Lewis-Acid-Catalysed Activation of Nitriles: A Microwave-Assisted Solvent-Free Synthesis of 2,4-Disubstituted Quinazolines and 1,3-Diazaspiro[5.5]undec-1-enes

Article abstract of DOI:10.1002/ejoc.201701585

Two different modes of cyclization take place to synthesize quinazoline, quinazolinone, and 1,3-diazaspiro[5.5]undec-1-ene derivatives through the Lewis-acid-catalysed activation of both aliphatic and aromatic nitriles in a single-step, solvent-free, and transition-metal-free reaction. An amidine is expected to form as an intermediate; this then undergoes intramolecular cyclization in a one-pot reaction sequence. The reaction is carried out under microwave irradiation using trimethylsilyltrifluoromethane sulfonate (TMSOTf) as a catalyst and nitriles as a nitrogen source with the respective reaction partners.

Full text of DOI:10.1002/ejoc.201701585

DOI: 10.1002/ejoc.201701585
Full Paper
Quinazolines and Azaspirocycles
Lewis-Acid-Catalysed Activation of Nitriles: A Microwave-
Assisted Solvent-Free Synthesis of 2,4-Disubstituted
Quinazolines and 1,3-Diazaspiro[5.5]undec-1-enes
Ujwal Pratim Saikia,[a] Geetika Borah,[b] and Pallab Pahari*[a]
Abstract: Two different modes of cyclization take place to syn- molecular cyclization in a one-pot reaction sequence. The reac-
thesize quinazoline, quinazolinone, and 1,3-diazaspiro[5.5]un- tion is carried out under microwave irradiation using trimethyl-
dec-1-ene derivatives through the Lewis-acid-catalysed activa- silyltrifluoromethane sulfonate (TMSOTf) as a catalyst and
tion of both aliphatic and aromatic nitriles in a single-step, sol- nitriles as a nitrogen source with the respective reaction part-
vent-free, and transition-metal-free reaction. An amidine is ex- ners.
pected to form as an intermediate; this then undergoes intra-
Introduction
N-Heterocycles are powerful pharmacophores that are found in
a large number of promising biologically active natural prod-
ucts as well as synthetic compounds.[1] Among the various N-
heterocycles, quinazolines[2] and 1-azaspirocycles[3] are privi-
leged classes of compounds that show a wide range of biologi-
cal activities with therapeutic potential, such as antibacterial,[4]
antiviral,[5] antifungal,[6] anti-inflammatory,[7] antihyperten-
sive,[8] antimalarial,[9] antitubercular,[10] anticonvulsant,[11] and
anticancer activities.[12] There are various positions on the ring
systems of these skeletons where substitutions can occur, re-
sulting in a diaspora of compounds that occur naturally and
synthetically. In addition, the presence of heteroatoms con-
strained by quaternary carbon centres gives well-defined bene-
fits, for instance in enhancing selectivity in drug binding.[13] The
growing importance of quinazoline and azaspiro derivatives is
also highlighted by the presence of these structural motifs in
either market-available drugs or promising drug candidates,
such as erysotramidine, lepadiformine, gefitinib, metolazone,
and erlotinib (Figure 1). Consequently, in recent decades, enor-
mous progress has been made in developing efficient and ver-
satile methods for the rapid synthesis and transformation of
these significant heterocyclic scaffolds.[14–21]
The first synthesis of quinazoline was by Griess in 1869;[15a]
he used cyanogen as a nitrogen source in a reaction with an-
thranilic acid. Von Niementowski optimized the reaction using
amides as a nitrogen source.[15b] Later, many different nitrogen
Figure 1. A few examples of biologically active quinazolines and spirocyclic
compounds.
sources and starting materials were studied. These reactions
include a three component reaction of ammonia with different
carbon sources and 2-aminocarbonyl compounds or 2-halo-
carbonyl compounds,[16] the reaction of 2-aminobenzylamine
with benzyl aldehydes or 2-aminocarbonyl compounds,[17] the
reaction of 2-amino-substituted aryl oximes with aldehydes,[18]
the reaction of amidines with 2-halocarbonyl compounds or
benzylamines,[19] the intramolecular cyclization of amidines,[19g]
and the reaction of nitriles with 2-aminobenzyl alcohols or
ketones (Scheme 1).[20]
Amidines have been found to be an efficient nitrogen source
for the synthesis of quinazolines; however, they must be synthe-
sized from the corresponding acetanilides using a two-step re-
action sequence.[19] An alternative approach involves the in-situ
generation of amidines from nitriles. Cook and Moffat reported
the synthesis of 3-phenyl-2,4-diazafluoranthene by the reaction
of 1-aminofluorenone with an in-situ-generated amidine pre-
pared from benzonitrile.[20a] The synthesis required HCl gas to
be passed through the reaction mixture for 11 h at a tempera-
[a] Chemical Science and Technology Division, CSIR-North East Institute of
Science and Technology,
Jorhat-785006, Assam, India
E-mail: ppahari@gmail.com
[b] Department of Chemistry, Dibrugarh University
Dibrugarh-786004, Assam, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701585.
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same reaction to produce a series of 1,3-diazaspiro[5.5]undec-
1-enes.
