Facile one-pot synthesis of 1,2,3,4-tetrahydroquinoline-3-carboxylic acids and their heterocyclic analogs

Article abstract of DOI:10.1080/00397910802044272

A facile one-pot method for the synthesis of 1,2,3,4-tetrahydroquinoline-3- carboxylic acids and their heterocyclic analogs based on the tert-amino effect. A set of 1,2,3,4-tetrahydroquinoline-3-carboxylic acids was readily prepared starting from various ortho-dialkylaminoaldehydes and Meldrum's acid using Me3SiCl in dimethylformamide (DMF) solution. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802044272

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Facile One-Pot Synthesis of
1,2,3,4-Tetrahydroquinoline-3-
carboxylic Acids and Their
Heterocyclic Analogs
Sergey V. Ryabukhin a b , Andrey S. Plaskon a b
Dmitriy M. Volochnyuk a c , Sergey E. Pipko a &
Andrey A. Tolmachev b
,
a Enamine Ltd., Kyiv, Ukraine
b National Taras Shevchenko University, Kyiv, Ukraine
c Institute of Organic Chemistry, National Academy
of Sciences of Ukraine, Kyiv, Ukraine
Version of record first published: 28 Aug 2008.
To cite this article: Sergey V. Ryabukhin , Andrey S. Plaskon , Dmitriy M. Volochnyuk ,
Sergey E. Pipko & Andrey A. Tolmachev (2008): Facile One-Pot Synthesis of 1,2,3,4-
Tetrahydroquinoline-3-carboxylic Acids and Their Heterocyclic Analogs, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:17, 3032-3043
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Synthetic Communications1, 38: 3032–3043, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802044272
Facile One-Pot Synthesis of 1,2,3,4-
Tetrahydroquinoline-3-carboxylic Acids and
Their Heterocyclic Analogs
Sergey V. Ryabukhin,1,2 Andrey S. Plaskon,1,2 Dmitriy
M. Volochnyuk,1,3 Sergey E. Pipko,1 and Andrey A. Tolmachev2
1Enamine Ltd., Kyiv, Ukraine
2National Taras Shevchenko University, Kyiv, Ukraine
3Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Kyiv, Ukraine
Abstract: A facile one-pot method for the synthesis of 1,2,3,4-tetrahydroquino-
line-3-carboxylic acids and their heterocyclic analogs based on the tert-amino
effect. A set of 1,2,3,4-tetrahydroquinoline-3-carboxylic acids was readily pre-
pared starting from various ortho-dialkylaminoaldehydes and Meldrum’s acid
using Me3SiCl in dimethylformamide (DMF) solution.
Keywords: Chlorotrimethylsilane, Meldrum’s acid, ortho-dialkylaminoaldehydes,
1,2,3,4-tetrahydroquinoline-3-carboxylic acids, tert-amino effect
Nipecotic acids 1 (Fig. 1) are widely used as anticonvulsant,[1] antinoci-
ceptive,[2] antiepileptic,[3a] anti-inflammatory,[2c] neuroprotective,[3a] neu-
roregulatoric,[2c,3b] anti-allodynic,[2d] and immunosuppressant[3c] agents.
Therefore, the development of effective methods for the synthesis of nipe-
cotic acids remains an interesting challenge. Only a few examples of
1,2,3,4-tetrahydroquinoline-3-carboxylic acids 2 (Fig. 1), which are benzo
analogs of nipecotic acid, have been described in the literature,[4] and the
heteroaromatic analogs are unknown.
Herein we report a facile method for the synthesis of 1,2,3,4-
tetrahydroquinoline-3-carboxylic acids 2 from ortho-dialkylaminoaldehydes
3 and Meldrum’s acid 4 that employs the tert-amino effect.[5,6] Previously it
Received December 11, 2007.
