Reduction of N-Nitrosaminoquinolinediones with LiAlH4 - An Easy Path to New Tricyclic Benzoxadiazocines

Article abstract of DOI:10.1002/hlca.201500146

3-Butylaminoquinolinediones (1) react with NaNO₂ in AcOH to give the corresponding N-nitrosoderivatives (2). The analogous reactions of 4-hydroxy-3-butylaminoquinolinediones (5), prepared by the reduction of 1 with NaBH₄, produce the corresponding nitrosamines (4). The reduction of both 2 and 4 with Zn under different conditions was non-productive, but the reduction of both compounds with LiAlH₄ at the oxo and lactame groups yielded impure products, generating new tricyclic benzoxadiazocines (9) by a reaction with HNCO. All compounds were characterized by IR, ¹H-, and ¹³C-NMR (in some cases, ¹⁵N-NMR also) spectroscopy and EI and/or ESI mass spectrometry. The X-ray structure of compound 9g was determined.

Full text of DOI:10.1002/hlca.201500146

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FULL PAPER
Reduction of N-Nitrosaminoquinolinediones with LiAlH4 – an Easy Path to New Tricyclic
Benzoxadiazocines
by Antonín Klµsek*a), Antonín Lycˇkab)c), Filip Krˇemena), AleÐ Ru˚zicˇkad), and Michal Rouchala)
ˇ
a) Department of Chemistry, Faculty of Technology, Tomas Bata University, CZ-76272 Zlín
(e-mail: klasek@ft.utb.cz)
b) Research Institute for Organic Syntheses (VUOS), Rybitví 296, CZ-53354 Pardubice 20
c) University of Hradec KrµlovØ, Faculty of Science, CZ-50003 Hradec KrµlovØ 3
d) Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, CZ-53210
Pardubice
3-Butylaminoquinolinediones (1) react with NaNO2 in AcOH to give the corresponding N-nitrosoderivatives (2). The
analogous reactions of 4-hydroxy-3-butylaminoquinolinediones (5), prepared by the reduction of 1 with NaBH4, produce the
corresponding nitrosamines (4). The reduction of both 2 and 4 with Zn under different conditions was non-productive, but the
reduction of both compounds with LiAlH4 at the oxo and lactame groups yielded impure products, generating new tricyclic
benzoxadiazocines (9) by a reaction with HNCO. All compounds were characterized by IR, 1H-, and 13C-NMR (in some cases,
15N-NMR also) spectroscopy and EI and/or ESI mass spectrometry. The X-ray structure of compound 9g was determined.
Introduction. – In our laboratory, we have paid much minoquinolinediones 1 and studied their reduction to the
attention to the reactivity of 3-alkyl/aryl-3-hydroxyquino- corresponding 3-hydrazino derivatives 3.
linediones and 3-alkyl/aryl-3-aminoquinolinediones. Re-
cently, we described the stereoselective reduction of 3-
Results and Discussion. – According to the literature,
hydroxyquinoline-2,4-diones with NaBH4 to the corre- the optimal route for the preparation of hydrazines 3 from
sponding cis-diols. In conc. H2SO4, these diols can undergo amines 1 should be through nitrosamines 2 (Scheme 1).
pinacol rearrangement giving 3-hydroxy-2-quinolones [1], The nitrosation of 1 with NaNO2 in AcOH proceeded
which frequently occur as secondary metabolites of fungi of smoothly, giving high yields of compounds 2 (Table 1).
the genus Penicillium [2]. Primary 3-aminoquinoline-2,4- The 15N-NMR spectra of compounds 2 (Table 2) showed
diones were also stereoselectively reduced with NaBH4 three 15N-NMR signals. Two of them (at ca. À 115 and
to give cis-3-amino-3,4-dihydro-4-hydroxyquinolin-2(1H)- þ 146 ppm) correspond to NBu and NO groups, which is
ones [3]. The deamination of the reduction products using in accord with the published values of À 128.5 (N) and
HNO2 produced mixtures of several compounds, from þ 152.4 (NO) ppm for Et2NNO [8][9].
which new indolin-2-ones and their 3-hydroxy and 3-nitro
Many reductions of nitrosamines to hydrazines are
derivatives were isolated as the products of the molecular described in the literature, mostly using Zn in acidic media.
rearrangement [3]. In our last article, we also demonstrat- We studied this reaction using 2b, 2e, and 2g. However, the
ed that 3-hydroxyquinolinediones can be converted to their reduction of these nitrosamines to hydrazines 3 was
3-aminoanalogues by a reaction with ammonium or unsuccessful. We found that compounds 2b, 2e, and 2g
alkylammonium ions [4].
react with Zn in AcOH in an unexpected manner. At
Primary and secondary 3-aminoquinolinediones are temperatures of approximately 08, the reaction did not
very reactive compounds and can easily be converted to proceed even with very long reaction times. At temper-
novel heterocyclic compounds, mostly in the course of atures approximately of 608 the reduction occurred, but the
molecular rearrangement. These rearrangements mainly reaction products were identified as 3-alkyl-4-hydroxyqui-
occur by a reaction with urea, thiourea, isocyanic, and nolin-2-(1H)-ones in all cases. Analogous results were
isothiocyanic acids in an acidic environment [5]. Similar obtained from experiments using Zn and AcOH in MeOH
rearrangements were also observed during acid treatment [10], Zn and NH4Cl in MeOH [11], or in EtOH in the
of the addition products of 3-aminoquinolinediones with presence of (NH4)2CO3 [12]. On the other hand, only the
organic isocyanates or thiocyanates [6][7].
starting compound was obtained by treatment of 2f with
We aimed to prepare 3-hydrazino derivatives 3, which Na2S2O4 in an aqueous base [13]. The expected compounds
might be suitable compounds to study cyclization to 3 were never isolated. It is interesting that during the
triazinoquinolinones with HNCO. For that purpose, we reduction of compounds 2 not only the NÀN bond, but the
prepared the 3-nitrosoamino derivatives 2 of the 3-alkyla- entire N(NO)Bu group is cleaved.
DOI: 10.1002/hlca.201500146
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Scheme 1
Therefore, we carried out experiments with the Zn compounds 5 and thus, 13C resonances at ca. 184 – 191 ppm
reduction of compounds 4. These compounds were pre- belonging to CO groups are shifted to ca. 68 – 72 ppm
pared by the nitrosation of compounds 5 (Table 1), which corresponding to the CHOH moiety (Table 4). Coupling
3
we acquired by the reduction of amines 1 with NaBH4 constants J(O1H,C(4)1H) ¼ 5.9 Æ 0.3 Hz were observed in
(Table 3). The CO group is reduced in compounds 1 to give the 1H-NMR for compounds 5. The cis-configuration of the
Table 1. Nitrosation of Compounds 1 and 5
Starting material
Substituents
R1
Product (yield [%])
Starting material
Product (yield [%])
R2
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
Me
Me
Me
Ph
Ph
Ph
Bu
Bn
Ph
Bu
Bn
Ph
Bu
Bn
Ph
2a (86)
2b (75)
2c (96)
2d (74)
2e (92)
2f (92)
2g (98)
2h (83)
2i (89)
5a
5b
5c
5d
5e
5f
5g
5h
5i
4a (91)
4b (62)
4c (97)
4d (91)
4e (71)
4f (80)
4g (80)
4h (71)
4i (85)
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Table 3. Reduction of Compounds 1 with NaBH4
Starting material
Substituents
Product (yield [%])
R1
R2
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
Me
Me
Me
Ph
Ph
Ph
Bu
Bn
Ph
Bu
Bn
Ph
Bu
Bn
Ph
5a (91)
5b (71)
5c (41)
5d (87)
5e (80)
5f (91)
5g (80)
5h (82)
5i (75)
OH and amino groups in 5 was demonstrated by their that the reduction proceeds at the C(4)-carbonyl and N¼O
reaction with triphosgene (CCl3OCOOCCl3), yielding the groups. However, in the 13C-NMR spectra, the presence of
cyclic carbamates 6. The subsequent nitrosation of 5 to the signal corresponding to the lactame group was absent
compounds 4 occurred easily. A proton signal inÀNHBu in and the signal at the highest frequency was at approx-
compounds 5 was not detectable in compounds 4, and the imately 151 ppm, which is characteristic for carbamates. In
corresponding 15N resonances in ÀNHBu (ca. À 336 Æ
comparison with starting compound 2, the product showed
3 ppm) were shifted to ca. À 126 Æ 3 ppm, corresponding the signal of the quaternary C-atom at approximately the
to a ÀN(NO)Bu fragment (Table 5). However, experi- same value, but a new signal from a tertiary C-atom at
ments on the reduction of 4 with Zn were unsuccessful just approx. 62 ppm appeared. Further study of the NMR
as for compounds 2. From the reaction of 4g, 4h, and 4i spectra showed that, after the reduction of the carbonyl and
with Zn in AcOH at 608, only the starting compounds were lactame groups in 2 with four H-atoms, compounds 8
recovered. Additionally, only the starting compounds were containing the configurationally unstable hemiaminal
recovered from 4h in the reaction with Na2S2O4 in an group were produced (Scheme 1). Despite to repeated
alkaline medium and, surprisingly, also from 4e and 4g by CC (SiO2), we were unable to purify the waxy compounds
the reaction with NaBH4. The corresponding hydrazines 7 8 sufficiently so that we could assign H- and 13C-NMR
1
were never found.