Results and Discussion
To start with, acetonitrile was selected as the nitrile source; it
was heated at reflux with 2-aminobenzophenone (1a) in the
presence of trimethylsilyl iodide as a catalyst. After 10 h at re-
flux under a nitrogen atmosphere, 2-methyl-2-phenylquin-
azoline (2a) was obtained in a moderate yield. When the reac-
tion was carried out under microwave heating conditions (MW)
for 10 min, a better yield of the product was obtained (Table 1,
entry 1). To optimize the reaction conditions, a number of dif-
ferent Lewis acids were tested (Table 1, entries 1–8). Trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) was identified as the
most effective catalyst (Table 1, entry 6). This reaction gave the
best yield of the product when a slight excess of the nitrile was
used as both reactant and solvent. Other solvents, like DMSO,
DMF, toluene, and THF, were not suitable for this purpose
(Table 1, entries 9–12).
Table 1. Optimization of the reaction conditions for the synthesis of quin-
azolines.[a]
Scheme 1. Different strategies for the synthesis of quinazolines. TBHP = tert-
butyl hydroperoxide; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene.
ture of 180–185 °C. Similar reaction conditions were used by
Dave et al. for the synthesis of 4-phenyl quinazoline deriva-
tives.[20b] Chen et al. reported the synthesis of quinazolines us-
ing amidines generated in situ from benzonitriles;[20c] an expen-
sive ruthenium carbonyl complex was used as a catalyst, and
also the reaction was limited to 2-aryl quinazolines only
(Scheme 1). Adib and coworkers used a one-pot but two-step
method for the synthesis of quinazolinones from anthranilic
acid and nitriles; a separate step was needed for the prepara-
tion of amidines from nitriles and hydroxylamine.[20d] More re-
cently, Abe et al. produced quinazolinones from anthranilic acid
and nitriles; POCl3 (5 equiv.) was needed for this reaction.[20e]
Although the reported methods are efficient and high yielding,
most of them are not free from drawbacks such as the require-
ment of harsh reaction conditions,[20a,20e] the use of expensive
catalysts and ligands,[20c] multistep synthesis of starting materi-
als,[19,20d] selectivity towards aromatic or aliphatic substrates,
and prolonged reaction times.[20a] Thus, it is highly desirable
to search for a more convenient and efficient approach to the
synthesis of these skeletons. Recent reports from our lab have
Entry
Catalyst
Solvent
Temp
[°C]
Time
[min]
Yield
[%]
1
2
3
4
5
6
7
8
TMSI
TMSCl
InCl3
AlCl3
CuBr2
TMSOTf
TMSOTf
H3PO3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
none
none
none
none
none
none
none
none
DMF
120
120
120
120
120
120
100
120
120
120
90
15
15
15
15
15
15
10
15
15
15
15
15
56
10
0
0
5
75
75
0
20
10
0
9
10
11
12
DMSO
THF
toluene
120
0
[a] Reaction conditions: 2-aminobenzophenone (1a; 1 equiv.), acetonitrile
(3 equiv.), catalyst (0.2 equiv.), solvent (2 mL), heated in a microwave reaction
vial (10 mL).
Having standardized the conditions, the reaction was carried
shown that the treatment of amines with nitriles in the pres- out with a few different benzophenone and nitrile substrates
ence of Lewis acids such as trimethylsilyl iodide (TMSI) led to (Table 2). We observed that benzophenones with substituents
the in-situ generation of amidines, which, upon hydrolysis, were on both the phenyl rings were almost equally reactive, and
converted into acetamides.[22]In this communication, we report gave the corresponding quinazolines 2a–2d in good yields. To
a single-step, mild, solvent-free, and transition-metal-free reac- vary the nitrogen source, benzonitrile was used, and 2-phenyl
tion for the synthesis of quinazolines from aminobenzo- quinazolines 2e–2g were produced. 2-Aminoacetophenones
phenones/acetophenones and of quinazolinones from 2-amino- gave 4-methyl quinazolines 2h–2j upon reaction with aceto-
benzoic acids through the trapping of in-situ-generated nitrile, benzonitrile, and propionitrile. The reaction was also
amidines by intramolecular cyclization. Homoallylic amines like found to be equally applicable to the synthesis of quinazol-
2-cyclohexylethylamines were also used as substrates in the inones. Using anthranilic acid as a substrate, 2-substituted quin-
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azolinones 2k–2o were prepared. Different nitriles, like aceto- for the reaction to occur. Thus the reaction of mesyl-protected
nitrile, propionitrile, adiponitrile, 2-bromobenzonitrile, and 2- 2-(cyclohex-1-en-1-yl)ethylamine 3a, prepared by treatment of
aminobenzonitrile, showed almost the same reactivity. Interest- the amine with benzenesulfonyl chloride, with acetonitrile pro-
ingly, in the case of adiponitrile, only one of the two nitrile duced 2-methyl-3-(phenylsulfonyl)-1,3-diazaspiro[5.5]undec-1-
groups took part in the reaction. All the products were charac- ene (4a). The structure of compound 4a was determined by
1
terized using IR spectroscopy, 1H and 13C NMR spectroscopy, complete spectroscopic analysis. The H and 13C NMR spectra
and HRMS. The structures were unequivocally assigned by com- confirmed the number and nature of the protons and carbons,
parison of their spectroscopic data with those of reported com- respectively. The crucial spiro and cyclic amidine carbons ap-
pounds. Also, the melting points of the products matched the peared at δ = 53.1 and 145.3 ppm, respectively. The quaternary
reported melting points.
nature of these two carbons was confirmed by their absence in
DEPT-135 and HMQC spectra (see Supporting Information). A
HMBC experiment also confirmed the presence of CH2 groups
adjacent to the spiro carbon, and a CH3 group adjacent to the
amidine carbon (see Supporting Information). The mass of the
compound was confirmed by HRMS.