Address correspondence to Sergey V. Ryabukhin, Enamine Ltd., 23 A. Matro-
sova St., 01103 Kyiv, Ukraine. E-mail: Ryabukhin@mail.enamine.net
3032

1,2,3,4-Tetrahydroquinoline-3-carboxylic Acids
3033
Figure 1. Nipecotic acids 1 and 1,2,3,4-tetrahydroquinoline-3-carboxylic acids 2.
has been demonstrated that the reaction of ortho-dialkylaminoaldehydes
3 with Meldrum’s acid 4 leads to spiro products 6.[7] The use of
chlorotrimethylsilane (TMSCl) as a promoter and water scavenger[5c,8] in
dimethylformamide (DMF) at 100 ꢀC leads to the formation of the target
acids 2 in 21–45% yield (Scheme 1, Table 1). This result is not surprising
considering that similar spiro compounds are known to transform into
the corresponding acids upon reflux under acidic conditions.[9]
At ambient temperature, the TMSCl-mediated reactions of ortho-
dialkylaminobenzaldehydes 3a–d and Meldrum’s acid 4 gave spiro
products 6 in nearly quantitative yields.
In the case of dialkylaminoaldehydes 3e,f, benzylidene derivatives 5
and spiro compounds 6 were formed at room temperature and 60 ꢀC
respectively. Previously it was reported that Meldrum’s acid 4 reacted
with ortho-dialkylaminoaldehydes 3 to give benzylidene intermediates
5, which underwent cyclization, leading eventually to compounds 6.[7]
The latter were heated in the presence of HCl generated from TMSCl
and H2O to yield acids 2 in 45–69% yield. On the basis of these results,
we have developed a one-pot, two-step procedure for the high-yield syn-
thesis of acids 2 without isolation of intermediate products 6. First, the
reaction mixture was heated for 12 h at 60 ꢀC to generate intermediate
spiro compounds 6 and then at 100 ꢀC (6 h for 2a–d, 10 h for 2e and
15 h for 2f) to accomplish the hydrolysis and decarboxylation. The appli-
cation of this two-step procedure results in a two-fold increase in the
yields of compounds 2 compared to the one-step procedure at 100 ꢀC.
Scheme 1. Synthesis of 1,2,3,4-tetrahydroquinoline-3-carboxylic acids from
ortho-dialkylaminoaldehydes and Meldrum’s acid.

3034
S. V. Ryabukhin et al.
Table 1. Yieldsa and ratio of diastereomers of acids 2a–f obtained
Yield at
60 þ 100
Ratio of
diastereomers
R,R=R,S
Yiꢀeld at
Aldehyde 3
Acid 2
100 C (%)a
ꢀC (%)a
3a
38
24
45
28
21
30
69
49
67
62
45
53
83=17
78=22
80=20
84=16b
81=19
71=29
2a
3b
3c
3d
3e
3f
2b
2c
2d
2e
2f
aYields refer to pure isolated products.
bIn this case, ratio for S,R=S,S is indicated.
ꢂThe signals of minor diastereomers in experimental part.
The application of the optimized procedure to compounds 3g–j
(Scheme 2) did not result in the corresponding acids. Aldehyde 3g
=
undergoes O CꢁN bond cleavage of pyrimidine cycle. Compounds 3h
and 3i did not react, whereas aldehyde 3j decomposed. Acids 2a–f are
Scheme 2. Heterocyclic and enaminic ortho- dialkylaminoaldehydes.

1,2,3,4-Tetrahydroquinoline-3-carboxylic Acids
3035
formed as a 4:1 mixture of two diastereomers that cannot be separated by
preparative high performance liquid chromatography (HPLC). Co-crys-
tallization of 2a–f with 1,4-diazabicyclo[2.2.2]octane (DABCO) also
failed to separate the diastereomers.
The composition and structure of all the compounds obtained were
unambiguously established by NMR spectroscopy (1H and 13C), mass
spectrometry, IR spectroscopy, and elemental analysis.
In conclusion, an efficient and facile methodology has been
elaborated for the preparative synthesis of 1,2,3,4-tetrahydroquinoline-
3-carboxylic acids 3a–d and their heterocyclic analogs 3e,f. It is based
on the reaction of aryl or heteroaryl 2-(dialkylamino)aldehydes with Mel-
drum’s acid using Me3SiCl as a promoter, water scavenger, and a source
of HCl, which catalyzes the heterocyclizations and transformation of
spiro products into acids.
EXPERIMENTAL
All chemicals were obtained from commercially available sources (Aldrich,
Fluka, Enamine Ltd.) and used without further purification. DMF was
freshly distilled and dried by standard methods; monitoring of water con-
centration in solvents (the solvent contained less than 0.05%, usually
0.02% of water) was performed using a Mettler Toledo DL31 KF Titrator.
All solvents for crystallizations were used without additional purification.