chemical shifts and coupling constants. The OH group at
In preliminary experiments, we found that the reduc- C(4) was subsequently reacted with HNCO to give the
tion of compounds 2 with LiAlH4 gave a mixture of corresponding carbamic acid, which eliminated H2O in the
products which did not crystallize and complete separation reaction with the second OH group at C(2) and formed an
by column chromatography (CC, SiO2) was infeasible. isolable tricyclic compound 9. For the formation of 9, the
These experiments also showed that the crude mixtures relative position cis of O-atoms at C(2) and C(4) in
from the reduction reacted with HNCO to give crystalline compound 8 is necessary. However, this orientation is not
compounds. Therefore, in subsequent experiments (Ta- mandatory in compounds 8. Due to the presence of the
ble 6), we carried out the reduction of compounds 2 and 4 hemiacetal group at C(2), the creation of interconverting
1
using three different methods. In Method A, crude products diastereoisomers is possible. The H,1H-COSY spectrum
of the reduction of 2 or 4 with LiAlH4 in THF were revealed in compound 9 the existence of an NHCH ··· CH
separated by CC (SiO2) and their IR, MS, and NMR fragment and 13C- as well as 15N-NMR chemical shifts that
spectra were examined. In Method B, crude products of the strongly supported the reduction of two CO groups in the
reduction of 2 or 4 were reacted with HNCO without original C(2) and C(4) positions in compounds 2. Unfortu-
isolation and separated by CC (SiO2). In Method C, some nately, we observed only two instead of four 15N chemical
selected crude products 8 obtained by Method A were shifts in compounds 9 (Table 7). That is why we could not
reacted with HNCO and then treated under the same support the structure 9 absolutely because we had no
conditions as in Method B. The results are given in Table 6. information about the NÀNO group. The presumptions
While the results of the reduction of compounds 2a – 2c are mentioned were validated by X-ray crystallography of
not very interesting because only the starting compounds compound 9gA (Fig.).
2a – 2c and compounds 4a – 4c were isolated, the reduction
of compounds 2d – 2i gave surprising results.
We obtained a single crystal of compound 9gAusing the
liquid diffusion method [14] with CH2Cl2 and benzene as
Our attention was primarily focused on the determi- the solvent-precipitant pair. The molecular structure of
nation of the structure of crystalline compounds obtained compound 9gA, as determined by single-crystal X-ray
by Method B and Method C. These compounds had an diffraction, is shown in the Figure. The structure of 9gA is
elemental composition and MW corresponding to 2 þ
composed of a bicyclic unsaturated central motif, where
4 H þ HNCOÀH2O, which means that the primary product one of the rings is the six-membered carbamate ring. The
of the reduction of 2 with four H-atoms reacted with second ring is connected to the NÀNO moiety that
HNCO and eliminated H2O. Initially, we were convinced resembles the known structures of several NÀNO species
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Helv. Chim. Acta 2016, 99, 50 – 62
Table 6. Reduction of Compounds 2 and 4 with LiAlH4 – Methods A, B, and Conversion of Crude Compounds 8 to Pure 9 (Method C)
Starting compound
Substitution
Method
Product(s) (yield [%])
R1
R2
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
Bu
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
B
B
C
C
C
C
2a (49)a), 4a (1)
2a (21)a), 4a (3)
2b (49)a)
H
Bn
Ph
Bu
Bn
Ph
Bu
Bn
Ph
2b (36)a)
H
4c (17)
4c (42)
Me
Me
Me
Ph
Ph
Ph
2d (5)a), 4d (15), 8d (43)b)
4d (19), 9d (43)
4e (5), 8e (51)b), 10e (3)
4e (8), 9e (43), 10e (3)
4f (5), 8f (49)b), 10f (5)
9fA (16), 9fB (10), 10f (10)
8g (42)b), 10g (13)
9gA (21), 10g (14)
8h (20)b), 10h (21)
9h (20), 10h (13)
8i (13)b), 10i (29)
4i (6), 10i (27), 9i (1)
9fA (9), 10f (10)
9gB (32), 10g (13)
9d (71)
4f
4g
8d
8e
8g
8h
Me
Ph
Me
Me
Ph
Ph
Bu
Bu
Bn
Bu
Bn
9e (18)
9gA (31)
9h (27)
Ph
b
a) Recovered starting compound. ) Products pure according to TLC, but impure according to 1H- and 13C-NMR.
found in the literature [15][16]. To the best of our conformers differentiated by the orientation of the ÀN¼O
knowledge, there is not even a remotely similar structure group.
present in the literature. On the other hand, all of the other
In the molecule of compounds 9, a 1,3,5-oxadiazocine
interatomic distances and angles are in line with previous ring is present. Even more than 1500 1,3,5-oxadiazocines
findings for the appropriate functional groups [17]. A H- are described in the literature, only some few of them
bond typical for an amido group, was found between two contain a CH2 bridge between C(2) and C(6) atoms, but the
pairs of NÀH ··· C¼O groups, moreover a weak intra- benzene ring and oxo group are joined in other positions
molecular H-bond was observed between the NÀH and [18][19].
N¼O groups. Three chiral C-atoms are present in the
Mostly, minor products were isolated from the reduc-
molecule of compound 9gA. From the X-ray results of tion of compounds 2 and 4 and identified as (2-butylami-
compound 9gA (Fig.), it follows that configurations of the no)- (10d) and (2-phenylamino)benzaldehyde (10g). These
atoms in position C(1) and C(9) are (1S*,9S*). The third compounds are formed mostly as late as AcOH and KNCO
chiral atom at position C(13) has the configuration (13R*). were added to the mixture. Therefore, they must arise from
The directions of the N¼O bond and C-butyl chain are the ring opening and following retroaldolization of the
antiparallel (i.e., a H-bond between NH and N¼O groups). compounds 8 (Scheme 2) under catalysis of very strong
However, these findings should not be present in all HNCO.
compounds 9, as it especially depends on the orientation of
the N¼O group. The NMR spectra of compounds 9 are
Conclusions. – The described reduction of 3-nitro-
given in Table 7. For 9f and 9g, two couples of individual saminoquinoline-2,4-diones 2 with LiAlH4 does not have
compounds, designated as 9fA, 9fB, and 9gA, 9gB, were an analogy in the literature. Above all, the very high
isolated. With high probability, these couples are two stability of the nitroso group to reduction is surprising. The
Scheme 2
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Helv. Chim. Acta 2016, 99, 50 – 62
(15N) MHz; (D6)DMSO soln.; d in ppm rel. to Me4Si as an internal
standard or to MeNO2 as an external standard in co-axial capillary; J in
Hz; manufacturerꢂs software for all 2D experiments (gradient-selected
(gs)-COSY, gs-TOCSY, gs-HMQC, gs-HMQC-RELAY, and gs-
HMBC). EI-MS (pos.): Shimadzu QP-2010 instrument within the
range of m/z 50 – 600 using a direct inlet probe (DI); analysis of
samples in CH2Cl2 (30 mg/ml), a sample of 10 ml of the soln. was
evaporated in DI cuvette at 508; ion-source temp., 2008; the energy of
electrons, 70 eV; only signals exceeding rel. abundance of 5% are
listed. ESI-MS (pos.): amaZon X ion-trap mass spectrometer (Bruker
Daltonics, DE-Bremen), equipped with an ESI source; individual
samples infused into the ion as MeOH/H2O 1:1soln. via a syringe pump
at a constant flow rate of 4 ml/min; further experimental conditions: m/
z range, 50 – 1500, electrospray voltage, À 4.2 kV, drying gas temp.,
2208, 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
analyses (C, H, N); Flash EA 1112 elemental analyzer (Thermo Fisher
Scientific); in %.
