Synthesis of 2-amino-5,5-dialkyl-4-arylmethylidene-2-oxazolines from 2-alkyl-4-arylbut-3-yn-2-ols and guanidine

Article abstract of DOI:10.1016/j.mencom.2012.03.022

Reaction between 2-alkyl-4-arylbut-3-yn-2-ols and guanidine in refluxing pyridine affords 2-amino-5,5-dialkyl-4-arylmethylidene-2-oxazolines.

Full text of DOI:10.1016/j.mencom.2012.03.022

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 114–116
Synthesis of 2-amino-5,5-dialkyl-4-arylmethylidene-2-oxazolines
from 2-alkyl-4-arylbut-3-yn-2-ols and guanidine
Denis S. Baranov,a Aleksey A. Ryabichev,a Victor I. Mamatyuk,b
Yurii V. Gatilov,b Victor G. Kartsevc and Sergei F. Vasilevsky*a
a Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
630090 Novosibirsk, Russian Federation. Fax: +7 383 330 7350; e-mail: vasilev@ns.kinetics.nsc.ru
b N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy
of Sciences, 630090 Novosibirsk, Russian Federation
c InterBioScreen Ltd., 119019 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2012.03.022
Reaction between 2-alkyl-4-arylbut-3-yn-2-ols and guanidine in refluxing pyridine affords 2-amino-5,5-dialkyl-4-arylmethylidene-
2-oxazolines.
Alkynes are convenient substrates for formation of diverse organic
systems, and widely used in search of promising materials and
medications.1 For instance, new analogues of natural aporphinoid
family alkaloids, possessing anti-cancer activity,2 were obtained
by reactions of 1-alkynyl-9,10-anthraquinones with guanidine3
and urea.4
benzenes, where R is substituent, having tertiary acetylenic alcohol
moiety. Electron-deficient alkynes, bearing additional OH group
in a-position to acetylenic carbon, may be of synthetic potential.
Indeed, the reaction of alkynols 1a–e† with guanidine in
refluxing pyridine led to heterocycles 2a–e in 35–75% yields‡
(Scheme 1). In case of 1a, along with predominant 2a (75%) the
minor product 3 was formed (7%).
To extend this chemistry, we have studied the reaction of
guanidine with 1- and 2-R-9,10-anthraquinones, and also 4-R-nitro-
†
Combustion analysis was performed with CHN-analyzer (Model 1106,
Carlo Erba, Italy). The NMR spectra were recorded on a Bruker AV 400
spectrometer (400.13 MHz) in CDCl3 and Bruker-BioSpin AVANCE 600
spectrometer (600 MHz) in DMSO-d6. Melting points were determined with
a Kofler apparatus. The IR spectra were recorded in KBr pellets on a Bruker
Vector 22 instrument. Column chromatography was performed on Merck 60
silica gel and the Silufol UV-254 plates were used for TLC analysis.
Synthesis of 2-alkyl-4-arylbut-3-yn-2-ols 1 (general procedure).
A mixture of iodoarene (9 mmol), 2-methylbut-3-yn-2-ol (0.8 g, 9 mmol),
PdCl2(PPh3)2 (20 mg, 0.028 mmol), CuI (10 mg, 0.052 mmol) and Et3N
(7 ml, 38.6 mmol) in 50 ml of toluene was stirred in argon atmosphere for
1.5–6 h at 65°C. The reaction mixture was cooled and filtered through
Al2O3 (25×20 mm), eluting with toluene. The solvents were evaporated at
reduced pressure, and the residue was recrystallized.
Ar
(NH2)2C=NH · HCl,
Me
K2CO3, Py
N
R
Ar
R
NH2
OH
O
2a–e
35–75%
Me
1a–e
NH2
O
Me
Me
N
O
O
+
2-Methyl-4-(9,10-anthraquinon-1-yl)but-3-yn-2-ol 1a: yield 2.2 g (82%),
mp 157–158°C (toluene) (lit.,10 157.5–158.5°C).
2-Methyl-4-(9,10-anthraquinon-2-yl)but-3-yn-2-ol 1b: yield 2.4 g (92%),
mp 133–134°C (toluene–hexane) (lit.,10 134–135°C).
