), 118 (100), 117 (27), 113 (10), 111 (12), 107
(9), 106 (9), 104 (10), 99 (11), 97 (17), 95 (9), 91 (55),90 (13), 89 12), 85 (32), 83 (26), 81 (13), 78 (11),
77 (40), 76 (10), 71 (40), 70 (16), 69 (25), 65 (16), 57 (81), 56 (13), 55 (41), 51 (19), 44 (42), 43 71), 42
(23), 41 (77). ESI-MS (pos.): 573.2 (25, [2M þ Na]þ), 314.2 (33, [M þ K]þ), 298.2 (100, [M þ Na]þ),
276.2 (12, [M þ H]þ), 254.2 (6, [M þ Na ꢁ CO2]þ), 232.2 (5, [M þ H ꢁ CO2]þ). Anal. calc. for C15H17NO4
(275.30): C 65.44, H 6.22, N 5.09; found: C 65.58, H 6.28, N 5.09.

Helvetica Chimica Acta – Vol. 96 (2013)
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4. General Procedure for the Rearrangement of Compounds cis-3. Under intensive stirring, the
starting compound cis-3 (0.75 mmol) was dissolved at 08 in conc. H2SO4 (2 ml), and stirring was
continued for 1 h at r.t. The mixture was blended with crushed ice (15 g), the deposited precipitate was
filtered with suction, washed with H2O (10 ml), then with a 3% soln. of NaHCO3 (4 ml) and H2O, and
recrystallized from an appropriate solvent. In the case of cis-3i, the crude mixture after blending with
crushed ice was extracted with CHCl3. The dried (Na2SO4) extract was evaporated to dryness and
worked-up by CC (SiO2). The yields are given in Table 3, for NMR spectra of compounds 5 and 6, see
Table 4.
4-Butyl-3-hydroxyquinolin-2(1H)-one (5a). Prepared from cis-3a in 71% yield. White solid. M.p.
179 – 1888 (benzene). IR: 3436, 3291, 2956, 2871, 1646, 1625, 1569, 1506, 1405, 1288, 1259, 1218, 1114, 952,
904, 755, 715, 682, 626, 565. EI-MS: 217 (Mþ, 20), 188 (13), 176 (11), 175 (100), 174 (14), 146 (19), 129
(8), 128 (22), 117 (10), 115 (8), 91 (7), 90 (7), 77 (13), 43 (7), 41 (9). ESI-MS (pos.): 457.3 (19, [2M þ
Na]þ), 345.8 (45, [3M þ Ca]2þ), 256.2 (21, [M þ K]þ), 240.2 (81, [M þ Na]þ), 218.2 (100, [M þ H]þ).
Anal. calc. for C13H15NO2 (217.26): C 71.87, H 6.96, N 6.45; found: C 72.12, H 6.94, N 6.51.
3-Hydroxy-4-phenylquinolin-2(1H)-one (5b). Prepared from cis-3b in 85% yield. White solid. M.p.
270 – 2718 (benzene). For 5b (viridicatin), m.p. of 266 – 2698 was reported [19]. IR: 3357, 3058, 2994,
2869, 1658, 1635, 1575, 1506, 1409, 1351, 1309, 1292, 1226, 1157, 952, 883, 759, 717, 698, 673, 611, 595. EI-
MS: 238 (14), 237 (91, Mþ), 236 (100), 191 (6), 190 (22), 180 (23), 165 (7), 152 (14), 118 (10), 95 (8), 90
(8), 77 (18), 76 (16), 57 (11), 43 (12). ESI-MS (pos.): 497.2 (25, [2M þ Na]þ), 375.7 (56, [3M þ Ca]2þ),
276.2 (36, [M þ K]þ), 260.2 (100, [M þ Na]þ), 238.2 (40, [M þ H]þ). Anal. calc. for C15H11NO2 (237.25):
C 75.94, H 4.67, N 5.90; found: C 76.02, H 4.71, N 5.83.