Crystallography. Single crystals of 9gAwere prepared by the liquid
diffusion method [14] with CH2Cl2/benzene as the solvent-precipitant
pair. The X-ray data were obtained at 150 K using Oxford Cryostream
low-temperature device on a Nonius Kappa CCD diffractometer with
MoKa radiation (l ¼ 0.71073 Š), a graphite monochromator, and the f
and c scan mode. Data reductions were performed with DENZO-SMN
[20]. The absorption was corrected by integration methods [21].
Structure was solved by direct method (SIR92) [22] and refined by full
matrix least-square based on F2 SHELXL97 [23]. The H-atoms were
mostly localized on a difference Fourier map; however, to ensure
uniformity of treatment of the crystal, all H-atoms were recalculated
into idealized positions (riding model) and assigned temp. factors
Hiso(H) ¼ 1.2 Ueq (pivot atom) or of 1.5 Ueq (Me). H-atoms in CH,
CH2, and Me moieties and H-atoms in aromatic rings were placed with
CÀH distances of 0.98, 0.97, 0.96, and 0.93 Š, NÀH bond being 0.86 Š.
Rint ¼ S j Fo2 À Fo2;mean j /SF2o, GOF ¼ [S(w(F2o À Fc2 )2)/(Ndiffrs À Nparams)]1/2
for all data, R(F)¼ S jj Fo jÀj Fc j /Sj Fo j for observed data, wR(F2)¼
[S(w(F2o À F2c )2)/(Sw(Fo2)2)]1/2 for all data.
Figure. Molecular Structure (ORTEP 50% probability level) of 9gA.
Selected Interatomic Distances [Š] and Angles [8]: O1 C6 1.3535(18),
O1 C1 1.4553(18), O3 N4 1.2469(19), N3 N4 1.3145(19), N3 C21
1.474(2), N3 C5 1.484(2), N1 C3 1.4011(19), N1 C11 1.4402(19), N1 C4
1.455(2), N2 C6 1.344(2), N2 C4 1.462(2), O2 C6 1.219(2), C1 C2
1.507(2), C1 C5 1.533(2), O3 N4 N3 114.20(14). Arbitrary atom
numbering: O(1)ÀC(6) corresponds to O(12)ÀC(11)¼O and
N(1)ÀC(4) to N(8)ÀC(9) in Scheme 1.
No. CCDC-1054592 for 9gA, deposited with the Cambridge
Crystallographic Data Centre, contains the supplementary crystallo-
graphic data for this article. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif.
cis-1,3-diols primarily formed react smoothly with HNCO
to form interesting tricyclic compounds 9, which have not
been described in the literature. Therefore, this reaction is
not merely interesting from a theoretical view-point, but
because of the simple reaction protocol, this reaction
presents an easy pathway for the preparation of novel
heterocyclic systems that might be interesting structures for
the study of biological activity due to the presence of the
1,3,5-diazocine skeleton.
2. Starting 3-Amino-1H,3H-quinoline-2,4-diones 2. Compounds 2
were prepared from corresponding 3-Cl derivatives as described in
[24].
3. General Procedure for the Nitrosation of Compounds 1 and 5.
Under intensive stirring, the starting compound 1 or 5 (2 mmol) was
dissolved in AcOH (10 ml). After cooling to 08, H2O (1 ml) and then
solid NaNO2 (206 mg, 3 mmol) was added during 5 min, and stirring
was continued for 15 min at r.t. Solid urea (45 mg, 0.75 mmol) was
added to quench redundant HNO2, and after 15 min, the mixture was
blended with crushed ice (15 g). The deposited precipitate was filtered
with suction, washed with H2O (10 ml), dried, and crystallized from an
appropriate solvent. In the cases when the crude product was pasty, the
mixture was extracted with CHCl3 (3 Â 20 ml), collected extracts were
evaporated to dryness and worked-up by CC (SiO2). The yields are
A. K., F. K., and M. R. thank for the financial support from the
internal grants of TBU in Zlin (Nos. IGA/FT/2014/010 and IGA/FT/
2015/008), funded from the resources of specific university research.
ˇ
The authors thank Mrs. H. Gerzovµ (Faculty of Technology, Tomas Bata
1
given in Table 1. H-, 13C-, and 15N-NMR spectra are given in Tables 2
University in Zlín) for technical help.
and 5.
3-Butyl-3-[butyl(nitroso)amino]quinoline-2,4(1H,3H)-dione (2a).
Prepared from 1a. Yield: 86%. Colorless solid. M.p. 118 – 1208 (cyclo-
hexane). IR: 3188, 3079, 2956, 2931, 2873, 1698, 1662, 1614, 1597, 1509,
1487, 1441, 1415, 1369, 1342, 1280, 1255, 1232, 1176, 1162, 1123, 1098,
870, 842, 770, 750, 720, 687, 666, 651. ESI-MS (pos.): 673.1 (5, [2M þ
K]þ), 657.3 (13, [2M þ Na]þ), 495.7 (10, [3M þ Ca]2þ), 356.2 (49,
[M þ K]þ), 340.2 (100, [M þ Na]þ), 318.2 (6, [M þ H]þ), 287.2 (17,
[M þ H À HNO]þ). Anal. calc. for C17H23N3O3 (317.38): C 64.33, H
7.30, N 13.24; found C 64.31, H 7.34, N 12.94.
Experimental Part
1. General. TLC: Alugramꢁ SIL G/UV254 foils (MachereyÀNagel);
elution with benzene/AcOEt 4 :1, CHCl3/EtOH 9 :1 and 1:1, and
CHCl3/AcOEt 7:3. 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. IR Spectra: Smart OMNI-Transmission Nicolet iS10
spectrophotometer; KBr; in cmÀ1. NMR Spectra: Bruker Avance 500
spectrometer operating at 500.13 (1H), 125.76 (13C), and 50.68
3-Benzyl-3-[butyl(nitroso)amino]quinoline-2,4(1H,3H)-dione
(2b). Prepared from 1b. Yield 75%. Colorless solid. M.p. 150 – 1528
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(benzene/hexane). IR: 3193, 3067, 2964, 2934, 2867, 1702, 1662, 1616,
1598, 1487, 1440, 1421, 1381, 1330, 1254, 1233, 1159, 1092, 1034, 929, 829,
782, 762, 719, 702, 687, 667, 510. EI-MS 321 (12, [M À NO]þ), 265 (6),
251 (10), 250 (46), 249 (13), 248 (9), 230 (8), 187 (14), 175 (7), 146 (6),
119 (9), 118 (22), 92 (16), 91 (100), 90 (6), 65 (9), 57 (11), 41 (14). ESI-
MS (pos.): 741.2 (6, [2M þ K]þ), 725.3 (15, [2M þ Na]þ), 390.2 (65,
[M þ K]þ), 374.3 (100, [M þ Na]þ), 352.3 (5, [M þ H]þ), 321.3 (31,
[M þ H À HNO]þ). Anal. calc. for C20H21N3O3 (351.40): C 68.36, H
6.02, N 11.96; found C 68.18, H 5.98, N 11.86.
3-[Butyl(nitroso)amino]-3-phenylquinoline-2,4(1H,3H)-dione
(2c). Prepared from 1c. Yield 96%. Colorless solid. M.p. 143 – 1468
(benzene). IR: 3202, 3142, 3085, 2996, 2956, 2931, 2872, 1719, 1681,
1615, 1596, 1485, 1467, 1447, 1437, 1421, 1361, 1328, 1245, 1227, 1185,
1158, 1118, 1082, 930, 870, 839, 776, 756, 746, 713, 667, 615. ESI-MS
(pos.) 697.2 (17, [2M þ Na]þ), 525.7 (13, [3M þ Ca]2þ), 376.1 (25,
[M þ K]þ), 360.1 (100, [M þ Na]þ), 338.1 (5, [M þ H]þ), 330.1 (10,
[M þ Na À NO]þ), 307.1 (28, [M À NO]þ). Anal. calc. for C19H19N3O3
(337.37): C 67.64, H 5.68, N 12.46; found C 67.52, H 5.75, N 12.50.