2-Methyl-4-(4-nitrophenyl)but-3-yn-2-ol 1c: yield 1.78 g (97%),
mp 104.5–105.5°C (toluene–hexane) (lit.,11 104.5–105°C).
3 (from 1a)
O
a R = Me, Ar =
2-Methyl-4-(4'-nitrobiphenyl-4-yl)but-3-yn-2-ol 1d: yield 1.5 g (60%),
mp 117–118°C. 1H NMR (CDCl3, 400 MHz) d: 1.65 (s, 6H, Me), 2.10
(br.s, 1H, OH), 7.55 (m, 4H, o-C6H4-, m-C6H4NO2), 7.72 (d, 2H, m-C6H4-,
O
O
J
8.56 Hz), 8.29 (d, 2H, o-C6H4NO2, J 8.80 Hz). 13C NMR (CDCl3, 100 MHz
)
d: 31.59 (2Me), 65.82 (C–OH), 81.65, 95.68 (CºC), 123.66, 124.31,
127.33, 127.81, 132.51, 138.47, 146.78, 147.35 (CAr). IR (n/cm–1): 3375
(OH), 2221 (CºC), 1516, 1342 (NO2). Found (%): C, 72.27; H, 5.22;
N, 4.81. Calc. for C17H15NO3 (%): C, 72.58; H, 5.37; N, 4.98.
b R = Me, Ar =
3,7-Dimethyl-1-(9,10-anthraquinon-1-yl)oct-6-en-1-yn-3-ol 1e: yield
1.418 g (44%), mp 90–91°C (hexane–toluene). 1H NMR (CDCl3, 400 MHz)
d: 1.68 (s, 3H, Me), 1.70 (s, 6H, 2Me), 1.90 (t, 2H, CH2, J 8.2 Hz), 2.43
(m, 2H, CH2) 2.89 (s, 1H, OH), 5.24 [m, 1H, (CH2)2CH=], 7.69 (t, 1H,
HAr, J 7.8 Hz), 7.79 (m, 2H, HAr), 7.83 (dd, 1H, HAr, J 1.3 and 7.5 Hz),
8.28 (m, 3H, HAr). 13C NMR (CDCl3, 100 MHz) d: 17.91, 25.91, 29.81
(3Me), 23.94, 43.51 [(CH2)2], 69.24 (C–OH), 83.27, 99.76 (CºC), 123.44,
124.17, 127.00, 127.51, 127.66, 132.50, 132.81, 132.93, 133.53, 133.92,
134.21, 134.48, 134.58, 140.30 (CAr, C=CAlk), 181.93, 182.69 (2C=O).
IR (n/cm–1): 3463 (OH), 2216 (CºC), 1676 (C=O). Found (%): C, 81.24;
H, 6.02. Calc. for C24H22O3 (%): C, 80.42; H, 6.19.
O
c R = Me, Ar = 4-O2NC6H4
d R = Me, Ar = 4-(4-O2NC6H4)C6H4
O
O
e R = Me2C=CH(CH2)2, Ar =
Scheme 1
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 114–116
Ar
O(3)
N(2)
Me
NH
B–
C(11)
Ar
Me
OH
+
NH
O(2)
C(9)
H2N
H
NH2
Me
NH
C(10)
NH2
Me OH
C(12)
C(7)
Ar
C(8)
Ar
H
B–
N
C(6)
N
Me
Me
C(4)
NH
NH
Me
Me
O
O
N(3)
C(2)
NH2
NH2
C(13)
C(5)
Ar
O
Ar
N(1)
H
O(1)
N
N
BH
C(14)
Me
Me
Me
Me
NH2
NH2
– NH3
NH2
O
Figure 1 Crystal structure of compound 2c.
Scheme 2
Combination of analytical and spectral (IR, 1H and 13C NMR
and mass spectra) data provided elucidation of the structure
of products 2a–e as 2-amino-5,5-dialkyl-4-arylmethylidene-
2-oxazolines. Structure of 2c was additionally proved by X-ray
diffraction analysis§ (Figure 1).
These transformations have analogy with cyclizations described
in literature,5,6 because the structure of the enamine intermediate is
similar to those of 1-(2-hydroxyethyl)guanidine and 1-(2-hydroxy-
ethyl)-3-nitroguanidine.