Melting points were measured with a Buchi melting-point apparatus
1
and are uncorrected. H NMR (400 MHz and 500 MHz) were recorded
on Varian Mercury-400 and Bruker Avance DRX-500 spectrometers
with TMS as an internal standard. 13C NMR (125 MHz) were recorded
on a Bruker Avance DRX-500 spectrometer with TMS as an internal
standard. LC=MS spectra were recorded using chromatography=mass
spectrometric system that consisted of a high-performance liquid chro-
matograph (Agilent 1100 series) equipped with diode-matrix and mass-
selective detector (Agilent LC=MSD SL). According to HPLC MS data,
all the synthesized compounds have purity greater than 95%. IR spectra
were recorded on a Nexus-470 spectrometer for samples in KBr discs.
Microanalyses were performed in the Microanalytical Laboratory of
the Institute of Organic Chemistry, National Academy of Sciences of
Ukraine. A Branson 2510E-MT ultrasonic bath was used.
General Procedure for One-Pot Synthesis of Acids 2
Ortho-dialkylaminoaldehydes 3a–f (2 mmol) and Meldrum’s acid 4
(288 mg, 2.0 mmol for 3a–d; 317 mg, 2.2 mmol for 3e; 346 mg, 2.4 mmol

3036
S. V. Ryabukhin et al.
for 3f) were placed in a 15-mL pressure tube and dissolved in DMF (2–
3 mL). Chlorotrimethylsilane (652 mg, 6 mmol) was added dropwise to
the solution. The tube was thoroughly sealed and heated on a water bath
for 6–15 h. After cooling, the flask was opened (caution! excessive press-
ure inside), and the reaction mixture was poured into water (15 mL) and
allowed to stand at 20 ꢀC in an ultrasonic bath for 1 h. The precipitate
formed was filtered and washed with small amount of i-PrOH. In the case
of no precipitation, the product was extracted with CH2Cl2 (2 ꢃ 15 mL)
after adding triethylamine (607 mg, 6 mmol). The organic layer was sepa-
rated, dried over Na2SO4, and concentrated. Recrystallization from an
appropriate solvent yielded target acids 2a–f.
General Procedure for Two-Stage Synthesis of Acids 2
Ortho-dialkylaminoaldehydes 3a–f (2 mmol) and Meldrum’s acid 4
(288 mg, 2.0 mmol for 3a–d; 317 mg, 2.2 mmol for 3e; 346 mg, 2.4 mmol
for 3f) were placed in a 15-mL pressure tube and dissolved in DMF
(2–3 mL). Chlorotrimethylsilane (652 mg, 6 mmol) was added dropwise
to the solution. The tube was thoroughly sealed and allowed to stand
at 60 ꢀC in an ultrasonic bath for 1 day and then heated on a water bath
for 6–15 h. After cooling, the flask was opened (caution! excessive press-
ure inside), and the reaction mixture was poured into water (15 mL) and
allowed to stand at 20 ꢀC in an ultrasonic bath for 1 h. The precipitate
formed was filtered and washed with a small amount of i-PrOH. In the
case of no precipitation, the product was extracted with CH2Cl2
(2 ꢃ 15 mL) after adding triethylamine (607 mg, 6 mmol). The organic
layer was separated, dried over Na2SO4, and concentrated. Recrystalliza-
tion from an appropriate solvent yielded target acids 2a–f.