4-Butyl-3-hydroxy-1-methylquinolin-2(1H)-one (5d). Prepared from cis-3d in 72% yield. White
solid. M.p. 118 – 1218 (benzene/hexane). IR: 3284, 2958, 2925, 2852, 1644, 1616, 1600, 1506, 1467, 1459,
1415, 1400, 1328, 1249, 1168, 1120, 1049, 954, 848, 781, 744, 682, 646, 599. EI-MS: 231 (22, Mþ), 202 (11),
190 (13), 189 (100), 188 (12), 161 (10), 160 (39), 149 (38), 132 (12), 131 (7), 130 (15), 117 (20), 115 (12),
113 (13), 111 (16), 109 (10), 99 (16), 98 (11), 97 (27), 95 (16), 91 (12), 71 (54), 69 (52), 67 (18), 57 (91),
55 (45), 43 (92), 41 (69). ESI-MS (pos.): 485.2 (18, [2M þ Na]þ), 366.8 (78, [3M þ Ca]2þ), 270.2 (10,
[M þ K]þ), 254.2 (100, [M þ Na]þ), 232.3 (55, [M þ H]þ). Anal. calc. for C14H17NO2 (231.29): C 72.70, H
7.41, N 6.06; found: C 72.62, H 7.44, N 6.05.
3-Hydroxy-1-methyl-4-phenylquinolin-2(1H)-one (5e). Prepared from cis-3e in 93% yield. White
solid. M.p. 212 – 2158 (benzene: [19]: 190 – 1918). IR: 3262, 3064, 2940, 1642, 1623, 1600, 1498, 1463, 1417,
1394, 1346, 1328, 1272, 1162, 1118, 948, 912, 782, 754, 742, 700, 673, 644, 559. EI-MS: 252 (15), 251 (91,
Mþ), 250 (100), 194 (18), 165 (13), 152 (11), 126 (6), 89 (6), 77 (12), 76 (9), 51 (5). ESI-MS (pos.): 525.2
(21, [2M þ Na]þ), 396.8 (51, [3M þ Ca]2þ), 290.2 (28, [M þ K]þ), 274.2 (100, [M þ Na]þ), 252.2 (53,
[M þ H]þ). Anal. calc. for C16H13NO2 (251.28): C 76.48, H 5.21, N 5.57; found: C 76.45, H 5.21, N 5.74.
4-Butyl-3-hydroxy-1-phenylquinolin-2(1H)-one (5g). Prepared from cis-3g in 61% yield besides 1g.
White solid. M.p. 167 – 1708 (benzene). IR: 3311, 2960, 2854, 1643, 1622, 1599, 1591, 1562, 1500, 1489,
1458, 1396, 1323, 1302, 1232, 1199, 1176, 1162, 1112, 1068, 1047, 978, 962, 901, 827, 781, 733, 752, 694, 661,
631, 511. EI-MS: 293 (17, Mþ), 278 (8), 264 (22), 252 (17), 251 (100), 250 (47), 222 (9), 196 (10), 195 (7),
168 (6), 167 (13), 77 (18), 69 (5), 55 (7), 51 (7), 43 (10), 41 (12). ESI-MS (pos.): 609.3 (18, [2M þ Na]þ),
459.8 (13, [3M þ Ca]2þ), 332.2 (29, [M þ K]þ), 316.3 (81, [M þ Na]þ), 294.3 (100, [M þ H]þ). Anal. calc.
for C19H19NO2 (293.36): C 77.79, H 6.53, N 4.77; found: C 77.64, H 6.53, N 4.40.
3-Hydroxy-1,4-diphenylquinolin-2(1H)-one (5h). Prepared from cis-3h in 65% yield. White solid.