The formation of an oxazole ring can be represented as con-
sequent stages of the guanidine addition to the triple bond of 1,
the generation of the alkoxide anion under the action of base
(guanidine or potassium carbonate) and cyclization with the
following elimination of the ammonia molecule (Scheme 2).
Detailed comparison of the physico-chemical properties of
compounds 2a–e shows, that main product of the reaction of
alcohol 1a with guanidine in 1-butanol is 2-amino-5,5-dimethyl-
4-[(9,10-anthraquinon-1-yl)methylidene]-2-oxazoline 2a rather
than its isomer 3H-4-(2-hydroxyprop-2-yl)anthra[9,1-de][1,3]-
diazocine-2,9-dione A, as it was reported earlier3 (Scheme 3).
‡
Reaction of 2-alkyl-4-arylbut-3-yn-2-ols 1 with guanidine. A mixture
of 2-methyl-4-arylbut-3-yn-2-ol 1 (3.4 mmol), guanidine hydrochloride
(1.95 g, 20.4 mmol) and K2CO3 (2.81 g, 20.4 mmol) in 40 ml of pyridine
was boiled for 16–60 h. Then CH2Cl2 (250 ml) and water (250 ml) were
added, the organic layer was separated, dried over Na2SO4 and evaporated to
dryness under reduced pressure. The crude product was purified by column
chromatography on Al2O3 (elution with toluene and mixture toluene–
ethyl acetate). Subsequent recrystallization gave pure compounds.
2-Amino-5,5-dimethyl-4-[(9,10-anthraquinon-1-yl)methylidene]-
2-oxazoline 2a: yield 847 mg (75%), mp 290–291°C (1,4-dioxane)
(lit.,3(b) 290–290.4°C). 1H NMR (CDCl3, 400 MHz) d: 1.67 (s, 6H, Me),
4.94 (br.s, 2H, NH2), 6.91 (s, 1H, CH=), 7.68 (t, 1H, HAr, J 7.8 Hz), 7.75
2-Amino-5,5-dimethyl-4-[(4'-nitrobiphenyl-4-yl)methylidene]-2-oxazoline
2d: yield 385 mg (35%), mp 269–270°C (ethyl acetate–toluene). 1H NMR
(CDCl3, 400 MHz) d: 1.56 (s, 6H, Me), 4.91 (br.s, 2H, NH2), 5.30 (s,
1H, CH=), 7.58 (dt, 2H, o-C6H4-, J 1.88, 2.15 and 8.33 Hz), 7.74 (dt, 2H,
m-C6H4NO2, J 2.15, 2.42 and 9.13 Hz), 7.87 (dt, 2H, m-C6H4-, J 1.88,
2.15 and 8.33 Hz), 8.27 (dt, 2H, o-C6H4NO2, J 2.15, 2.42 and 9.13 Hz).
13C NMR (CDCl3, 100 MHz) d: 27.77 (2Me), 90.33 (CMe2), 100.78
(HC=), 124.25, 127.25, 127.29, 128.27, 134.60, 139.05, 146.70, 147.87
(CAr), 160.14 (=C<), 165.07 (CNH2). IR (n/cm–1): 3383, 3502 (NH2),
1547 (C=N), 1338, 1375 (NO2). Found (%): C, 66.59; H, 5.11; N, 12.92. Calc.
for C18H17N3O3 (%): C, 66.86; H, 5.30; N, 13.00.