Data
(3aR)-7-Nitro-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-4-
carboxylic Acid (2a)
ꢀ
1
ꢂ
Mp 192–193 C (EtOH). H NMR (400MHz, DMSO-d6 —signals of minor
diastereomer—see Table 1) d ¼ 1.55 (m, 1H, CH) and 1.83ꢂ (m, 1H, CH),
1.94ꢂ (m, 1H, CH) and 2.18(m, 1H, CH), 2.06 (m, 1H, CH), 2.22 (m, 1H,
CH), 2.82 (m, 1H, CH), 3.06 (m, 1H, CH), 3.10 (m, 1H, CH) and 3.18ꢂ
(m, 1H, CH), 3.25 (m, 1H, CH), 3.51 (m, 2H, CH), 6.43ꢂ (d, 3JHH ¼ 9.0 Hz,
Hz, 1H, CH) and 6.47 (d, 3JHH ¼ 9.0 Hz, 1H, CH), 7.85ꢂ (s, 1H, CH) and
3
7.91 (s, 1H, CH), 7.87ꢂ (d, JHH ¼ 9.0 Hz, 1H, CH) and 7.94 (d,
3JHH ¼ 9.0 Hz, 1H, CH), 12.52 (s, 1H, COOH). 13C NMR (125MHz,
ꢂ
DMSO-d6 —signals of minor diastereomer—see Table 1) d ¼ 21.5ꢂ

1,2,3,4-Tetrahydroquinoline-3-carboxylic Acids
3037
and 23.5, 29.2ꢂ and 31.3, 31.1ꢂ and 31.7, 42.4, 47.8, 59.0ꢂ and 60.3, 109.4ꢂ and
109.6, 119.7ꢂ and 120.2, 124.57ꢂ and 124.61, 124.9ꢂ and 125.2, 135.5 and
135.8ꢂ, 149.2 and 150.1ꢂ, 172.4ꢂ and 174.8. IR (KBr): n ¼ 3660ꢁ3260 (br,
=
OH), 3109, 2976, 2931, 1701 (C O), 1603 (NO2), 1578, 1518, 1487, 1437,
1396, 1302 (NO2), 1250, 1203, 1174, 1099, 802, 750 cmꢁ1. APSI MS:
Mþ þ 1 ¼ 263, Mþ ꢁ1 ¼ 261. Anal. calcd. for C13H14N2O4: C, 59.54; H,
5.38; N, 10.68. Found: C, 59.71; H, 5.27; N, 10.60.
(4aR)-2,3,4,4a,5,6-Hexahydro-1H-pyrido[1,2-a]quinoline-5-carboxylic
Acid (2b)
Mp 154–155 ꢀC (i-PrOH-hexane). 1H NMR (500 MHz, DMSO-d6)
d ¼ 1.38 (m, 2H, CH), 1.47 (m, 1H, CH), 1.61 (m, 1H, CH), 1.70–1.87
2
3
(m, 2H, CH), 2.82 (dd, JHH ¼ 17.4 Hz, JHH ¼ 5.6 Hz, 1H, CH), 2.92
(m, 1H, CH), 3.07 (m, 2H, CH), 3.71 (m, 1H, CH), 4.11 (d,
2JHH ¼ 13.7 Hz, 1H, CH), 6.79 (m, 1H, CH), 6.99–7.15 (m, 3H, CH),
13
12.78 (br. s, 1H, COOH). C NMR (125 MHz, DMSO-d6) d ¼ 21.56ꢂ
and 21.64, 23.7ꢂ and 24.4, 26.0, 29.6, 41.3, 49.4, 57.9, 115.47 and
151.54ꢂ, 127.7 and 127.8ꢂ, 128.0, 129.1ꢂ and 129.4, 130.5, 141.1 and
141.3ꢂ, 173.6 and 174.8ꢂ. IR (KBr): n ¼ 3660ꢁ3300 (br, OH), 3016,
=
2951, 2931, 1732 (C O), 1500, 1435, 1385, 1257, 1209, 1173, 741,
677 cmꢁ1. APSI MS: Mþ þ 1 ¼ 232, Mþ ꢁ1 ¼ 230. Anal. calcd. for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.57; H, 7.57; N, 6.15.
(4aR)-8-Nitro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline-5-
carboxylic Acid (2c)
ꢀ
1
Mp 182–183 C (EtOH). H NMR (500 MHz, DMSO-d6) d ¼ 1.28–1.47
(m, 2H, CH), 1.52–1.75 (m, 3H, CH), 1.81 (m, 1H, CH), 2.67 (m, 1H,
CH) and 2.94ꢂ (m, 1H, CH), 2.84–2.91 (m, 2H, CH), 2.98 (m, 1H, CH)
and 3.10ꢂ (m, 1H, CH), 3.57 (m, 1H, CH) and 3.75ꢂ (m, 1H, CH), 4.15
2
2
(d, JHH ¼ 13.0 Hz, 1H, CH) and 4.23ꢂ (d, JHH ¼ 13.0 Hz, 1H, CH),
3
3
6.88 (d, JHH ¼ 9.3 Hz, 1H, CH) and 6.94ꢂ (d, JHH ¼ 9.3 Hz, 1H,
CH), 7.83–7.91 (m, 2H, CH), 12.66 (s, 1H, COOH). 13C NMR
(125 MHz, DMSO-d6) d ¼ 24.59ꢂ and 24.62, 24.8 and 25.1ꢂ, 25.7 and
26.8ꢂ, 28.1 and 32.1ꢂ, 44.0, 48.4ꢂ and 49.3, 57.9 and 58.3ꢂ, 111.1ꢂ and
111.3, 121.5 and 122.1ꢂ, 124.77 and 124.81ꢂ, 124.9ꢂ and 125.8, 136.05
and 136.08ꢂ, 150.3ꢂ and 151.0, 173.4 and 174.4ꢂ. IR (KBr): n ¼ 3660–
=
3300 (br, OH), 2939, 2858, 1709 (C O), 1603 (NO2), 1581, 1491, 1439,
1408, 1319 (NO2), 1198, 1109, 935, 892, 806, 748, 600 cmꢁ1. APSI MS:
Mþ þ 1 ¼ 277, Mþ ꢁ1 ¼ 275. Anal. calcd. for C14H16N2O4: C, 60.86;
H, 5.84; N, 10.14. Found: C, 61.05; H, 5.71; N, 10.09.

