A Palladium-Catalyzed Method for the Synthesis of 2-(α-Styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: Access to 2-(α-Styryl)quinazolin-4(3H)-ones and 3-(α-Styryl)-1,2,4-benzothiadiazine-1,1-dioxides

Article abstract of DOI:10.1021/acs.joc.6b01242

An efficient synthesis of 2-(α-styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides has been achieved in 39-94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides with allenamides 13-15 and 22, respectively. Base treatment of the N-tosylated products provides an easy access to 2-(α-styryl)quinazolin-4(3H)-ones and 3-(α-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of the natural product Luotonin F.

Full text of DOI:10.1021/acs.joc.6b01242

Article
pubs.acs.org/joc
A Palladium-Catalyzed Method for the Synthesis of 2‑(α-Styryl)-2,3-
dihydroquinazolin-4-ones and 3‑(α-Styryl)-3,4-dihydro-1,2,4-
benzothiadiazine-1,1-dioxide: Access to 2‑(α-Styryl)quinazolin-
4(3H)‑ones and 3‑(α-Styryl)-1,2,4-benzothiadiazine-1,1-dioxides
Priyanka Kundu, Amrita Mondal, and Chinmay Chowdhury*
Organic & Medicinal Chemisty Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata-700032,
India
S
* Supporting Information
ABSTRACT: An efficient synthesis of 2-(α-styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-styryl)-3,4-dihydro-1,2,4-benzo-
thiadiazine-1,1-dioxides has been achieved in 39−94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides
with allenamides 13−15 and 22, respectively. Base treatment of the N-tosylated products provides an easy access to 2-(α-
styryl)quinazolin-4(3H)-ones and 3-(α-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method
has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of
the natural product Luotonin F.
channel opener,6d among others, and their uses in the
development of therapeutics. For example, compound 5 has
INTRODUCTION
■
Quinazolin-4(3H)-one (1a, Figure 1) constitutes an important
shown promising activity in the area of diabetes and obesity
class of heterocycles being an integral part of a large number of
being a potent HCV NS5B polymerase inhibitor,7 while
naturally occurring alkaloids (∼150) and drug candidates.1 It
Diazoxide (compound 6, Figure 1) is a K+[ATP] channel
exhibits a broad range of biological activities such as
anticancer,2a,b antiviral,2c antimalarial,2d antifungal,2e and
agonist and has a beneficial effect in obese hyperinsulinemic
adults.8
human microsomal prostaglandin synthase 1 (mPGES-1)
inhibitor.2f The 2-styryl derivatives are considered as privileged
Though a number of methods using either conventional
reagents9,10 or transition metal catalysts11,12 are known for the
structures in medicinal chemistry because of their promising
synthesis of 1a and 1b, only a limited number,13 which mainly
pharmacological effects. For example, compounds of type 2
rely on acid-13a,b,d,e or base13f-promoted Knoevenagel con-
(Figure 1) exhibit significant cytotoxicity in L1210 murine
densation of 2-methyl quinazolinones with aromatic/hetero-
aromatic aldehydes, exist for the synthesis of 2-β-styryl
derivatives of quinazolin-4(3H)-ones (e.g., 2, 4). On the
leukemia cells and inhibitory effects on tubulin polymer-
izations,3 while CP-465,022 (3, Figure 1) is recognized as a
noncompetitive antagonist of AMPA-selective glutamate
receptors.4 Very recently, compound 4a was discovered as a
other hand, the synthetic methods available for 2-β-styryl
derivatives of benzothiadiazine-1,1-dioxide are rare.14 To the
potent antibiotic by high throughput virtual screening of a large
number of compounds; further optimization by screening
studies of analogues led to the development of an even better
candidate 4b, which showed remarkable in vitro and in vivo
best of our knowledge, there is no reported synthesis of 2-(α-
styryl)quinazolin-4(3H)-ones 7 (a regioisomer of the β-styryl
counterpart) and their benzothiadiazine-1,1-dioxide analogues
8, which could serve as important pharmacophores in drug
(methicillin-resistant Staphylococus aureus mouse model)
efficacy with improved pharmacokinetics.5
On the other hand, 1,2,4-benzothiadiazine-1,1-dioxides 1b
discovery. This prompted us to establish convenient methods
for their general synthesis. Following our efforts15 to identify
form another class of remarkably important heterocycles
because of their wide range of activities such as antihypertensi-
Received: May 24, 2016
ve,6a antiviral,6b antimicrobial,6c and ATP sensitive potassium
© XXXX American Chemical Society
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Figure 1. General structures of quinazolin-4(3H)-ones, 1,2,4-benzothiadiazine-1,1-dioxides, and their 2-β-styryl derivatives, and examples of
biologically active compounds belonging to these classes.
lead compounds having significant anticancer properties, we
also became interested to get access to the scaffolds 7 and 8,
which could enable us to explore their potency in cancer
therapy.