Table 2. Synthesis of quinazolines by the reaction of 2-aminobenzophenones/
acetophenones and anthranilic acids with nitriles.
Optimization of the reaction conditions revealed that the
best yield was obtained by treatment of 3 (1 equiv.), nitrile
(1 equiv.), and TMSOTf (0.2 equiv.) at 80 °C under microwave
irradiation for 10 min. Under these optimal reaction conditions,
a number of different mesyl-protected 3a–3f and tosyl-pro-
tected 3g–3k 2-(cyclohex-1-en-1-yl)ethylamines were subjected
to the spirocyclization reaction (Table 3). Aliphatic and aromatic
nitriles with electron-donating and electron-withdrawing
groups were equally reactive, and 1,3-diazaspiro[5.5]undec-1-
enes 4a–4k were obtained. The structures of all the compounds
1
were determined by IR spectroscopy, H and 13C NMR spectro-
scopy, and HRMS. For further confirmation of the identities of
the spiro and cyclic amidine carbons, DEPT-135 analysis was
carried out for 4g, 4i, 4j, and 4k (see Supporting Information).
2D HMQC and HMBC experiments for 4g gave results similar to
those obtained for 4a (see Supporting Information). Unfortu-
nately, a crystal structure could not be obtained.
Table 3. Preparation of 1,3-diazaspiro[5.5]undec-1-enes.[a]
Encouraged by the above results, we decided to further ex-
plore the scope of the reaction. Earlier results from our lab
showed that in the presence of a Lewis acid, N-acyl-2-(cyclohex-
1-en-1-yl)ethylamines undergo an intramolecular cyclization to
give 1,3-spirooxazine derivatives.[23] We envisaged that the
amidine formed by the reaction of 2-(cyclohex-1-en-1-yl)ethyl-
amine and a nitrile might undergo a similar intramolecular
cyclization, with a single Lewis acid acting as catalyst for both
reactions. Accordingly, an experiment was carried out by heat-
ing a mixture of 2-(cyclohex-1-en-1-yl)ethylamine and aceto-
nitrile under microwave irradiation in the presence of a catalytic
amount of TMSOTf. The reaction failed to produce any isolable
product. We carried out a series of experiments, and observed
that arylsulfonyl protection of the primary amine was necessary
[a] Reaction conditions: amine (1 equiv.), nitrile (3 equiv.), catalyst (0.2 equiv.),
heated in a microwave reaction vial (10 mL) at 80 °C for 10 min.
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aminoacetophenone/anthranilic acid (1 mmol) in the appropriate
nitrile (3 mmol) in a microwave reaction vessel (10 mL). The vial
was sealed with a Teflon septum, and the mixture was heated under
microwave irradiation at 100 °C for 10 min. The mixture was cooled,
and the reaction was quenched by the addition of ammonia (1 mL).
Low-boiling nitriles were removed under vacuum. The remaining
solution was extracted with ethyl acetate (2 × 20 mL). The com-
bined organic layer was washed with water (2 × 10 mL), sodium
thiosulfate (10 mL), sodium hydrogen carbonate (10 mL), and brine
(10 mL). The mixture was dried with Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by col-
umn chromatography to give the corresponding quinazolines 2a–
2j and quinazolinones 2k–2o.
Mechanistically, it may be proposed that electron-rich nitriles
are activated by coordination with TMSOTf. Nucleophilic attack
of the amine onto the activated nitrile produces an amidine 5
or 7. In 5, the amidine nitrogen attacks the carbonyl to produce
6, which undergoes aromatization to give quinazoline deriva-
tives 2 (Scheme 2). In the case of 7, the amidine nitrogen at-
tacks the activated double bond to produce spirocyclic interme-
diate 9 via intermediate 8. Finally, 1,3-diazaspiroundecene 4 is
obtained by removal of the TMS group by hydrolysis.
2-Methyl-4-phenylquinazoline (2a):[24] Low-melting solid. IR (KBr):
ν = 2922, 1614, 1550, 1447, 1377, 1263 cm–1 1H NMR (500 MHz,
.
˜
CDCl3): δ = 8.02 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.83
(t, J = 8.5 Hz, 1 H), 7.74–7.71 (m, 2 H), 7.54–7.51 (m, 3 H), 7.49 (t,
J = 8.0 Hz, 1 H), 2.93 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
168.8 (C), 164.0 (C), 151.6 (C), 137.5 (C), 133.8 (CH), 130.0 (CH), 128.8
(CH), 128.8 (CH), 128.3 (CH), 127.2 (CH), 126.9 (CH), 121.2 (C), 26.5
(CH3) ppm. HRMS (ESI): calcd. for C15H13N2 [M + H]+ 221.1079; found
221.1076.
6-Chloro-2-methyl-4-phenylquinazoline (2b): Yellow solid. M.p.