3038
S. V. Ryabukhin et al.
(4aS)-8-Nitro-1,2,4,4a,5,6-hexahydro[1,4]oxazino[4,3-a]quinoline-5-
carboxylic Acid (2d)
Mp 229–230 ꢀC (EtOH). 1H NMR (400 MHz, DMSO-d6) d ¼ 2.57 (m, 1H,
2
CH), 2.81–2.92 (m, 1H, CH), 2.98 (m, 1H, CH), 3.14 (t, JHH ¼ 12.8 Hz,
2
1H, CH), 3.26 (t, JHH ¼ 10.8 Hz, 1H, CH), 3.42ꢂ (m, 1H, CH), and
3.74 (m, 1H, CH), 3.45–3.59 (m, 2H, CH), 3.88 (m, 1H, CH), 3.94–4.07
3
(m, 1H, CH), 6.94 (d, JHH ¼ 9.2 Hz, 1H, CH) and 6.97ꢂ (d,
13
3JHH ¼ 9.2 Hz, 1H, CH), 7.83–7.98 (m, 2H, CH), 12.80 (br. s, 1H,
COOH). C NMR (125 MHz, DMSO-d6) d ¼ 27.9ꢂ and 29.4, 38.5ꢂ and
39.5, 46.7 and 48.2ꢂ, 55.9ꢂ and 56.6, 66.1ꢂ and 66.3, 68.1ꢂ and 70.2,
111.3 and 112.1ꢂ, 122.5 and 122.7ꢂ, 124.2ꢂ and 124.7, 124.8 and 125.3ꢂ,
137.1 and 137.2ꢂ, 150.8 and 150.9ꢂ, 173.0ꢂ and 174.0. IR (KBr):
=
n ¼ 3660–3150 (br, OH), 2966, 2922, 1716 (C O), 1605 (NO2), 1585,
1508, 1491, 1435, 1408, 1321 (NO2), 1255, 1101, 1055, 947, 750 cmꢁ1. APSI
MS: Mþþ1 ¼ 279, Mþꢁ1 ¼ 277. Anal. calcd. for C13H14N2O5: C, 56.11;
H, 5.07; N, 10.07. Found: C, 56.28; H, 4.96; N, 10.02.
(5aR)-3-Methyl-1-phenyl-1,4,5,5a,6,7,8,9-octahydropyrazolo[4,3-c]
quinolizine-5-carboxylic Acid (2e)
ꢀ
1
Mp 200–201 C (i-PrOH). H NMR (400 MHz, DMSO-d6) d ¼ 1.21 (m,
1H, CH), 1.31 (m, 1H, CH), 1.42–1.56 (m, 2H, CH), 1.63 (m, 1H,
CH), 1.78 (m, 1H, CH), 2.05 (s, 3H, CH3), 2.07–2.16 (m, 1H, CH),
2
2.56–2.67 (m, 2H, CH), 2.82 (m, 1H, CH), 3.33 (d, JHH ¼ 13.2 Hz,
1H, CH), 3.43 (m, 1H, CH), 7.24 (m, 1H, CH), 7.39 (m, 4H, CH),
12.24 (br. s, 1H, COOH). 13C NMR (125 MHz, DMSO-d6) d ¼ 12.6,
20.3 and 20.4ꢂ, 24.8 and 25.0ꢂ, 27.1, 33.6, 48.0, 48.2, 61.7, 103.9 and
104.0ꢂ, 126.4, 128.2, 128.7, 139.5, 142.5 and 142.6ꢂ, 153.9 and 154.1ꢂ,
174.0 and 174.7ꢂ. IR (KBr): n ¼ 3660–3100 (br, OH), 3064, 2929, 1709
=
(C O), 1597, 1527, 1502, 1441, 1271, 1203, 1120, 1070, 1014, 916, 775,
758, 690 cmꢁ1. APSI MS: Mþ þ 1 ¼ 312, Mþ ꢁ1 ¼ 310. Anal. calcd.