3-Butyl-3-[butyl(nitroso)amino]-1-methylquinoline-2,4(1H,3H)-
dione (2d). Prepared from 1d. Yield 74%. Colorless solid. M.p. 98 –
1008 (cyclohexane). IR: 2951, 2872, 1693, 1655, 1600, 1473, 1417,
1397, 1361, 1345, 1300, 1243, 1171, 1145, 1106, 1049, 1031, 960, 925, 869,
775, 752, 723, 697, 683, 663, 630, 491. EI-MS: 331 (4, Mþ), 301 (11), 246
(5), 245 (26), 231 (11), 230 (61), 229 (10), 202 (10), 201 (10), 200 (9),
189 (18), 188 (12), 176 (9), 162 (14), 160 (9), 146 (10), 140 (31), 134
(9), 133 (7), 132 (6), 105 (9), 104 (8), 84 (100), 77 (8), 57 (15), 41 (18).
ESI-MS (pos.): 701.1 (6, [2M þ K]þ), 685.3 (11, [2M þ Na]þ), 370.2
(100, [M þ K]þ), 354.2 (78, [M þ Na]þ), 332.2 (16, [M þ H]þ), 301.2
(35, [M þ H À HNO]þ). Anal. calc. for C18H25N3O3 (331.41): C 65.23,
H 7.60, N 12.68; found: C 65.23, H 7.77, N 12.64.
3-Benzyl-3-[butyl(nitroso)amino]-1-methylquinoline-2,4(1H,3H)-
dione (2e). Prepared from 1e. Yield 92% yield. Colorless solid. M.p.
114 – 1178 (hexane). IR: 3031, 2955, 2870, 1692, 1662, 1601, 1474, 1456,
1412, 1367, 1336, 1304, 1245, 1190, 1175, 1143, 1100, 1041, 986, 930, 841,
777, 757, 730, 701, 683, 663, 610, 523. EI-MS 365 (2, Mþ), 336 (7), 335
(29), 279 (6), 265 (20), 264 (86), 263 (32), 262 (17), 244 (18), 243 (7),
202 (5), 201 (34), 190 (7), 189 (15), 175 (9), 162 (13), 146 (6), 134 (9),
132 (7), 118 (32), 105 (12), 104 (14), 91 (100), 78 (7), 77 (13). ESI-MS
(pos.): 753.2 (5, [2M þ Na]þ), 567.7 (11, [3M þ Ca]2þ), 404.1 (51,
[M þ K]þ), 388.2 (100, [M þ Na]þ), 385.2 (44, [2M þ Ca]2þ), 366.2
(5), [M þ H]þ), 267.1 (8, [M þ Na À Bn]þ), 245.1 (11, [M þ H À
Bn]þ). Anal. calc. for C21H23N3O3 (365.43): C 69.02, H 6.34, N 11.50;
found: C 69.30, H 6.38, N 11.64.
3-[Butyl(nitroso)amino]-1-methyl-3-phenylquinoline-2,4(1H,3H)-
dione (2f). Prepared from 1f. Yield 92%. Yellowish solid. M.p. 98 – 1008
(cyclohexane). IR: 2956, 2873, 1710, 1674, 1601, 1472, 1415, 1355, 1301,
1264, 1234, 1178, 1143, 1079, 1035, 958, 939, 874, 813, 775, 757, 720, 701,
665, 613, 531. EI-MS 351 (10, Mþ), 321 (15), 252 (10), 251 (61), 250
(100), 244 (12), 223 (8), 222 (45), 207 (6), 160 (14), 134 (9), 117 (7),
105 (16), 104 (92), 91 (6), 77 (17), 57 (9), 41 (13). ESI-MS (pos.): 725.3
(12, [2M þ Na]þ), 546.7 (8, [3M þ Ca]2þ), 390.1 (61, [M þ K]þ), 374.2
(100, [M þ Na]þ), 352.2 (9, [M þ H]þ), 321.2 (35, [M þ H À HNO]þ).
Anal. calc. for C20H21N3O3 (351.39): C 68.36, H 6.02, N 11.96; found: C
68.13, H 6.10, N 11.98.
3-Benzyl-3-[butyl(nitroso)amino]-1-phenylquinoline-2,4(1H,3H)-
dione (2h). Prepared from 1h. Yield 83%. Colorless solid. M.p. 140 –
1438 (cyclohexane). IR: 3027, 2955, 2870, 1697, 1665, 1602, 1493,
1465, 1408, 1330, 1268, 1239, 1184, 1163, 1102, 1070, 1028, 1001, 925,
865, 816, 765, 755, 748, 723, 710, 703, 663, 638, 529. EI-MS: 427 (4, Mþ),
398 (9), 397 (31), 327 (27), 326 (97), 325 (34), 324 (15), 306 (12), 298
(6), 264 (8), 263 (35), 251 (11),237 (11), 233 (10), 224 (13), 196 (34),
195 (100), 167 (18), 166 (8), 118 (29), 103 (8), 92 (13), 91 (93), 77 (19),
57 (13), 41 (20). ESI-MS (pos.): 877.3 (8, [2M þ Na]þ), 466.2 (64,
[M þ K]þ), 450.2 (100, [M þ Na]þ), 447.2 (16, [2M þ Ca]2þ), 428.2 (7,
[M þ H]þ), 397.3 (48, [M À NO]þ). Anal. calc. for C26H25N3O3
(427.49): C 73.05, H 5.89, N 9.83; found: C 72.87, H 5.95, N 9.54.
3-[Butyl(nitroso)amino]-1,3-diphenylquinoline-2,4(1H,3H)-dione
(2i). Prepared from 1i. Yield 89%. Colorless solid. M.p. 158 – 1618
(benzene/hexane). IR: 2960, 2875, 1710, 1676, 1602, 1491, 1461, 1418,
1342, 1251, 1239, 1187, 1175, 1160, 1116, 1083, 1038, 1002, 976, 925, 868,
777, 763, 756, 748, 701, 689, 665, 634, 597, 557, 539, 512. ESI-MS (pos.):
865.1 (7, [2M þ K]þ ), 849.3 (24, [2M þ Na]þ), 827.2 (6, [2M þ H]þ),
639.7 (11, [3M þ Ca]2þ), 452.2 (55, [M þ K]þ), 436.2 (100, [M þ
Na]þ), 414.2 (13, [M þ H]þ), 383.2 (37, [ M À NO]þ). Anal. calc. for
C25H23N3O3 (413.47): C 72.62, H 5.61, N 10.16; found: C 72.88, H 5.61, N
10.12.
3-Butyl-3-[butyl(nitroso)amino]-3,4-dihydro-4-hydroxyquinolin-
2(1H)-one (4a). Prepared from 5a. Yield 91%. Colorless solid. M.p.
165 – 1678 (cyclohexane). IR: 3238, 2959, 2933, 2874, 1673, 1600, 1491,
1459, 1388, 1331, 1298, 1242, 1203, 1146, 1121, 1047, 959, 846, 757, 711,
663, 618, 605. ESI-MS (pos.): 661.3 (15, [2M þ Na]þ), 498.7 (7, [3M þ
Ca]2þ), 358.1 (36, [M þ K]þ), 342.2 (100, [M þ Na]þ), 320.2 (9, [M þ
H]þ), 289.2 (9, [M þ H À HNO]þ). Anal. calc. for C17H25N3O3
(319.40): C 63.93, H 7.89, N 13.16; found: C 63.76, H 7.96, N 12.80.
3-Benzyl-3-[butyl(nitroso)amino]-3,4-dihydro-4-hydroxyquinolin-
2(1H)-one (4b). Prepared from 5b. Yield 62%. Colorless solid. M.p.
83 – 868 (hexane). IR: 3562, 3210, 3086, 2959, 2929, 2871, 1678, 1617,
1599, 1495, 1467, 1456, 1390, 1336, 1319, 1263, 1213, 1170, 1085, 1041,
1030, 965, 940, 871, 813, 752, 707, 677, 650, 606, 578, 527, 497. ESI-MS
(pos.): 729.3 (7, [2M þ Na]þ), 392.2 (54, [M þ K]þ), 376.2 (100, [M þ
Na]þ), 354.2 (25, [M þ H]þ). Anal. calc. for C20H23N3O3 (353.41): C
67.97, H 6.56, N 11.89; found: C 68.13, H 6.82, N 11.63.
3-[Butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-3-phenylquinolin-
2(1H)-one (4c). Prepared from 5c. Yield 97%. Colorless solid. M.p.