(m, 2H, HAr), 8.15 (m, 1H, HAr), 8.26 (m, 2H, HAr), 8.76 (dd, 1H, HAr
,
2-Amino-5-methyl-5-(4-methylpent-3-en-1-yl)-4-[(9,10-anthraquinon-
1-yl)methylidene]-2-oxazoline 2e: yield 717 mg (53%), mp 173–174°C
(toluene–hexane). 1H NMR (CDCl3, 400 MHz) d: 1.57 (s, 3H, Me), 1.62
(s, 3H, Me), 1.65 (s, 3H, Me), 1.91 (m, 2H, CH2), 2.06 (m, 2H, CH2),
5.13 [m, 1H, (CH2)2CH=], 5.60 (br.s, 2H, NH2), 6.76 (s, 1H, Aq-CH=),
7.67 (t, 1H, HAr, J 7.8 Hz), 7.75 (qd, 2H, HAr, J 1.6 and 7.5 Hz), 8.15 (dd,
1H, HAr, J 1.3 and 7.5 Hz), 8.25 (dd, 2H, HAr, J 1.9 and 6.7 Hz), 8.61
(dd, 1H, HAr, J 1.3 and 8.1 Hz). 13C NMR (CDCl3, 100 MHz) d: 17.79,
25.87, 26.71 (3Me), 22.39, 40.62 [(CH2)2], 92.81 (R3C–O), 100.39 (–CH=),
123.47, 124.99, 126.67, 127.34, 128.14, 132.33, 132.57, 132.83, 133.32,
134.15, 134.91, 135.36, 137.02, 140.95 (CAr, C=CAlk), 160.65 (=C–N),
166.20 (CNH2), 184.15, 185.13 (2C=O). IR (n/cm–1): 3398 (NH2), 1663
(C=O), 1560 (C=N). Found (%): C, 74.84; H, 5.78; N, 6.89. Calc. for
C25H24N2O3 (%): C, 74.98; H, 6.04; N, 7.00.
J 1.5 and 8.1 Hz). 1H NMR (DMSO-d6, 600 MHz, 320 K) d: 1.54 (s, 6H,
Me), 6.95 (s, 1H, CH=), 7.67 (m, 1H, HAr), 7.68 (br.s, 2H, NH2), 7.83
(m, 1H, HAr), 7.88 (m, 1H, HAr), 7.89 (m, 1H, HAr), 8.11 (m, 1H, HAr),
8.16 (m, 1H, HAr), 9.16 (m, 1H, HAr). 13C NMR (DMSO-d6, 150 MHz)
d: 27.39 (2Me), 88.84 (CMe2), 94.80 (CH=), 122.81, 125.60, 125.91,
126.93, 132.00, 132.23, 133.46, 134.33, 134.45, 134.92, 135.55, 141.51
(CAr), 166.48 (=C<), 166.98 (CNH2), 183.22, 184.44 (2C=O). 15N NMR
(DMSO-d6, 60 MHz) d: 72.34 (t, NH2, J 90.3 Hz), 179.21 (s, N). Found
(%): C, 72.25; H, 4.70; N, 8.44. Calc. for C20H16N2O3 (%): C, 72.28;
H, 4.85; N, 8.43.
2-Amino-5,5-dimethyl-4-[(9,10-anthraquinon-2-yl)methylidene]-
2-oxazoline 2b: yield 847 mg (75%), mp 277–278°C (ethyl acetate).
1H NMR (CDCl3, 400 MHz) d: 1.60 (s, 6H, Me), 5.37 (s, 1H, CH=), 6.20
(br.s, 2H, NH2), 7.79 (m, 2H, HAr), 8.03 (m, 1H, HAr), 8.22 (d, 1H, HAr
,
J 8.06 Hz), 8.32 (m, 2H, HAr), 8.53 (d, 1H, HAr, J 1.61 Hz). 13C NMR
(CDCl3, 100 MHz) d: 27.63 (2Me), 90.66 (CH=), 99.63 (CMe2), 125.25,
127.20, 127.36, 127.61, 129.54, 132.79, 133.69, 133.70, 133.92, 134.16,
134.21, 144.80 (CAr), 164.19 (=C<), 166.74 (CNH2), 182.79, 184.57
(2C=O). IR (n/cm–1): 3330, 3380 (NH2), 1695, 1666 (C=O), 1568 (C=N).
Found (%): C, 72.56; H, 4.79; N, 8.51. Calc. for C20H16N2O3 (%): C, 72.28;
H, 4.85; N, 8.43.
12-Amino-2,2-dimethyl-2H-chromeno[4,5,6-cde]benzo[h]quinoline-
1,6-dione 3: yield 78 mg (7%), mp 259–260°C (toluene–ethyl acetate)
(lit.,3(b) 259.6–260°C).