for C18H21N3O2: C, 69.43; H, 6.80; N, 13.49. Found: C, 69.60; H, 6.63;
N, 13.41.
(4aR)-2,3,4,4a,5,6-Hexahydro-1H-benzo[g]pyrido[1,2-a]-1,8-
naphthyridine-5-carboxylic Acid (2f)
ꢀ
1
Mp 220–221 C (EtOH). H NMR (400 MHz, DMSO-d6) d ¼ 1.33 (m,
1H, CH), 1.41 (m, 1H, CH), 1.59–1.68 (m, 2H, CH), 2.39–2.48 (m, 2H,
CH), 2.92 (m, 1H, CH), 3.00 (m, 1H, CH), 3.25 (m, 1H, CH), 3.33 (m,
1H, CH), 3.72 (m, 1H, CH), 4.22 (m, 1H, CH), 7.50 (m, 3H, CH), 7.61

1,2,3,4-Tetrahydroquinoline-3-carboxylic Acids
3039
3
(d, JHH ¼ 7.6 Hz, 1H, CH), 7.77 (s, 1H, CH), 12.74 (br. s, 1H, COOH).
13C NMR (125 MHz, DMSO-d6) d ¼ 23.7 and 23.8ꢂ, 26.3ꢂ and 26.6, 27.0,
28.4, 44.1, 49.1, 62.6, 109.8 and 109.9ꢂ, 120.2 and 120.5ꢂ, 122.7ꢂ and
122.8, 123.6 and 123.9ꢂ, 125.5 and 125.6ꢂ, 128.1 and 128.4ꢂ, 128.9ꢂ
and 129.1, 145.2 and 145.3ꢂ, 149.6ꢂ and 149.8, 174.1 and 174.9ꢂ. IR
=
(KBr): n ¼ 3650–3200 (br, OH), 3061, 2931, 1707 (C O), 1587, 1522,
1436, 1261, 1208, 1130, 752, 696 cmꢁ1. APSI MS: Mþ þ 1 ¼ 283,
Mþꢁ1 ¼ 281. Anal. calcd. for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92.
Found: C, 72.13; H, 6.59; N, 9.85.
2,2-Dimethyl-5-[(3-methyl-1-phenyl-5-piperidin-1-yl-1H-pyrazol-
4-yl)methylene]-1,3-dioxane-4,6-dione (5e)
Mp 157–158 ꢀC (EtOH). 1H NMR (500 MHz, DMSO-d6) d ¼ 1.51 (m, 6H,
3CH2), 1.75 (s, 6H, 2CH3), 2.05 (s, 3H, CH3), 2.99 (m, 4H, 2NCH2), 7.54
(m, 5H, CH), 8.28 (s, 1H, CH). IR (KBr): n ¼ 2997, 2983, 2935, 1713
=
(C O), 1560, 1512, 1448, 1375, 1360, 1281, 1203, 1101, 974, 930, 825,
789, 775 cmꢁ1. APSI MS: Mþ þ 1 ¼ 396. Anal. calcd. for C22H25N3O4:
C, 66.82; H, 6.37; N, 10.63. Found: C, 66.97; H, 6.18; N, 10.71.