219 – 2298 (benzene). IR: 3368, 3199, 3079, 2954, 2927, 2870, 1682, 1613,
1598, 1488, 1452, 1404, 1365, 1334, 1248, 1175, 1134, 1084, 957, 928, 823,
756, 701, 669, 611, 586, 536. ESI-MS (pos.): 528.7 (8, [3M þ Ca]2þ),
378.1 (47, [M þ K]þ, 362.2 (100, [M þ Na]þ), 359.2 (44, [2M þ Ca]2þ),
340.2 (8, [M þ H]þ, 309.2 (30, [M À NO]þ). Anal. calc. for C19H21N3O3
(339.39): C 67.24, H 6.24, N 12.38; found: C 67.02, H 6.21, N 12.24.
3-Butyl-3-[butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-1-methyl-
quinolin-2(1H)-one (4d). Prepared from 5d. Yield 91%. Yellow oil. IR:
3423, 2959, 2872, 1678, 1605, 1498, 1468, 1416, 1376, 1306, 1272, 1202,
1129, 1037, 953, 825, 755, 684, 639, 619, 602, 553, 509. ESI-MS (pos.):
689.3 (11, [2M þ Na]þ), 519.8 (10, [3M þ Ca]2þ), 372.2 (100, [M þ
K]þ), 356.2 (99, [M þ Na]þ), 334.2 (22, [M þ H]þ, 326.2 (7, [M þ
Na À NO]þ), 303.2 (8, [M þ H À HNO]þ). Anal. calc. for C18H27N3O3
(333.43): C 64.84, H 8.16, N 12.60; found: C 64.72, H 8.03, N 12.42.
3-Benzyl-3-[butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-1-methyl-
quinolin-2(1H)-one (4e). Prepared from 5e. Yield 71%. Colorless solid.
M.p. 185 –1888 (benzene/cyclohexane). IR: 3497, 3034, 2958, 2871, 1668,
1605, 1498, 1475, 1439, 1405, 1365, 1341, 1270, 1182, 1130, 1037, 962, 877,
846, 800, 754, 730, 706, 685, 633, 598, 565, 505. EI-MS: 337 (8, [M À
NO]þ), 279 (8), 266 (22), 265 (100), 264 (6), 248 (8), 236 (7), 229
(15), 175 (5), 174 (14), 167 (21), 149 (44), 132 (6), 118 (34), 113 (8), 106
(11), 92 (7), 91 (78), 71 (15), 70 (12), 57 (21), 43 (12). ESI-MS (pos.):
757. 3 (7, [2M þ Na]þ), 570.7 (31, [3M þ Ca]2þ), 406.2 (76, [M þ K]þ),
390.2 (100, [M þ Na]þ), 387. 2 (51, [2M þ Ca]2þ), 368.2 (6, [M þ H]þ),
337. 2 (38, [M þ HÀ HNO]þ). Anal. calc. for C21H25N3O3 (367.44): C
68.64, H 6.86, N 11.44; found: C 68.34, H 6.89, N 11.42.
3-Butyl-3-[butyl(nitroso)amino]-1-phenylquinoline-2,4(1H,3H)-
dione (2g). Prepared from 1g. Yield 98%. Yellowish solid. M.p. 142 –
1468 (cyclohexane). IR: 3062, 3037, 2963, 2933, 2863, 1700, 1666,
1600, 1491, 1463, 1416, 1346, 1328, 1304, 1280, 1260, 1241, 1183, 1161,
1119, 1092, 1069, 1026, 960, 853, 791, 774, 751, 726, 705, 691, 661, 629,
523, 508. EI-MS: 363 (4, [M À NO]þ), 307 (6), 292 (14), 251 (6), 250
(5), 224 (6), 199 (10), 196 (28), 195 (100), 167 (8), 140 (10), 84 (48), 77
(7), 57 (16), 41 (19). ESI-MS (pos.): 825.2 (9, [2M þ K]þ), 809.4 (49,
[2M þ Na]þ), 787.0 (11, [2M þ H]þ), 609.9 (5, [3M þ Ca]2þ), 432.2 (30,
[M þ K]þ), 416.3 (72, [M þ Na]þ), 394.3 (19, [M þ H]þ), 363.4 (100,
[M þ H À HNO]þ). Anal. calc. for C23H27N3O3 (393.48): C 70.21, H
6.92, N 10.68; found: C 69.84, H 6.82, N 10.66.
ꢀ 2016 Verlag Helvetica Chimica Acta AG, Zürich
www.helv.wiley.com

60
Helv. Chim. Acta 2016, 99, 50 – 62
3-[Butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-1-methyl-3-phe-
cis-3-(Butylamino)-3,4-dihydro-4-hydroxy-3-phenylquinolin-
2(1H)-one (5c). Prepared from 1c. Yield 41%. Colorless solid. M.p.
144 – 1468 (hexane). IR: 3201, 3079, 2958, 2923, 2867, 1681, 1616, 1598,
1486, 1454, 1365, 1253, 1205, 1132, 1078, 1041, 1004, 970, 904, 867, 829,
781, 757, 701, 682, 667, 634, 586, 545, 520, 480. EI-MS: 310 (8, Mþ), 221
(7), 189 (13), 162 (6), 161 (10), 160 (9), 132 (11), 122 (9), 120 (12), 119
(100), 118 (33), 105 (8), 104 (53), 77 (20). ESI-MS (pos.): 311.3 (100,
[M þ H]þ). Anal. calc. for C19H22N2O2 (310.39): C 73.52, H 7.14, N
9.03; found: C 73.76, H 7.21, N 8.97.
nylquinolin-2(1H)-one (4f). Prepared from 5f. Yield 80%. Colorless
solid. M.p. 209 – 2118 (benzene). IR: 3327, 2956, 2930, 2872, 1673, 1606,
1493, 1467, 1451, 1438, 1396, 1360, 1310, 1250, 1213, 1192, 1140, 1100,
1041, 952, 929, 853, 809, 756, 750, 708, 683, 636, 595, 572, 536. ESI-MS
(pos.): 729.2 (15, [2M þ Na]þ), 549.7 (14, [3M þ Ca]2þ), 392.1 (51,
[M þ K]þ), 376.2 (100, [M þ Na]þ), 373.2 (19, [2M þ Ca]2þ), 323.2 (6,
[M À NO]þ). Anal. calc. for C20H23N3O3 (353.42): C 67.97, H 6.56, N
11.89; found: C 67.97, H 6.57, N 11.86.
3-Butyl-3-[butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-1-phenyl-
quinolin-2(1H)-one (4g). Prepared from 5g. Yield 80%. Colorless solid.
M.p. 126 – 1288 (cyclohexane). IR: 3426, 2956, 2872, 1665, 1605, 1494,
1465, 1411, 1334, 1297, 1254, 1205, 1151, 1065, 1050, 1039, 956, 926, 836,
749, 696, 658, 612, 585, 553, 515. EI-MS: 365 (8, [M À NO]þ), 294 (11),
293 (30), 278 (7), 276 (12), 266 (6), 264 (12), 252 (18), 251 (100), 250
(10), 198 (7), 197 (41), 196 (15), 180 (9), 168 (21), 167 (8), 140 (24), 85
(6), 84 (81), 77 (6), 57 (19), 55 (5), 41 (21). ESI-MS (pos.): 813.4 (18,
[2M þ Na]þ), 612.9 (10, [3M þ Ca]2þ), 434.3 (41, [M þ K]þ), 418.3
(100, [M þ Na]þ), 396.3 (7, [M þ H]þ), 388.2 (10, [M þ Na À NO]þ),
365.4 (7, [M þ H À HNO]þ). Anal. calc. for C23H29N3O3 (395.49): C
69.85, H 7.39, N 10.62; found: C 69.81, H 7.40, N 10.52.
3-Benzyl-3-[butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-1-phe-
nylquinolin-2(1H)-one (4h). Prepared from 5h. Yield 71%. Colorless
solid. M.p. 242 – 2468 (benzene). IR: 3435, 3028, 2953, 2872, 1662, 1605,
1494, 1466, 1453, 1411, 1334, 1295, 1264, 1188, 1086, 1051, 1041, 964, 925,
886, 854, 751, 729, 702, 695, 680, 637, 612, 589, 549, 516. EI-MS: 399 (7,
[M À NO]þ), 328 (27), 327 (100), 326 (6), 291 (11), 197 (22), 196 (10),
180 (8), 174 (9), 168 (17), 167 (7), 118 (30), 92 (6), 91 (62), 77 (6), 71
(6), 57 (13), 41 (11). ESI-MS (pos.): 897.1 (6, [2M þ K]þ), 881.3 (6,
[2M þ Na]þ), 468.2 (35, [M þ K]þ), 452.1 (100, [M þ Na]þ), 430.2 (6,
[M þ H]þ), 399.3 (7, [M À NO]þ). Anal. calc. for C26H27N3O3 (429.51):
C 72.71, H 6.33, N 9.78; found: C 72.85, H 6.35, N 9.73.