105–107 °C (lit.[25] 107–109 °C). IR (KBr): ν = 3059, 1548, 1478, 1386,
˜
1
1296, 1145, 1072 cm–1. H NMR (500 MHz, CDCl3): δ = 8.02 (d, J =
2.0 Hz, 1 H), 7.97 (d, J = 9.0 Hz, 1 H), 7.80 (dd, J = 9.0, 2.0 Hz, 1 H),
7.77–7.71 (m, 2 H), 7.63–7.57 (m, 3 H), 2.94 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 168.0 (C), 164.4 (C), 150.1 (C), 136.9 (C), 134.8
(CH), 132.6 (C), 130.4 (CH), 130.1 (CH), 129.9 (CH), 129.0 (CH), 126.0
(CH), 121.8 (C), 26.8 (CH3) ppm. HRMS (ESI): calcd. for C15H12N2Cl [M
+ H]+ 255.0689; found 255.0687.
4-(4-Bromophenyl)-2-methylquinazoline (2c): Pale yellow solid.
M.p. 160–162 °C. IR (KBr): ν = 3051, 1588, 1549, 1483, 1398, 1332,
˜
1
1215 cm–1. H NMR (500 MHz, CDCl3): δ = 7.99 (d, J = 7.5 Hz, 1 H),
7.97 (d, J = 7.5 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.67 (d, J = 8.0 Hz,
2 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.50 (t, J = 7.5 Hz, 1 H), 2.91 (s, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 167.5 (C), 164.0 (C), 151.7 (C),
136.3 (C), 134.0 (CH), 132.1 (CH), 131.6 (CH), 128.5 (CH), 127.3 (CH),
126.7 (CH), 124.7 (C), 120.9 (C), 26.7 (CH3) ppm. HRMS (ESI): calcd.
for C15H12N2Br [M + H]+ 299.0184; found 299.0181.
Scheme 2. Plausible mechanism of quinazoline and diazaspirocycle forma-
tion.
Conclusions
6-Chloro-4-(2-fluorophenyl)-2-methylquinazoline (2d): White
We have developed a rapid and efficient, transition-metal-free,
solvent-free, single-step reaction in which a variety of 2,4-disub-
stituted quinazolines, 2-substituted quinazolinones, and 1,3-di-
azaspiro[5.5]undec-1-enes are synthesized, starting from 2-
aminophenyl carbonyl compounds and N-tosyl-2-(cyclohex-
enyl)ethylamines. Nitriles activated by TMSOTf were used as the
nitrogen source, and the reaction was carried out under sol-
vent-free conditions. The reaction was equally applicable to
both aliphatic and aromatic nitriles. Very short reaction times,
a broad substrate scope, clean reactions, and mild conditions
solid. M.p. 138–140 °C (lit.[26] 139–141 °C). IR (KBr): ν = 3064, 1608,
˜
1556, 1492, 1380, 1215 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.95
(d, J = 9.0 Hz, 1 H), 7.79 (dd, J = 9.0, 2.0 Hz, 1 H), 7.70 (t, J = 2.0 Hz,
1 H), 7.58–7.52 (m, 2 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.29–7.24 (m, 1 H),
2.93 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 164.5 (C), 164.1
(C), 159.9 (d, J = 250.0 Hz, C), 149.6 (C), 135.2 (CH), 132.8 (C), 132.2
(d, J = 9.0 Hz, CH); 131.6 (d, J = 3.0 Hz, CH), 130.0 (CH), 125.7 (d, J =
3.0 Hz, CH), 125.1 (d, J = 3.5 Hz, CH), 124.8 (d, J = 15.0 Hz, C), 122.6
(C), 116.5 (d, J = 21.0 Hz, CH), 26.7 (CH3) ppm. HRMS (ESI): calcd. for
C15H11N2FCl [M + H]+ 273.0595; found 273.0590.
are significant features of this process. Research into applica- 6-Chloro-4-(2-fluorophenyl)-2-phenylquinazoline (2e): Pale yel-
low solid. M.p. 178–180 °C (lit.[27] 180–181 °C). IR (KBr): ν = 3072,
tions of this method for the synthesis of more complex and
biologically important quinazolines and azaspirocyclic deriva-
tives is ongoing.
˜
1616, 1560, 1532, 1392 cm–1. H NMR (500 MHz, CDCl3): δ = 8.65–
8.60 (m, 2 H), 8.08 (d, J = 9.0 Hz, 1 H), 7.81 (dd, J = 9.0, 2.0 Hz, 1 H),
7.76 (t, J = 2.0 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.61–7.47 (m, 4 H),
7.39 (t, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 164.0 (C), 160.9 (C), 160.1 (d, J = 250 Hz, C),
150.1 (C), 137.8 (C), 135.1 (CH), 133.0 (C), 132.2 (d, J = 7.5 Hz, CH),
132.0 (d, J = 3.0 Hz, CH), 131.1 (CH), 130.9 (CH), 128.9 (CH), 128.8
(CH), 125.8 (d, J = 3.0 Hz, CH), 125.2 (d, J = 15.0 Hz, C), 124.9 (d, J =
1
Experimental Section
General Procedure for the Synthesis of Quinazolines: TMSOTf
(0.2 equiv.) was added to a solution of 2-aminobenzophenone/2-
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2.5 Hz, CH), 123.2 (C), 116.5 (d, J = 21 Hz, CH) ppm. HRMS (ESI):
135.1 (CH), 127.3 (CH), 126.6 (CH), 126.4 (CH), 120.6 (C), 29.4 (CH2),
11.9 (CH3) ppm. HRMS (ESI): calcd. for C10H11N2O [M + H]+ 175.0871;
found 175.0874.
calcd. for C20H13N2FCl [M + H]+ 335.0751; found 335.0758.