2,2-Dimethyl-70-nitro-10,20,30,3a0-tetrahydro-50H-spiro[1,3-dioxane-5,40-
pyrrolo[1,2-a]quinoline]-4,6-dione (6a)
Mp 217–218 ꢀC (EtOH). 1H NMR (400 MHz, DMSO-d6) d ¼ 1.48 (m, 1H,
CH), 1.73 (s, 3H, CH3), 1.82 (s, 3H, CH3), 2.02 (m, 2H, CH), 2.14 (m, 1H,
2
CH), 3.21 (m, 1H, CH), 3.32 (d, JHH ¼ 16.7 Hz, 1H, CH), 3.64
2
(d, JHH ¼ 16.7 Hz, 1H, CH), 3.73 (m, 1H, CH), 4.01 (m, 1H, CH), 6.65
3
3
(d, JHH ¼ 8.5 Hz, 1H, CH), 8.00 (d, JHH ¼ 8.5 Hz, 2H, CH), 8.01 (s,
1H, CH). 13C NMR (125 MHz, DMSO-d6) d ¼ 23.0, 28.1, 28.3, 29.7,
35.3, 46.3, 48.4, 64.3, 106.2, 110.5, 118.4, 124.91, 124.92, 136.0, 148.9,
=
=
164.1, 169.2. IR (KBr): n ¼ 2968, 2927, 1772 (C O), 1736 (C O), 1605
(NO2), 1520, 1489, 1437, 1396, 1306 (NO2), 1261, 1173, 1095, 818,
750 cmꢁ1. APSI MS: Mþþ1 ¼ 347. Anal. calcd. for C17H18N2O6: C,
58.96; H, 5.24; N, 8.09. Found: C, 59.10; H, 5.12; N, 8.17.
2,2-Dimethyl-20,30,40,4a0-tetrahydro-10H,60H-spiro[1,3-dioxane-5,50-
pyrido[1,2-a]quinoline]-4,6-dione (6b)
Mp 148–149 ꢀC (i-PrOH) [150].[7b] 1H NMR (500 MHz, DMSO-d6)
d ¼ 1.21 (m, 1H, CH), 1.43 (m, 2H, CH), 1.53 (m, 1H, CH), 1.59 (m,
1H, CH), 1.74 (s, 3H, CH3), 1.75 (s, 3H, CH3), 1.78 (m, 1H, CH), 2.77

3040
S. V. Ryabukhin et al.
2
2
(t, JHH ¼ 12.5 Hz, 1H, CH), 3.26 (AB-syst, JHH ¼ 16.8 Hz, 2H,
2
CH2), 3.41 (d, JHH ¼ 11.5 Hz, 1H, CH), 4.04 (m, 1H, CH), 6.64
3
3
(t, JH,H ¼ 8.3 Hz, 1H, CH), 6.90 (d, JH,H ¼ 8.3 Hz, 1H, CH), 6.98 (d,
3JH,H ¼ 8.3 Hz, 1H, CH), 7.04 (t, JH,H ¼ 8.3 Hz, 1H, CH). 13C NMR
3
(125 MHz, DMSO-d6) d ¼ 23.8, 24.1, 27.5, 28.1, 30.1, 32.1, 48.5, 52.1,
61.3, 106.0, 113.6, 118.0, 120.8, 127.3, 129.0, 144.6, 165.3, 168.5. IR
=
=
(KBr): n ¼ 3068, 2968, 2951, 1770 (C O), 1741 (C O), 1605, 1512,
1462, 1383, 1298, 1271, 1203, 1101, 1028, 964, 933, 746 cmꢁ1. APSI
MS: Mþ þ 1 ¼ 316. Anal. calcd. for C18H21NO4: C, 68.55; H, 6.71;
N, 4.44. Found: C, 68.72; H, 6.57; N, 4.52.
2,2-Dimethyl-80-nitro-20,30,40,4a0-tetrahydro-10H,60H-spiro[1,3-
dioxane-5,50-pyrido[1,2-a]quinoline]-4,6-dione (6c)
Mp 209–210 ꢀC (EtOH). 1H NMR (500 MHz, DMSO-d6) d ¼ 1.24
(m, 1H, CH), 1.40 (m, 1H, CH), 1.52 (m, 1H, CH), 1.61 (m, 1H,
CH), 1.67 (m, 1H, CH), 1.77 (s, 3H, CH3), 1.78 (s, 3H, CH3), 1.81 (m,
1H, CH), 3.06 (t, 2JHH ¼ 13.2 Hz, 1H, CH), 3.28 (d,
2
2JHH ¼ 16.5 Hz, 1H, CH), 3.52 (d, JHH ¼ 16.5 Hz, 1H, CH), 3.74 (d,
3JHH ¼ 12.0 Hz, 1H, CH), 4.22 (m, 1H, CH), 7.04 (m, 1H, CH); 7.93
=
(m, 2H, CH). IR (KBr): n ¼ 3001, 2972, 2947, 2920, 1767 (C O), 1736
=
(C O), 1605 (NO2), 1583, 1497, 1396, 1317 (NO2), 1296, 1259, 1213,
1103, 928, 814, 754 cmꢁ1. APSI MS: Mþþ1 ¼ 361. Anal. calcd. for
C18H20N2O6: C, 59.99; H, 5.59; N, 7.77. Found: C, 60.16; H, 5.46;
N, 7.70.