3-[Butyl(nitroso)amino]-3,4-dihydro-4-hydroxy-1,3-diphenylqui-
nolin-2(1 H)-one (4i). Prepared from 5i. Yield 85%. Colorless solid.
M.p. 201 – 2048 (benzene/hexane). IR: 3272, 3064, 2961, 2869, 1686,
1604, 1592, 1492, 1457, 1396, 1335, 1295, 1260, 1216, 1179, 1131, 1091,
1080, 958, 935, 862, 832, 803, 767, 737, 722, 697, 615, 590, 526, 504. EI-
MS: 386 (12), 385 (43, [M À NO]þ), 314 (14), 313 (31), 312 (21), 286
(8), 208 (12), 197 (14), 196 (8), 180 (12), 168 (11), 167 (6), 160 (23),
105 (12), 104 (100), 77 (12), 57 (9), 41 (12). ESI-MS (pos.): 869.2 (6,
[2M þ K]þ), 853.3 (19, [2M þ Na]þ), 642.8 (14, [3M þ Ca]2þ), 454.2
(55, [M þ K]þ), 438.2 (100, [M þ Na]þ), 435.2 (27, [2M þ Ca]2þ),
408.2 (10, [M þ Na À NO]þ). Anal. calc. for C25H25N3O3 (415.48): C
72.27. H 6.06, N 10.11; found: C 72.43, H 6.14, N 9.98.
cis-3-Butyl-3-(butylamino)-3,4-dihydro-4-hydroxy-1-methylquino-
lin-2(1H)-one (5d). Prepared from 1d. Yield 87%. Colorless solid. M.p.
100 – 1028. IR: 3289, 2960, 2929, 2868, 1672, 1602, 1496, 1474, 1458,
1413, 1377, 1352, 1301, 1262, 1238, 1204, 1137, 1111, 1068, 1044, 972, 916,
900, 882, 852, 836, 807, 754, 695, 672, 619, 561, 532, 450. EI-MS: 304 (2,
Mþ), 247 (19), 233 (6), 217 (6), 216 (39), 215 (23), 174 (7), 173 (9), 146
(11), 142 (24), 118 (8), 98 (17), 84 (100), 72 (10), 57 (9), 41 (10). ESI-
MS (pos.): 305.2 (100, [M þ H]þ). Anal. calc. for C18H28N2O2 (304.43):
C 71.02, H 9.27, N 9.20; found: C 71.28, H 9.38, N 9.11.
cis-3-Benzyl-3-(butylamino)-3,4-dihydro-4-hydroxy-1-methylqui-
nolin-2(1H)-one (5e). Prepared from 1e. Yield 80%. Colorless solid.
M.p. 113 – 1168 (cyclohexane). IR: 3408, 3028, 2954, 2925, 2871, 1664,
1604, 1496, 1477, 1460, 1413, 1350, 1320, 1303, 1238, 1207, 1124, 1080,
1060, 1048, 1031, 995, 936, 881, 783, 754, 738, 721, 698, 687, 664, 645, 594,
504. ESI-MS (pos.): 339.3 (100, [M þ H]þ). Anal. calc. for C21H26N2O2
(338.44): C 74.52, H 7.74, N 8.28; found: C 74.51, H 7.64, N 8.13.
cis-3-(Butylamino)-3,4-dihydro-4-hydroxy-1-methyl-3-phenylqui-
nolin-2(1H)-one (5f). Prepared from 1f. Yield 91%. Colorless solid.
M.p. 134 – 1368. IR: 3268, 2961, 2867, 2746, 1663, 1603, 1494, 1477, 1460,
1453, 1418, 1354, 1309, 1264, 1195, 1119, 1082, 1042, 1008, 952, 885, 864,
840, 773, 755, 721, 707, 681, 654, 626, 576, 549, 512. EI-MS: 324 (1, Mþ),
253 (8), 237 (6), 236 (34), 235 (50), 222 (7), 189 (9), 162 (15), 161 (11),
160 (9), 146 (11), 120 (11), 119 (100), 118 (38), 106 (6), 105 (8), 104
(47), 91 (9), 77 (14), 72 (7). ESI-MS (pos.): 325.2 (100, [M þ H]þ).
Anal. calc. for C20H24N2O2 (324.42): C 74.04, H 7.46, N 8.54; found: C
74.30, H 7.55, N 8.32.
cis-3-Butyl-3-(butylamino)-3,4-dihydro-4-hydroxy-1-phenylquino-
lin-2(1H)-one (5g). Prepared from 1g. Yield 80%. Colorless solid. M.p.
127 – 1308 (hexane). IR: 3309, 3064, 3039, 2948, 2861, 1673, 1604, 1590,
1492, 1459, 1382, 1332, 1294, 1265, 1232, 1203, 1159, 1124, 1074, 1024,
1002, 958, 921, 865, 840, 809, 782, 765, 740, 696, 663, 651, 619, 532, 514,
499, 435. EI-MS: 366 (3, Mþ), 279 (5), 278 (23), 180 (11), 169 (8), 168
(5), 142 (32), 98 (16), 85 (7), 84 (100), 70 (6), 57 (18), 41 (19). ESI-MS
(pos.): 367.4 (100, [M þ H]þ). Anal. calc. for C23H30N2O2 (366.49): C
75.37, H 8.25, N 7.64; found: C 75.26, H 8.27, N 7.64.
4. General Procedure for the Reduction of Compounds 1 with
NaBH4. To the stirred soln. of 1 (1 mmol) in MeOH (5 ml) was added
NaBH4 (42 mg, 1.1 mmol) at 08 in small portions during 15 min and the
stirring was continued for 20 min. Then, crushed ice (7.5 ml) was added,
the mixture was acidified with conc. HCl, and 6% soln. of NaHCO3
(4.5 ml) was added. The deposited precipitate was filtered with suction,
dried, and crystallized from appropriate solvent. In some cases, the
precipitate was separated by CC (SiO2). The results are given in
cis-3-Benzyl-3-(butylamino)-3,4-dihydro-4-hydroxy-1-phenylqui-
nolin-2(1H)-one (5h). Prepared from 1h in yield 82% besides 4-
hydroxy-2-quinolone (4%). Colorless solid. M.p. 64 – 688 (hexane); IR:
3426, 3065, 3031, 2956, 2927, 2870, 1688, 1602, 1591, 1494, 1458, 1327,
1299, 1266, 1236, 1196, 1157, 1128, 1072, 1020, 961, 795, 760, 725, 697,
652, 596, 508. EI-MS: 310 (22), 309 (100, [M À Bn]þ), 291 (9), 236 (12),
208 (18), 180 (11), 118 (8), 91 (24), 84 (25). ESI-MS (pos.): 401.3 (100,
[M þ H]þ). Anal calc. for C26H28N2O2 (400.51): C 77.97, H 7.05, N 6.99;
found: C 77.63, H 7.28, N 6.65.
1
Table 2, H- and 13C-NMR spectra are given in Table 4.
cis-3-Butyl-3-(butylamino)-3,4-dihydro-4-hydroxyquinolin-2(1H)-
one (5a). Prepared from 1a. Yield 91%. Colorless solid. M.p. 119 – 1218
(benzene/cyclohexane). IR: 3433, 3305, 3020, 2952, 2930, 2858, 1681,
1657, 1595, 1488, 1438, 1371, 1351, 1300, 1249, 1233, 1151, 1076, 830, 753,
716, 670, 660, 630. ESI-MS (pos.): 291.2 (100, [M þ H]þ). Anal. calc.
for C17H26N2O2 (290.40): C 70.31, H 9.02, N 9.65; found: C 69.92, H 9.20,
N 9.54.
cis-3-Benzyl-3-(butylamino)-3,4-dihydro-4-hydroxyquinolin-
2(1H)-one (5b). Prepared from 1b. Yield 71%. Colorless solid. M.p.