M.p. 254 – 2578 (benzene). IR: 3291, 3062, 1637, 1623, 1602, 1592, 1492, 1455, 1392, 1322, 1272, 1191, 1126,
1068, 985, 954, 823, 755, 744, 694, 659, 615, 516. EI-MS: 314 (21), 313 (100, Mþ), 312 (98), 256 (16), 254
(15), 179 (9), 178 (6), 152 (9), 151 (5), 127 (10), 77 (19), 51 (11). ESI-MS (pos.): 649.2 (10, [2M þ Na]þ),
489.7 (10, [3M þ Ca]2þ), 352.2 (14, [M þ K]þ), 336.2 (100, [M þ Na]þ), 314.2 (25, [M þ H]þ). Anal. calc.
for C21H15NO2 (313.35): C 80.49, H 4.82, N 4.47; found: C 80.35m, H 4.80, N 4.42.
3-Hydroxyquinolin-2(1H)-one (6c). Prepared from cis-3c in 59% yield. White solid. M.p. 263 – 2708
(benzene). For 6c, m.p. 261 – 2638 was reported [28]. IR: 3276, 3166, 3056, 3000, 1654, 1625, 1612, 1575,
1504, 1400, 1349, 1290, 1274, 1249, 1184, 1126, 939, 906, 862, 755, 736, 701, 603, 551. ESI-MS (pos.): 522.2
(8, [3M þ K]þ), 361.2 (10, [2M þ K]þ), 345.1 (48, [2M þ Na]þ), 342.2 (35, [4M þ Ca]2þ), 261.7 (80, [3M þ

1916
Helvetica Chimica Acta – Vol. 96 (2013)
Ca]2þ), 200.1 (6, [M þ K]þ), 184.1 (100, [M þ Na]þ), 162.2 (33, [M þ H]þ). Anal. calc. for C9H7NO2
(161.16): C 67.07, H 4.38, N 8.69; found: C 66.88, H 4.55, N 8.62.
3-Hydroxy-1-methylquinolin-2(1H)-one (6f). Prepared from cis-3f in 63% yield. White solid. M.p.
168 – 1798, then 187 – 1898 (benzene/cyclohexane: [29]: 1868). IR: 3251, 3037, 1654, 1617, 1600, 1504, 1465,
1421, 1334, 1299, 1245, 1182, 1116, 1041, 933, 883, 777, 752, 738, 727, 682, 532. EI-MS: 175 (65, Mþ), 167
(10), 155 (7), 149 (22), 147 (36), 146 (12), 141 (10), 127 (15), 125 (18), 123 (14), 122 (9), 118 (22), 113
(32), 111 (29), 109 (16), 99 (22), 97 (35), 95 (21), 91 (11), 90 (6), 85 (52), 83 (43), 81 (25), 77 (15), 71
(87), 70 (19), 69 (43), 67 (12), 57 (100), 56 (29), 55 (34), 43 (51), 41 (19). ESI-MS (pos.): 564.2 (27,
[3M þ K]þ), 389.2 (74, [2M þ K]þ), 373.2 (38, [2M þ Na]þ), 370.1 (13, [4M þ Ca]2þ), 282.7 (90, [3M þ
Ca]2þ), 214.1 (14, [M þ K]þ), 198.2 (69, [M þ Na]þ), 176.2 (100, [M þ H]þ). Anal. calc. for C10H9NO2
(175.18): C 68.56, H 5.18, N 8.00; found: C 68.36, H 5.23, N 7.89.
3-Hydroxy-1-phenylquinolin-2(1H)-one (6i). Prepared from cis-3i in 58% yield. White solid. M.p.
184 – 1858 (benzene/hexane). IR: 3255, 3029, 1650, 1631, 1600, 1488, 1459, 1411, 1317, 1290, 1234, 1184,
1124, 1074, 944, 904, 881, 777, 761, 752, 696, 667, 613. ESI-MS (pos.): 513.2 (5, [2M þ K]þ), 497.2 (40,
[2M þ Na]þ), 494.1 (6, [4M þ Ca]2þ), 375.7 (19, [3M þ Ca]2þ), 276.2 (7, [M þ K]þ), 260.2 (100, [M þ
Na]þ), 238.2 (36, [M þ H]þ). Anal. calc. for C15H11NO2 (237.25): C 75.94, H 4.67, N 5.90; found: C
75.80, H 4.70, N 5.71.
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Received February 4, 2013