Encouraged by the recent spectacular advances in the area of
palladium-catalyzed heteroannulations involving intramolecular
nucleophilic attack of the nitrogen atom onto an allene
moiety19 and in continuation of our work20 on the synthesis of
novel heterocycles of biological interests, we envisioned that
allenamide 13, generated easily from the acetylenic substrate 10
which was used successfully in our previous synthesis20a of (E)-
2-arylmethylidene-1,4-benzodiazepinones 12, could undergo
reaction with aryl/vinyl halides 11 under palladium catalysis,
affording the requisite N-tosyl-2,3-dihydroquinazolin-4-one 9
(Scheme 1). Our hypothesis indeed proved to be viable after
choosing an appropriate catalyst and a suitable base. We then
expanded the scope of this reaction to 1,2,4-benzothiadiazine-
1,1-dioxides as well. In a subsequent step, we also realized the
convenient synthesis of products 9 employing a suitable base.
Herein, we describe the results obtained so far in detail.
Previous workers reported the synthesis of the N3-alkylated
derivatives of 1a through oxidation of 2,3-dihydroquinazolin-
4(1H)-ones using conventional oxidants [e.g., DDQ,16a
KMnO4,16b MnO2,16c I216d] or metal catalysts.16e,f Therefore,
we assumed that the synthesis of 7 could also be achieved easily
by oxidizing the corresponding dihydro analogues 9 (Figure 1,
R2 = H). Scrutiny of the literature revealed only one earlier
example, that of Broggini et al.17 for the synthesis of N-Boc-2-α-
styryl-1,2-dihydroquinazolin-4-ones 9 (R2 = Boc). However,
Boc deprotection of the reported compound 9 (R2 = Boc, R1 =
Ph, R = Me), followed by oxidation of the resulting product
using conventional oxidants,16a−d delivered only a trace amount
of 7 (R1 = Ph, R = Me) in a few cases. This prompted us to
conceive a novel strategy for the synthesis through a base-
promoted reaction on 9 containing acidic aminal hydrogen (at
C2). However, application of this strategy on 9 (R2 = Boc, R1 =
Ph, R = Me) employing various bases failed to deliver any
product. As N-tosylated heterocycles have been reported18 to
undergo elimination of the protecting group (i.e., Ts) under
basic conditions along with a neighboring proton to generate a
double bond, we chose the sulphonyl moiety as an alternative
N-protecting agent to establish a viable synthesis of 7 (Scheme
1). Thus, we needed to synthesize N-sulphonyl derivatives of 9
(R2 = SO2R) as precursors, which are unknown in the
literature.
RESULTS AND DISCUSSION
■
Synthesis of anthranilic allenamide 13, the requisite starting
substrate, was achieved (with 85% yield) easily upon base
treatment of the N-propargylated anthranilamide 10. There-
after, we attempted the synthesis of N-sulphonyl-2-α-styryl-2,3-
dihydroquinazolin-4-ones 9 at room temperature through
palladium-catalyzed reactions. Initially, carrying out the reaction
of 13 with phenyl iodide (11a) employing the catalyst, solvent,
and base used by Broggini et al.17 required 14 h to produce the
desired product 9aa (75% yield), thereby marking the process
as sluggish (Table 1, entry 1). In order to find the optimal
reaction conditions, we performed a series of reactions on the
model substrates 11a and 13 by changing catalyst, base, solvent,
etc.; selected results are summarized in Table 1. Employment of
our recently reported20a catalytic system [Pd/C, PPh3, K2CO3,
DMF] in this reaction required even more time (26 h) to
complete this reaction at rt (Table 1, entry 2 vs 1).
Interestingly, replacing the catalyst by Pd(dba)2 reduced the
reaction time (15 h) and improved the yield (90%) significantly
(Table 1, entry 3). To our disappointment, switching to a more
polar solvent like DMSO proved to be ineffective, decreasing
the yield to 50% even after increasing the reaction time to 60 h
(Table 1, entry 4), while an alkaline base (i.e., KOH) proved to
be completely inefficient, showing no sign of product formation
(Table 1, entry 5). We were encouraged to note that the use of
Pd(MeCN)2Cl2/PPh3 and K2CO3 in DMF produced the
product 9aa within 8 h, albeit in moderate (47%) yield
(Table 1, entry 6). Gratifyingly, use of Pd(OAc)2 allowed the
reaction to be completed within 1 h at rt, affording product 9aa
in 94% yield (Table 1, entry 7). The use of other bases (e.g.,
Scheme 1. Our Previous Work and Envisaged Route for the
Present Synthesis of 7
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iodides 11a−l, furnishing the expected products 9aa−al with
moderate to excellent yields (Table 2, entries 1−12).