189 – 1948 (hexane). IR: 3192, 3062, 2954, 2928, 2872, 1679, 1597, 1493,
1471, 1438, 1376, 1339, 1253, 1226, 1200, 1119, 1070, 1030, 1017, 868, 807,
757, 718, 700, 683, 587, 504. ESI-MS (pos.): 325.2 (100, [M þ H]þ).
Anal. calc. for C20H24N2O2 (324.42): C 74.04, H 7.46, N 8.64; found: C
73.83, H 7.51, N 8.54.
cis-3-(Butylamino)-3,4-dihydro-4-hydroxy-1,3-diphenylquinolin-
2(1H)-one (5i). Prepared from 1i. Yield 75%. Colorless solid. M.p.
139 – 1438 (benzene). IR: 3065, 2956, 2858, 1683, 1674, 1604, 1493, 1457,
1338, 1297, 1261, 1182, 1133, 1087, 1004, 944, 892, 776, 763, 720, 704, 694,
660, 595, 515. EI-MS: 386 (4, Mþ), 315 (11), 299 (7), 298 (29), 297 (16),
189 (4), 180 (13), 162 (26), 161 (13), 120 (10), 119 (100), 118 (26), 105
(7), 104 (47), 77 (12). ESI-MS (pos.): 387.3 (100, [M þ H]þ). Anal.
calc. for C25H26N2O2 (386.49): C 77.69, H 6.78, N 7.25; found: C 77.41, H
6.95, N 7.26.
5. General Procedure for the Reduction of Compounds 2 and 4 with
LiAlH4 and Following Reaction with HNCO. Method A. To the soln. of
2 or 4 (0.75 mmol) in anh. THF (8 ml) was added LiAlH4 (86 mg,
2.1 mmol) in a small portions during 1.5 h at r.t. The mixture was heated
to reflux for 1 – 3 h according to results of TLC. After cooling, H2O
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Helv. Chim. Acta 2016, 99, 50 – 62
61
(75 ml), 15% NaOH (75 ml), and once again H2O (75 ml), were
gradually added. The suspension was filtered with suction; the
precipitate was washed with THF (5 ml). The filtrate was evaporated
to dryness and worked-up by CC (SiO2).
Method B. The reduction was carried out by the same manner as in
Method A. After filtration of the suspension and washing of precipitate,
the filtrates were evaporated to dryness. After addition of AcOH (2 ml)
and KNCO (81 mg, 1 mmol), the mixture was stirred at r.t. for 1.5 h,
evaporated to a small volume and, after addition of H2O (5 ml), three
times extracted with CHCl3. The collected extracts were dried with
K2CO3 and evaporated to dryness. The oily residue was separated by
column chromatography.
Method C. Some selected oily fractions from the CC of the
products of Method A, pure according to TLC, were dissolved in AcOH
(2 ml) and then treated by Method B. The yields are given in Table 6.
11-Butyl-11-[butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-methyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9d). Prepared from 2d
by Method B in 43% yield and from 8d by Method C in 71% yield.
Colorless solid. M.p. 271 – 2738 (AcOEt). IR: 3274, 2957, 2930, 2871,
1708, 1673, 1608, 1579, 1504, 1463, 1420, 1394, 1335, 1256, 1220, 1199,
1155, 1127, 1092, 1071, 1021, 993, 948, 927, 857, 837, 750, 628, 616, 586,
543. ESI-MS (pos.): 759.3 (8, [2M þ K]þ), 743.4 (18, [2M þ Na]þ),
721.4 (5, [2M þ H]þ), 560.3 (6, [3M þ Ca]2þ), 399.2 (100, [M þ K]þ),
383.2 (66, [M þ Na]þ), 361.3 (24, [M þ H]þ). Anal. calc. for
C19H28N4O3 (360.45): C 63.31, H 7.83, N 15.54; found: C 63.25, H 7.91,
N 15.60.
11-Benzyl-11-[butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-methyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9e). Prepared from 2e
by Method B in 43% yield and from 8e by Method C in 18% yield.
Colorless solid. M.p. 276 – 2788 (AcOEt). IR: 3272, 3029, 2958, 2872,
1709, 1676, 1606, 1580, 1502, 1465, 1418, 1393, 1264, 1217, 1112, 1086,
1023, 947, 883, 857, 838, 749, 702, 635, 618, 566. ESI-MS (pos.): 811.3 (9,
[2M þ Na]þ), 433.1 (32, [M þ K]þ), 417.2 (100, [M þ Na]þ), 395.2 (5,
[M þ H]þ). Anal. calc. for C22H26N4O3 (394.47): C 66.99, H 6.54, N
14.20; found: C 66.65, H 6.52, N 14.30).
11-[Butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-methyl-11-phenyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9fA). Prepared from 2f
by Method B in 26% yield and from 4f by Method B in 9% yield. It rises
also from 9fB by its heating over m.p. Colorless solid. M.p. 235 – 2408
(AcOEt). IR: 3287, 2960, 2874, 1721, 1695, 1604, 1503, 1444, 1411, 1337,
1248, 1216, 1150, 1100, 1084, 1001, 964, 915, 860, 827, 761, 750, 698, 678,
609, 555, 508. ESI-MS (pos.): 783.3 (25, [2M þ Na]þ), 761.3 (5, [2M þ
H]þ), 419.1 (61, [M þ K]þ), 403.2 (100, [M þ Na]þ), 381.2 (6, [M þ
H]þ). Anal. calc. for C21H24N4O3 (380.44): C 66.30, H 6.36, N 14.73;
found: C 65.98, H 6.39, N 14.80.
11-[Butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-methyl-11-phenyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9fB). Prepared from 2f
by Method B in 11% yield. Colorless solid. M.p. 155 – 161 and then
229 – 2358 (AcOEt/cyclohexane). IR: 3396, 3229, 3125, 2959, 1738,
1713, 1607, 1581, 1500, 1447, 1421, 1339, 1249, 1213, 1197, 1153, 1101,
1079, 1044, 1016, 973, 942, 920, 821, 764, 708, 698, 632, 615, 557, 512.
ESI-MS (pos.): 783.3 (15, [2M þ Na]þ), 590.2 (44, [3M þ Ca]2þ), 419.1
(47, [M þ K]þ), 403.2 (100, [M þ Na]þ), 400.2 (48, [2M þ Ca]2þ),
381.2 (23, [M þ H]þ). Anal. calc. for C21H24N4O3 (380.44): C 66.30, H
6.36, N 14.73; found: C 66.13, H 6.32, N 14.71.
11-Butyl-11-[butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-phenyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9gA). Prepared from 2g
by Method B in 21% yield and from 8g by Method C in 31% yield.
Colorless solid. M.p. 218 – 2278 (benzene/hexane). IR: 3243, 3134, 2958,
2932, 2871, 1720, 1608, 1595, 1581, 1496, 1432, 1412, 1381, 1338, 1243,
1206, 1158, 1090, 1002, 906, 871, 837, 757, 736, 704, 631, 607, 546, 500. EI-
MS: 423 (20), 422 (70, Mþ), 350 (11), 349 (41), 348 (6), 291 (14), 278
(8), 277 (13), 275 (6), 266 (11), 263 (11), 262 (10), 250 (23), 249 (33),
248 (15), 234 (16), 233 (7), 208 (24), 207 (91), 206 (22), 196 (11), 195
(15), 194 (17), 193 (8), 180 (17), 167 (8), 140 (21), 131 (12), 98 (12), 85
(9), 84 (100), 77 (10), 59 (7), 57 (28), 55 (10), 43 (10), 41 (24). ESI-MS
(pos.): 867.4 (8, [2M þ Na]þ), 845.3 (5, [2M þ H]þ), 461.2 (67, [M þ
K]þ), 445.2 (100, [M þ Na]þ), 423.3 (44, [M þ H]þ). Anal. calc. for
C24H30N4O3 (422.52): C 68.22, H 7.16, N 13.26; found C 68.24, H 7.26, N
13.27.