2,4-Diphenylquinazoline (2f): White solid. M.p. 119–121 °C (lit.[26]
117–119 °C). IR (KBr): ν = 3058, 1610, 1556, 1545, 1331 cm–1 1H
.
5-(4-Oxo-3,4-dihydroquinazolin-2-yl)pentane Nitrile (2m): Yel-
˜
1
NMR (500 MHz, CDCl3): δ = 8.68 (dd, J = 8.0, 1.5 Hz, 2 H), 8.15 (d,
J = 8.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.90–7.84 (m, 3 H), 7.61–
7.45 (m, 7 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.5 (C), 160.4
(C), 152.2 (C), 138.4 (C), 137.8 (C), 133.8 (CH), 130.7 (CH), 130.4 (CH),
130.1 (CH), 129.3 (CH), 128.8 (CH), 128.7 (CH), 127.2 (CH), 121.9 (C)
ppm. HRMS (ESI): calcd. for C20H15N2 [M + H]+ 283.1235; found
283.1236.
low solid. M.p. 180–182 °C. H NMR (500 MHz, CDCl3): δ = 12.22 (s,
1 H), 8.27 (dd, J = 8.0, 1.5 Hz, 1 H), 7.77 (dt, J = 7.5, 1.5 Hz, 1 H),
7.68 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 1 H), 2.85 (t, J = 7.5 Hz,
2 H), 2.45 (t, J = 7.5 Hz, 2 H), 2.12–2.02 (m, 2 H), 1.90–1.80 (m, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 164.7 (C), 155.6 (C), 149.5 (C),
135.2 (CH), 127.5 (CH), 126.9 (CH), 126.4 (CH), 120.6 (C), 119.6 (C),
34.7 (CH2), 26.3 (CH2), 25.0 (CH2), 17.2 (CH2) ppm. HRMS (ESI): calcd.
for C13H14N3O [M + H]+ 228.1137; found 228.1135.
4-(4-Bromophenyl)-2-phenylquinazoline (2g): Pale yellow solid.
M.p. 152–154 °C (lit.[17d] 154–156 °C). IR (KBr): ν = 3063, 1535, 1484,
2-(2-Bromophenyl)quinazolin-4(3H)-one (2n): Pale brown solid.
˜
1
1340, 1011 cm–1. H NMR (500 MHz, CDCl3): δ = 8.66 (d, J = 7.0 Hz,
1
M.p. 173–175 °C (lit.[30] 175–177 °C). H NMR (500 MHz, CDCl3): δ =
2 H), 8.14 (d, J = 8.5 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.87 (t, J =
8.5 Hz, 1 H), 7.78–7.84 (m, 4 H), 7.57–7.47 (m, 4 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 167.3 (C), 160.4 (C), 152.2 (C), 138.2 (C), 136.7
(C), 133.9 (CH), 132.0 (CH), 131.9 (CH), 130.8 (CH), 129.5 (CH), 128.8
(CH), 128.7 (CH), 127.4 (CH), 126.7 (CH), 124.8 (C), 121.6 (C) ppm.
HRMS (ESI): calcd. for C20H14N2Br [M + H]+ 361.0340; found
361.0334.
9.65 (s, 1 H), 8.29 (d, J = 8.0 Hz, 1 H), 7.82–7.66 (m, 4 H), 7.55–7.45
(m, 2 H), 7.39 (dt, J = 7.5, 1.5 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 162.5 (C), 152.2 (C), 149.0 (C), 135.1 (CH), 133.9 (CH),
132.2 (CH), 131.4 (CH), 130.1 (C), 128.2 (CH), 128.2 (CH), 127.6 (CH),
126.7 (CH), 121.3 (C), 121.1 (C) ppm. HRMS (ESI): calcd. for
C14H10N2OBr [M + H]+ 300.9977; found 300.9980.
2-(2-Aminophenyl)quinazolin-4(3H)-one (2o): Colourless solid.
1
M.p. 153–155 °C (lit.[31] 155–156 °C). H NMR (500 MHz, CDCl3): δ =
2,4-Dimethylquinazoline (2h): Yellow solid. M.p. 287–289 °C
(lit.[19a] 288–290 °C). IR (KBr): ν = 2990, 1625, 1410, 1395, 1280,
˜
8.39 (d, J = 8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.68–7.58 (m, 2 H),
7.31 (t, J = 7.5 Hz, 1 H), 7.21–7.15 (m, 1 H), 6.80–6.70 (m, 2 H), 5.89
(s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 162.3 (C), 161.0 (C),
150.0 (C), 148.8 (C), 133.2 (CH), 131.3 (CH), 131.2 (CH), 128.1 (CH),
125.6 (CH), 121.9 (CH), 120.0 (C), 117.2 (CH), 117.0 (CH), 112.6 (C)
ppm. HRMS (ESI): calcd. for C14H12N3O [M + H]+ 238.0980; found
238.0974.
1
1075 cm–1. H NMR (500 MHz, CDCl3): δ = 8.04 (d, J = 8.0 Hz, 1 H),
7.91 (d, J = 8.0 Hz, 1 H), 7.83 (t, J = 8.0 Hz, 1 H), 7.56 (t, J = 8.0 Hz,
1 H), 2.90 (s, 3 H), 2.83 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
168.4 (C), 163.7 (C), 150.1 (C), 133.9 (CH), 128.4 (CH), 126.9 (CH),
125.1 (CH), 122.4 (C), 26.6 (CH3), 21.9 (CH3) ppm. HRMS (ESI): calcd.
for C10H11N2 [M + H]+ 159.0922; found 159.0918.