§
Crystal data for compound 2c. C12H14N3O3, Mr = 248.26, ortho-
rhombic, P212121, a = 6.3532(9), b = 7.3907(12) and c = 24.559(4) Å, V =
1153.1(3) Å3, Z = 4, dcalc = 1.430 g cm–3, m(MoKa) = 0.105 mm–1, T =
150(2) K. All measurements were performed with a Bruker KAPPA
APEX2 CCD diffractometer [l(MoKa) = 0.71073 Å, w-scans, crystal size
0.01×0.22×0.24 mm]. 11805 reflections were measured (2q < 52°), from
which 2152 are independent (Rint = 0.1004), wR2 = 0.1319 and GOF = 0.982
for all independent reflections [R1 = 0.0537 for 1443 observed reflections
with I > 2s(I)]. All calculations were performed using SHELX-97.12
CCDC 867605 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2012.
2-Amino-5,5-dimethyl-4-(4-nitrobenzylidene)-2-oxazoline 2c: yield
560 mg (66%), mp 198–199°C (toluene). 1H NMR (CDCl3, 400 MHz) d:
1.56 (s, 6H, Me), 5.00 (br.s, 2H, NH2), 5.29 (s, 1H, CH=), 7.88 (dt, 2H,
m-C6H4NO2, J 1.96, 2.45 and 9.05 Hz), 8.13 (dt, 2H, o-C6H4NO2, J 1.96,
2.45 and 9.05 Hz). 13C NMR (CDCl3, 100 MHz) d: 27.50 (2Me), 91.10
(CMe2), 99.77 (CH=), 123.91 (m-C6H4NO2), 127.55 (o-C6H4NO2), 144.25,
145.28 (CAr), 164.04 (=C<), 166.05 (CNH2). IR (n/cm–1): 3365, 3497
(NH2), 1540 (C=N), 1323, 1371 (NO2). Found (%): C, 58.47; H, 5.21;
N, 16.73. Calc. for C12H13N3O3 (%): C, 58.29; H, 5.30; N, 16.99.
– 115 –

Mendeleev Commun., 2012, 22, 114–116
Me
In summary, heterocyclization of 2-alkyl-4-arylbut-3-yn-2-ols
Me
OH
with guanidine leads to 2-amino-5,5-dialkyl-4-arylmethylidene-
2-oxazolines in 35–75% yields. The products synthesized may
be useful for medicinal chemistry, since their structural analogues
possess high psychoactive properties (aminorex, 4-methylamino-
rex)8 and hypotensive activity (rilmenidine based preparations).9
O
This work was supported by the Russian Foundation for Basic
Research (grant no. 10-03-00257a) and the Chemical Service
Centre of the Siberian Branch of the Russian Academy of Sciences.
O
1a
NH
H2N
NH2
References
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Me
Me
OH
Me
Me
O
H
O
N
2 (a) B.-W.Yu, L.-H. Meng, J.-Y. Chen, T.-X. Zhou, K.-F. Cheng, J. Ding and
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NH2
O
O
N
N
O
A
2a
Scheme 3
This mistake is connected with the fact, that the structures
of A and 2a have the same elemental composition and molecular
ion in mass spectra, and similar IR and NMR spectra. In addition,
earlier,3(b) NMR spectra were recorded in DMSO-d6 at 297 K.
Under these conditions the signal of NH2 group was not observed.
In the spectra of 2b–e recorded in CDCl3 solutions (due to higher
solubility of compounds 2b–e) broad signals of two protons of
NH2 group appear at 4.91–6.20 ppm. Therefore, we carried out
prolonged accumulation of signals for sample A in CDCl3 under
normal conditions and recorded spectra in DMSO-d6 at 320 K,
which allowed us to detect signals of NH2 protons at 4.94 ppm in
CDCl3 and at 7.68 ppm in DMSO-d6. Thus, the correct structure
2a was assigned.
As stretching vibrations of NH2 group of 2a and presumable
signals of OH and NH groups of A in the IR spectra should
be close, their identification was difficult. Moreover, attempted
preparation of monocrystal of 2a for X-ray analysis was unsuc-
cessful. The authors apologize for making mistake in earlier
paper.3(b)
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12 G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112.
The starting compounds were obtained under the standard
Sonogashira reaction conditions7 in the system PdCl2(PPh3)2–
CuI–Et3N from 2-alkylbut-3-yn-2-ols and the corresponding
iodoarenes.†
Received: 8th November 2011; Com. 11/3834
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