Heteroaryl iodides without any substitution (11b,c) also
produced desired products 9ab−ac, though with somewhat
lower yields (66−73%) compared to phenyl iodide (11a),
proving their lower reactivity in this reaction (Table 2, entries
2−3 vs entry 1). An electron-donating group enhanced the
reactivity (in 11j), delivering product 9aj with 89% yield (Table
2, entry 10). On the other hand, irrespective of the substitution,
all aryl iodides 11d−i possessing either electron-donating (viz.,
Me, OMe) or electron-withdrawing groups (viz., CF3, CHO,
CO2Me, NO2) efficiently participated in this reaction to
produce the products (9ad−ai) within 2.5 h with 66−86%
yields (Table 2, entries 4−9). Additionally, olefinic iodides were
found to be reactive under the conditions (Table 2, entries 11
and 12). Though vinyl iodide 11k furnished the product 9ak
with moderate yield (39%), 2,4-dimethyl-5-iodo-uracil (11l)
afforded the desired compound 9al with 63% yield.
Unfortunately, neither any aryl bromide/chloride nor allena-
mide without N-alkylation (of the amidic nitrogen) reacted.
To check the effect of other N-protecting groups, the
reactivity of trifluoroacetanilide substituted allenamide 14
toward different aryl iodides was explored (Table 2, entries
13−16). Interestingly, this gave direct access to the N-
deprotected products (Table 2, entries 13−16), which is
similar to the observations of Cacchi and co-workers.21
Furthermore, the presence of an electron-withdrawing group
in the iodide facilitated the reaction compared to an electron-
donating group (Table 2, entry 16 vs 15).
Table 1. Optimization of the Reaction Conditions for the
Synthesis of 9aa at Room Temperature
a
b
c
Sl. no.
cat.
base
solvent
time (h) yield (%)
1
2
Pd(PPh3)4
10% Pd/C
Pd(dba)2
K2CO3
K2CO3
K2CO3
K2CO3
KOH
CH3CN
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
14
26
15
60
2
75
68
90
50
0
3
4
Pd(dba)2
5
Pd(dba)2
6
Pd(MeCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
K2CO3
K2CO3
KOtBu
Cs2CO3
Et3N
8
47
94
91
82
88
65
7
1
8
1
9
4
10
11
2.5
30
K2CO3
a
Reaction conditions: 13 (1.0 equiv), 11a (1.0 equiv), palladium
catalyst (0.05 equiv), PPh3 (0.12 equiv, except for entry 1), base (4.0
b
equiv) in a solvent under argon. PPh3 was used as ligand except for
c
entry 1. Yields of isolated pure products.
KOtBu, Cs2CO3, Et3N) neither improved the yield nor reduced
the reaction time (Table 1, entries 8−10). Additionally,
Pd(PPh3)2Cl2 proved unsuitable (Table 1, entry 11). DMF
was found to be the best solvent. Thus, the reaction conditions
of entry 7 of Table 1 appeared to be optimal.
Encouraged by these results, we became interested to test
allenamide 15, which has a free amine group, in this reaction.
Interestingly, this too resulted in the formation of the desired
products with moderate to good yields (Table 2, entries 17−
Using the optimized reaction conditions, we then extended
the scope of this procedure to anthranilic allenamides 13−15
and a range aryl/heteroaryl/vinyl iodides 11a−l (Table 2).
Indeed, allenamide 13 reacted successfully with a series of
a
Table 2. Palladium-Catalyzed Synthesis of 2-(α-Styryl)-2,3-dihydroquinazolin-4-ones 9
a
Reaction conditions: 13/14/15 (1.0 equiv), 11 (1.0 equiv), Pd(OAc)2 (0.05 equiv), PPh3 (0.12 equiv), K2CO3 (4.0 equiv) in DMF under argon.
Yield of isolated pure product.
b
C
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20). However, in line with our previous observation, an iodide
possessing an electron-withdrawing group (e.g., CO2Me)
turned out to be more reactive compared to one having an
electron-donating group like OMe (Table 2, entry 19 vs 18,
20). From these studies, it is apparent that allenamide 13
containing the N-tosyl group possessed better reactivity than
other allenamides (14, 15) and delivered the products with very
good yields. This underlines the crucial role of the acidic
hydrogen attached to the aryl amino moiety (in allenamide),
acting as a nucleophile during cyclization.
Bis-heteroannulated products 17a and 17b could also be
accessed easily, though in moderate yields, when allenamide 13
was allowed to react with aryl diiodides 16a and 16b under the
optimized reaction conditions, suggesting polyheteroannulation
to be a viable process in one pot (Scheme 2).
used the allenesulfonamide derivative 22 for the synthesis of 3-
(α-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 23.