4-Methyl-2-phenylquinazoline (2i): Yellow solid. M.p. 69–70 °C
General Procedure for Synthesis of 1,3-Diazaspiro[5.5]undec-1-
ene Derivatives: TMSOTf (0.2 equiv.) was added to a solution of
tosyl protected 2-(cyclohex-1-en-1-yl)ethan-1-amine (1 mmol) in the
appropriate nitrile (3 mmol) in a microwave reaction vessel (10 mL).
The vial was sealed with a Teflon septum, and the mixture was
heated under microwave irradiation at 80 °C for 10 min. The mixture
was cooled, and the reaction was quenched by the addition of am-
monia (1 mL). Low-boiling nitriles were removed under vacuum.
The remaining solution was extracted with ethyl acetate (2 ×
20 mL). The combined organic layer was washed with water (2 ×
10 mL), sodium thiosulfate (10 mL), sodium hydrogen carbonate
(10 mL), and brine (10 mL). The organic phase was dried with
Na2SO4, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography to give 1,3-diaza-
spiro[5.5]undec-1-ene derivatives 4a–4k.
(lit.[26] 71–74 °C). IR (KBr): ν = 3059, 1614, 1581, 1546, 1256,
˜
1
1160 cm–1. H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 1 H),
7.95 (d, J = 8.0 Hz, 1 H), 7.68–7.63 (m, 3 H), 7.51 (t, J = 8.0 Hz, 1 H),
7.21 (t, J = 8.0 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 8.0 Hz,
1 H), 2.71 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.0 (C),
147.5 (C), 144.8 (C), 130.2 (CH), 129.9 (CH), 129.4 (CH), 126.5 (C),
126.0 (CH), 123.7 (CH), 121.8 (C), 121.2 (CH), 117.4 (CH), 19.1 (CH3)
ppm. HRMS (ESI): calcd. for C15H13N2 [M + H]+ 221.1079; found
221.1076.
2-Ethyl-4-methylquinazoline (2j):[16d] Yellow oil. IR (KBr): ν = 2971,
˜
1616, 1561, 1495, 1390, 1287, 1195 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 8.01 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 8.5 Hz, 1 H), 7.79 (t, J =
8.5 Hz, 1 H), 7.51 (t, J = 8.5 Hz, 1 H), 3.05 (q, J = 7.5 Hz, 2 H), 2.88
(s, 3 H), 1.41 (t, J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 168.3 (C), 167.9 (C), 150.1 (C), 133.6 (CH), 128.6 (CH), 126.7 (CH),
125.1 (CH), 122.6 (C), 33.3 (CH2), 21.9 (CH3), 13.3 (CH3) ppm. HRMS
(ESI): calcd. for C11H13N2 [M + H]+ 173.1079; found 173.1073.
2-Methyl-3-(phenylsulfonyl)-1,3-diazaspiro[5.5]undec-1-ene
1
(4a): Pale brown solid. M.p. 105–107 °C. H NMR (500 MHz, CDCl3):
δ = 7.77 (d, J = 8.0 Hz, 2 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.49 (t, J =
8.0 Hz, 2 H), 3.64 (t, J = 6.0 Hz, 2 H), 2.21 (s, 3 H), 1.62–1.15 (m, 12
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 145.3 (C), 140.3 (C), 133.3
(CH), 129.5 (CH), 126.8 (CH), 53.1 (C), 42.2 (CH2), 38.0 (CH2), 30.6
(CH2), 25.9 (CH2), 25.6 (CH3), 21.9 (CH2) ppm. HRMS (ESI): calcd. for
C16H23N2O2S [M + H]+ 307.1480; found 307.1485.
2-Methylquinazolin-4(3H)-one (2k): Yellow solid. M.p. 228–229 °C
(lit.[28] 229–230 °C). IR (KBr): ν = 3013, 2912, 1730, 1442, 1273,
˜
1
1120 cm–1. H NMR (500 MHz, CDCl3): δ = 12.07 (s, 1 H), 8.26 (dd,
J = 8.0, 1.5 Hz, 1 H), 7.76 (dt, J = 8.0, 1.5 Hz, 1 H), 7.66 (d, J = 8.0 Hz,
1 H), 7.46 (t, J = 8.0 Hz, 1 H), 2.59 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 164.2 (C), 153.3 (C), 149.2 (C), 134.9 (CH), 126.9 (CH),
126.4 (CH), 126.1 (CH), 120.1 (C), 22.1 (CH3) ppm. HRMS (ESI): calcd.
for C9H9N2O [M + H]+ 161.0715; found 161.0716.
2-Ethyl-3-(phenylsulfonyl)-1,3-diazaspiro[5.5]undec-1-ene (4b):
Yellow solid. M.p. 115–117 °C. 1H NMR (500 MHz, CDCl3): δ = 7.77
(d, J = 8.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.49 (dd, J = 8.5, 7.5 Hz,
2 H), 3.59 (t, J = 6.0 Hz, 2 H), 2.58 (q, J = 6.0 Hz, 2 H), 1.65–1.09 (m,
12 H), 1.03 (t, J = 6.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
149.2 (C), 140.4 (C), 133.2 (CH), 129.4 (CH), 126.9 (CH), 52.9 (C), 42.3
(CH2), 38.4 (CH2), 32.0 (CH2), 30.5 (CH2), 26.1 (CH2), 21.9 (CH2), 12.2
(CH3) ppm. HRMS (ESI): calcd. for C17H27N2O3S [M + H]+ 339.1742;
found 339.1747.