11-Butyl-11-[butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-phenyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9gB). Prepared from 4g
by Method B in 32% yield. Colorless solid. M.p. 202 – 2058 (benzene/
hexane). IR: 3235, 3130, 2958, 2931, 2871, 1712, 1606, 1596, 1579, 1497,
1465, 1450, 1415, 1396, 1332, 1302, 1252, 1205, 1158, 1129, 1092, 1069,
993, 961, 910, 823, 757, 728, 697, 660, 611, 551, 499. EI-MS: 423 (28), 422
(99, Mþ), 392 (11), 350 (9), 349 (35), 348 (8), 321 (29), 320 (100), 291
(7), 277 (8), 264 (16), 263 (39), 262 (31), 248 (10), 246 (9), 234 (11),
233 (7), 221 (14), 220 (6), 219 (8), 208 (12), 207 (19), 206 (10), 196
(11), 195 (9), 194 (14), 193 (8), 180 (16), 140 (17), 131 (12), 98 (11), 84
(56), 77 (10), 57 (12), 41 (15). ESI-MS (pos.): 867.4 (9, [2M þ Na]þ),
653.3 (19, [3M þ Ca]2þ), 461.2 (21, [M þ K]þ), 445.2 (62, [M þ Na]þ),
423.3 (100, [M þ H]þ). Anal. calc. for C24H30N4O3 (422.52): C 68.22, H
7.16, N 13.26, found: C 68.51, H 7.28, N 13.15.
11-Benzyl-11-[butyl(nitroso)amino]-1,2,3,6-tetrahydro-1-phenyl-
4H-2,6-methano-5,1,3-benzoxadiazocin-4-one (9h). Prepared from 2h
by Method B in 20% yield and from 8h by Method C in 27% yield.
Colorless solid. M.p. 220 – 2298 (benzene/hexane). IR: 3399, 3237, 3130,
2958, 2872, 1721, 1607, 1495, 1463, 1416, 1382, 1340, 1244, 1204, 1109,
1084, 998, 892, 867, 756, 729, 702, 629, 593. ESI-MS (pos.): 935.4 (10,
[2M þ Na]þ), 913.3 (6, [2M þ H]þ), 495.2 (6, [M þ K]þ), 479.2 (100,
[M þ Na]þ ), 457.3 (27, [M þ H]þ). Anal. calc. for C27H28N4O3 (456.54):
C 71.03, H 6.18, N 12.27; found: C 70.95, H 6.51, N 11.90.
11-[Butyl(nitroso)amino]-1,2,3,6-tetrahydro-1,11-diphenyl-4H-2,6-
methano-5,1,3-benzoxadiazocin-4-one (9i). Prepared from 2i by Meth-
od B in 1% yield. Colorless solid. M.p. 260 – 2648 (benzene/cyclo-
hexane). IR: 3447, 3266, 2961, 1739, 1606, 1577, 1498, 1445, 1409, 1382,
1337, 1291, 1235, 1207, 1105, 1081, 1014, 880, 758, 722, 695, 632. ESI-MS
(pos.): 907.4 (8, [2M þ Na]þ), 885.3 (5, [2M þ H]þ), 683.3 (5, [3M þ
Ca]2þ, 481.2 (26, [M þ K]þ), 465.2 (100, [M þ Na]þ), 443.3 (15,
[M þ H]þ). Anal. calc. for C26H26N4O3 (442.51): C 70.57, H 5.92, N
12.66; found C 70.95, H 5.71, N 12.5.
2-(Methylamino)benzaldehyde (10d). Isolated from the reduction
of 2e (Method A, yield 3%; Method B, yield 3%), 2f (Method A, yield
5%; Method B, yield 13%), and 4f (Method B, yield 10%). Yellow oil.
B.p. 1288/15 Torr. IR and 1H-NMR data were identical with those
published [25].
2-(Phenylamino)benzaldehyde (10g). Isolated from the reduction
of 2g (Method A, yield 13%; Method B, yield 14%), 4g (Method B,
13%), 2h (Method A, yield 21%; Method B, yield 14%), and 2i
(Method A, yield 29%; Method B, yield 27%). Yellow solid. M.p. 70 –
728 (hexane). For 10g, a m.p. of 70 – 718 was published. The 1H-NMR
data were identical with those reported [26].
6. General Procedure for the Conversion of Impure Compounds 8
to 9. Method C. To the soln. of selected crude compound 8, obtained by
reduction of 2 by Method A (0.25 mmol) in AcOH (2 ml), KNCO
(27 mg, 0.33 mmol) was added. The mixture was stirred at r.t. for 2 h,
crushed ice (15 ml) was added, and the sediment was filtered with
suction. If oily compound arose, the mixture was extracted three times
with CHCl3. The collected extracts were dried with K2CO3 and
evaporated to dryness. The oily residue was separated by CC (SiO2).
The following compounds 9, identical in all respects to those prepared
from corresponding compounds 2 by Method B, were prepared: 9d
(yield 71%), 9e (yield 18%), 9gA (yield 31%), and 9h (yield 21%).
7. General Procedure for the Reaction of Compounds 5 with
Triphosgene. Triphosgene (¼ bis(trichloromethyl)carbonate; 43 mg,
0.145 mmol) was added in several portions during 1 h to the well-
stirred soln. of 5 (0.4 mmol), Et3N (120 ml, 0.87 mmol), and 4-
(dimethylamino)pyridine (DMAP; 20 mg, 0.18 mmol) in benzene
(10 ml). The soln. was stirred at r.t. for 4 h, and the progress of the
reaction was monitored by TLC. The suspension was filtered, and the
filtrate was evaporated to dryness. H2O (15 ml) was added to the
residue, and the suspension was extracted with CHCl3 (3 Â 20 ml).
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Helv. Chim. Acta 2016, 99, 50 – 62
Collected extracts were washed with HCl (2.5%), dried, evaporated,
and the residue was crystallized from the appropriate solvent. The
mother liquors were subjected to CC (SiO2).
[8] S. Berger, S. Braun, H.-O. Kalinowski, in ꢃNMR Spectroscopy of
the Non-Metallic Elementsꢂ, Wiley, Chichester, 1996, p. 214.
[9] J. P. Gouesnard, G. J. Martin, Org. Magn. Reson. 1979, 12, 263.
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[12] B. T. Hayes, T. S. Stevens, J. Chem. Soc. C 1970, 1088.
[13] B. F. Powell, C. G. Overberger, J.-P. Anselme, J. Heterocycl. Chem.
1983, 20, 121.
3,3a-Dibutyl-3,3a,5,9b-tetrahydro-5-methyl[1,3]oxazolo[4,5-c]qui-
noline-2,4-dione (6d). Prepared from 5d. Yield 22%. Colorless solid.
M.p. 125 – 1278 (benzene/hexane). IR: 3060, 2957, 2930, 2871, 1763,
1692, 1614, 1465, 1356, 1332, 1287, 1262, 1207, 1180, 1105, 1069, 1040,
1025, 1007, 979, 958, 916, 860, 825, 779, 755, 667, 636, 528. ESI-MS
(pos.): 683.3 (31, [2M þ Na]þ, 369.2 (27, [M þ K]þ), 353.2 (99, [M þ
Na]þ), 331.2 (100, [M þ H]þ), 287.2 (17, [M þ H À CO2]þ). Anal.
calc. for C19H26N2O3 (330.42): C 69.06, H 7.93, N 8.48; found: C 68.88, H
8.15, N 8.54.
[14] P. G. Jones, Chem. Brit. 1981, 17, 222.
[15] H. Sarker, M. L. Greer, S. C. Blackstock, J. Org. Chem. 1966, 61,
3177.
3-Butyl-3,3a,5,9b-tetrahydro-5-methyl-3a-phenyl[1,3]oxazolo[4,5-
c]quinoline-2,4-dione (6f). Prepared from 5f. Yield 42%. Colorless
solid. M.p. 151 – 1558 (benzene/hexane). IR: 3517, 3071, 2977, 2958,
2932, 2897, 2855, 1769, 1686, 1615, 1491, 1465, 1448, 1388, 1344, 1296,
1264, 1203, 1114, 1077, 1040, 1023, 975, 722, 870, 777, 764, 750, 714, 700,
684, 662, 637, 580, 544. ESI-MS (pos.): 723.3 (28, [M þ Na]þ), 389.1 (17,
[M þ K]þ), 373.2 (89, [M þ Na]þ), 351.2 (100, [M þ H]þ), 307.2 (40,
[M þ H À CO2]þ). Anal. calc. for C21H22N2O3 (350.16): C 71.98, H 6.33,
N 7.99; found: C 72.09, H 6.34, N 8.05.
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R. Taylor, J. Chem. Soc., Perkin Trans. 2 1987, S1.
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kin, A. V. Belik, O. N. Chupakhin, Russ. Chem. Bull. 1999, 48,
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