2,2-Dimethyl-80-nitro-10,20,40,4a0-tetrahydro-60H-spiro[1,3-dioxane-5,50-
[1,4]oxazino[4,3-a]quinoline]-4,6-dione (6d)
Mp 220–221 ꢀC (EtOH). 1H NMR (500 MHz, DMSO-d6) d ¼ 1.74 (s, 3H,
CH3), 1.81 (s, 3H, CH3), 3.15–3.24 (m, 2H, CH), 3.36 (d, 2JHH ¼ 16.4 Hz,
2
2
1H, CH), 3.47 (d, JHH ¼ 13.2 Hz, 1H, CH), 3.60 (d, JHH ¼ 16.4 Hz,
2
2
1H, CH), 3.78 (d, JHH ¼ 11.2 Hz, 1H, CH), 3.89 (d, JHH ¼ 11.2 Hz, 1H,
2
2
CH), 3.94 (d, JHH ¼ 11.2 Hz, 1H, CH), 4.08 (d, JHH ¼ 13.2 Hz, 1H,
3
CH), 7.07 (d, JHH ¼ 8.8 Hz, 1H, CH), 7.97 (s, 1H, CH), 7.98 (d,
3JxHH ¼ 8.8 Hz, 1H, CH). 13C NMR (125 MHz, DMSO-d6) d ¼ 28.1,
29.7, 34.1, 46.1, 47.3, 58.7, 66.2, 66.6, 106.7, 111.8, 120.0, 124.2,
124.9, 137.6, 150.3, 164.1, 168.0. IR (KBr): n ¼ 2968, 2924, 1769
=
=
(C O), 1738 (C O), 1604 (NO2), 1587, 1510, 1437, 1319 (NO2),
1256, 1104, 1058, 751 cmꢁ1. APSI MS: Mþ þ 1 ¼ 363. Anal. calcd. for
C17H18N2O7: C, 56.35; H, 5.01; N, 7.73. Found: C, 56.51; H, 4.89;
N, 7.64.

1,2,3,4-Tetrahydroquinoline-3-carboxylic Acids
3041
2,2,30-Trimethyl-10-phenyl-10,40,60,70,80,90-hexahydro-5a0H-spiro
[1,3-dioxane-5,50-pyrazolo[4,3-c]quinolizine]-4,6-dione (6e)
Mp 166–167 ꢀC (EtOH). 1H NMR (400 MHz, DMSO-d6) d ¼ 1.38
(m, 3H, CH), 1.46 (m, 1H, CH), 1.60–1.68 (m, 1H, CH), 1.73 (s, 3H,
CH3), 1.79 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.14 (m, 1H, CH), 3.11
2
(AB-syst, JHH ¼ 16.1 Hz, 2H, CH2), 3.18–3.26 (m, 2H, CH), 3.38 (m,
3
1H, CH), 7.28 (t, JHH ¼ 7.6 Hz, 1H, CH), 7.40–7.59 (m, 4H, CH). IR
=
=
(KBr): n ¼ 3061, 3001, 2935, 1780 (C O), 1738 (C O), 1599, 1502,
1450, 1383, 1323, 1288, 1203, 1113, 1070, 1024, 945, 775, 702 cmꢁ1. APSI
MS: Mþ þ 1 ¼ 396. Anal. calcd. for C22H25N3O4: C, 66.82; H, 6.37; N,
10.63. Found: C, 66.95; H, 6.16; N, 10.54.
ACKNOWLEDGMENT
The authors acknowledge V. V. Polovinko (‘‘Enamine Ltd.’’) and
Dr. S. A. Alekseev (Department of Chemistry of Kyiv National Taras
Shevchenko University) for spectral measurements and D. A. Dontsova
and Dr. A. N. Shivanyuk for helpful discussions.
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