2-Ethylquinazolin-4(3H)-one (2l): Yellow solid. M.p. 228–230 °C
(lit.[29] 229–231 °C). IR (KBr): ν = 3037, 1680, 1605, 1462, 1120 cm–1
.
˜
1H NMR (500 MHz, CDCl3): δ = 12.04 (s, 1 H), 8.27 (dd, J = 8.0, 1.0 Hz,
1 H), 7.76 (dt, J = 8.0, 1.5 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.46 (t,
J = 8.0 Hz, 1 H), 2.83 (q, J = 7.5 Hz, 2 H), 1.43 (t, J = 7.5 Hz, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 164.6 (C), 157.9 (C), 149.5 (C),
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5-[3-(Phenylsulfonyl)-1,3-diazaspiro[5.5]undec-1-en-2-yl]- (CH2), 36.0 (CH2), 32.1 (CH2), 26.4 (CH2), 26.0 (CH2), 24.9 (CH2), 21.9
pentanenitrile (4c): Yellow semi-solid. 1H NMR (500 MHz, CDCl3):
δ = 7.78–7.74 (m, 2 H), 7.63–7.49 (m, 3 H), 3.58 (t, J = 6.0 Hz, 2 H),
2.62 (t, J = 7.0 Hz, 2 H), 2.28 (t, J = 7.0 Hz, 2 H), 1.75–1.08 (m, 16 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 146.9 (C), 140.1 (C), 133.4 (CH),
129.5 (CH), 126.8 (CH), 118.9 (C), 53.1 (C), 42.3 (CH2), 38.5 (CH2), 36.0
(CH2), 32.1 (CH2), 26.3 (CH2), 26.0 (CH2), 24.4 (CH2), 21.8 (CH2), 16.8
(CH2) ppm. HRMS (ESI): calcd. for C20H28N3O2S [M + H]+ 374.1902;
found 374.1908.
(CH2), 21.7 (CH3), 17.1 (CH2) ppm. HRMS (ESI): calcd. for C21H30N3O2S
[M + H]+ 388.2059; found 388.2051.
2-Phenyl-3-tosyl-1,3-diazaspiro[5.5]undec-1-ene (4j): Yellow
1
semi-solid. H NMR (500 MHz, CDCl3): δ = 7.58–7.52 (m, 4 H), 7.43
(t, J = 8.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H),
3.79 (t, J = 6.5 Hz, 2 H), 2.49 (s, 3 H), 1.85–1.20 (m, 12 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 149.3 (C), 144.3 (C), 138.5 (C), 136.6 (C),
129.7 (CH), 129.6 (CH), 128.9 (CH), 127.7 (CH), 127.7 (CH), 54.8 (C),
42.5 (CH2), 38.3 (CH2), 32.1 (CH2), 25.9 (CH2), 22.0 (CH2), 21.7 (CH3)
ppm. HRMS (ESI): calcd. for C22H27N2O2S [M + H]+ 383.1793; found
383.1790.
2-(4-Nitrobenzyl)-3-(phenylsulfonyl)-1,3-diazaspiro[5.5]undec-
1-ene (4d): Yellow solid. M.p. 153–155 °C. 1H NMR (500 MHz, CDCl3):
δ = 8.07 (d, J = 8.5 Hz, 2 H), 7.64 (d, J = 8.5 Hz, 2 H), 7.57 (t, J =
8.5 Hz, 1 H), 7.46 7.57 (t, J = 7.5 Hz, 2 H), 7.38 7.57 (t, J = 7.5 Hz, 2
H), 4.14 (s, 2 H), 3.52 (t, J = 6.0 Hz, 2 H), 1.60–1.15 (m, 12 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 146.8 (C), 146.1 (C), 145.7 (C), 139.5
(C), 133.6 (CH), 130.0 (CH), 129.5 (CH), 127.0 (CH), 123.4 (CH), 53.9
(C), 43.4 (CH2), 42.5 (CH2), 38.5 (CH2), 31.9 (CH2), 26.0 (CH2), 21.8
(CH2) ppm. HRMS (ESI): calcd. for C22H26N3O4S [M + H]+ 428.1644;
found 428.1648.
2-(1-Phenylethyl)-3-tosyl-1,3-diazaspiro[5.5]undec-1-ene (4k):
Yellow semi-solid. 1H NMR (500 MHz, CDCl3): δ = 7.40 (d, J = 8.0 Hz,
2 H), 7.21–7.12 (m, 7 H), 4.56 (q, J = 7.0 Hz, 1 H), 3.72–3.64 (m, 1 H),
3.18–3.10 (m, 1 H), 2.37 (s, 3 H), 1.85–1.70 (m, 2 H), 1.58–1.42 (m, 4
H), 1.38 (d, J = 7.0 Hz, 3 H), 1.40–1.17 (m, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 150.0 (C), 144.4 (C), 143.8 (C), 137.5 (C), 129.7
(CH), 128.3 (CH), 127.9 (CH), 127.0 (CH), 126.3 (CH), 53.4 (C), 45.0
(CH), 42.6 (CH2), 39.1 (CH2), 39.0 (CH2), 33.8 (CH2), 26.4 (CH2), 22.2
(CH3), 22.1 (CH2), 21.7 (CH2), 21.6 (CH3) ppm. HRMS (ESI): calcd. for
C24H31N2O2S [M + H]+ 411.2106; found 411.2099.
2-(4-Nitrophenyl)-3-(phenylsulfonyl)-1,3-diazaspiro[5.5]undec-
1-ene (4e): Yellow solid. M.p. 149–151 °C 1H NMR (500 MHz, CDCl3):
δ = 8.17 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 2 H), 7.65–7.46 (m,
5 H), 3.69 (t, J = 6.0 Hz, 2 H), 1.47 (t, J = 6.0 Hz, 2 H), 1.44–1.10 (m,
10 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 148.5 (C), 147.9 (C),
144.7 (C), 138.7 (C), 133.9 (CH), 129.7 (CH), 129.5 (CH), 127.7 (CH),
123.2 (CH), 55.5 (C), 42.5 (CH2), 38.3 (CH2), 31.9 (CH2), 25.9 (CH2),
21.9 (CH2) ppm. HRMS (ESI): calcd. for C21H24N3O4S [M + H]+
414.1488; found 414.1484.
Acknowledgments
The work is financially supported by the Department of Science
and Technology (DST)-SERB, New Delhi, India (GPP0299) and
the Council of Scientific and Industrial Research (CSIR), New
Delhi, India (HCP0001, MLP3000/03, and OLP2002). The authors
thank the analytical facility CSIR-NEIST for recording the spec-
troscopic data.
2-(1-Phenylethyl)-3-(phenylsulfonyl)-1,3-diazaspiro[5.5]undec-
1-ene (4f): Pale brown semi-solid. 1H NMR (500 MHz, CDCl3): δ =
7.56–7.46 (m, 3 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.20–7.11 (m, 5 H), 4.54
(q, J = 7.0 Hz, 1 H), 3.75–3.65 (m, 1 H), 3.19–3.11 (m, 1 H), 1.85–1.42
(m, 6 H), 1.39 (d, J = 7.0 Hz, 3 H), 1.37–1.15 (m, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 149.9 (C), 144.3 (C), 140.4 (C), 133.0 (CH),
129.2 (CH), 128.3 (CH), 127.9 (CH), 127.0 (CH), 126.4 (CH), 53.5 (C),
45.1 (CH), 42.8 (CH2), 39.1 (CH2), 39.0 (CH2), 33.8 (CH2), 26.3 (CH2),
22.2 (CH2), 22.1 (CH2), 21.7 (CH3) ppm. HRMS (ESI): calcd. for
Keywords: Nitrogen heterocycles · Cyclization · Spiro
compounds · Amines · Cyanides
C
23H29N2O2S [M + H]+ 397.1950; found 397.1945.
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2-Methyl-3-tosyl-1,3-diazaspiro[5.5]undec-1-ene (4g): Pale
brown solid. M.p. 208–210 °C. 1H NMR (500 MHz, CDCl3): δ = 7.68
(d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 3.67 (t, J = 6.0 Hz, 2 H),
2.42 (s, 3 H), 2.25 (s, 3 H), 1.69–1.61 (m, 4 H), 1.50–1.20 (m, 8 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 145.7 (C), 144.4 (C), 137.4 (C),
130.1 (CH), 127.0 (CH), 53.2 (C), 42.2 (CH2), 38.1 (CH2), 30.5 (CH2),
26.0 (CH2), 25.6 (CH3), 22.0 (CH2), 21.8 (CH3) ppm. HRMS (ESI): calcd.
for C17H27N2O3S [M + H]+ 339.1742; found 339.1747.
2-Ethyl-3-tosyl-1,3-diazaspiro[5.5]undec-1-ene (4h): Pale brown
solid. M.p. 178–180 °C. 1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J =
7.5 Hz, 2 H), 7.28 (d, J = 7.5 Hz, 2 H), 3.59 (t, J = 5.5 Hz, 2 H), 2.58
(q, J = 7.0 Hz, 2 H), 2.39 (s, 3 H), 1.65–1.55 (m, 2 H), 1.51 (t, J =
5.5 Hz, 2 H), 1.42–1.10 (m, 8 H), 1.03 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 149.7 (C), 144.2 (C), 137.3 (C), 130.0 (CH),
126.9 (CH), 52.9 (C), 42.3 (CH2), 38.3 (CH2), 31.7 (CH2), 30.5 (CH2),
26.0 (CH2), 21.9 (CH2), 21.7 (CH3), 12.4 (CH3) ppm. HRMS (ESI): calcd.
for C18H29N2O3S [M + H]+ 353.1899; found 353.1905.
5-(3-Tosyl-1,3-diazaspiro[5.5]undec-1-en-2-yl)pentanenitrile
(4i): Yellow semi-solid. 1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J =
8.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 3.58 (t, J = 7.0 Hz, 2 H), 2.62
(t, J = 7.0 Hz, 2 H), 2.41 (s, 3 H), 2.29 (t, J = 7.0 Hz, 2 H), 1.80–1.10
(m, 16 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.2 (C), 144.4 (C),
137.3 (C), 130.1 (CH), 126.9 (CH), 120.0 (C), 53.1 (C), 42.2 (CH2), 38.5
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Received: November 15, 2017
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