An initial base (KOtBu)-promoted isomerization of the
precursor acetylene compound (21) furnished the desired
allenesulfonamide 22. Since this compound was found to
decompose during chromatographic purifications, we directly
exposed the crude allenesulfonamide (obtained after usual
workup) to react with phenyl iodide (11a) and 3-iodo-pyridine
(11b) separately under optimized reaction conditions; to our
disappointment, conducting these reactions at rt required 30
and 45 h, respectively, to deliver the corresponding products
23a (47%) and 23b (55%), proving them inconvenient to
pursue. Pleasingly, the reactions were found to be completed
within 25−30 min upon heating at 60 °C, and the yield
improved as well (Table 3, entries 1 and 2). Furthermore, a
Table 3. Palladium-Catalyzed Synthesis of 3-(α-Styryl)-3,4-
dihydro-1,2,4-benzothiadiazine-1,1-dioxide 23
Scheme 2. Synthesis of Bis-heteroannulated Products 17a−
a b
,
a
b
c
SI. No.
RI (11)
time (min)
product
yield (%)
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
30
25
30
15
10
60
30
15
10
23a
23b
23c
23d
23e
23f
67
62
40
63
88
39
52
63
61
a
Reaction conditions: 13 (1.0 equiv), 16a/16b (0.5 equiv), Pd(OAc)2
(0.05 equiv), PPh3 (0.12 equiv), K2CO3 (4.0 equiv) in DMF under
argon.
To check the scope of this method further, an internal alkyne
18 was probed. It was surprising to find that even phenyl
substituted crude allenamide 19 (having a propensity toward
decomposition during purification through silica-gel column
chromatography) reacted successfully with iodo compound 11g
under the optimized reaction conditions to furnish the
stereoselective product 20 in 55% yield (Scheme 3). The
(E)-stereochemistry of the product was confirmed by 2D
NMR. Of particular interest was the weak, but perceptible,
NOE cross peaks observed between the signals for the ortho
protons (with respect to the olefinic double bond, as marked
with green arrow) of the two phenyl rings of the styryl unit
which established the geometry shown (see the Supporting
Information).
11g
23g
23m
23n
IC6H4F-p; 11m
IC6H4Br-p; 11n
a
Reaction conditions: 21 (1.0 equiv), KOtBu (2.0 equiv) in DMF.
Reaction conditions: Crude 22 treated with 11 (1.0 equiv),
Pd(OAc)2 (0.05 equiv), PPh3 (0.12 equiv), and K2CO3 (4.0 equiv)
b
c
in DMF under argon. Yield was calculated based on 21.
heteroaryl iodide (Table 3, entry 3) and aryl iodides containing
either electron-donating (Table 3, entries 4, 6) or electron-
withdrawing (Table 3, entries 5, 7, 8, 9) groups underwent
reaction successfully with crude allenesulfonamide 22 within
10−60 min to afford the expected products in moderate to very
good yields (39−88%).
After having accomplished a general synthesis of 2-(α-styryl)-
2,3-dihydroquinazolin-4-ones 9, we planned to replace the
carbonyl (CO) group of allenamide 13 by a SO2 group and
The structures of the products23 were unambiguously
deduced from spectroscopic (1H, 13C NMR, HRMS) and
a b
,
Scheme 3. Reaction of Phenyl Substituted Allenamide 19 with Iodo Compound 11g
a
b
Reaction conditions: KOtBu (2.0 equiv), in DMF at rt under an argon atmosphere. Reaction conditions: Crude 19 treated with 11g (1.0 equiv),
Pd(OAc)2 (0.05 equiv), PPh3 (0.12 equiv), and K2CO3 (4.0 equiv) in DMF under argon.
D
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a b
,
Scheme 4. Base-Promoted Synthesis of Products 7, 8
a
Reaction conditions: For substrate 9a (1.0 equiv), 5.0 equiv of NaH (60% dispersion in mineral oil) used; for substrate 23 (1.0 equiv), 2.0 equiv of
b
the same base used, as excess base (5.0 equiv) was detrimental for yields. Yield of isolated pure product.
analytical data. These were further supported by single crystal
X-ray diffraction analysis (see the Supporting Information) of a
few products (9aa, 9bd, and 23g).22
After achieving the synthesis of 2-(α-styryl)-2,3-dihydro-
quinazolin-4-ones 9 and their benzothiadiazine-1,1-dioxide
variants 23, attention was turned toward the synthesis of the
unsaturated analogues 7 through a base-promoted reaction as
depicted in Scheme 4. Initially, we performed a series of
reactions on model compound 13a varying the base and solvent
as well; representative data are shown in Table 4. KOtBu-
within 30 min (Table 4, entry 5); however, decreasing the
amount of NaH (3 equiv) caused incomplete conversion of
starting material even after 48 h. Further, changing the solvent
to acetonitrile was not useful (Table 4, entry 6). Thus, reaction
conditions of entry 5 in Table 4 proved optimal. We then
checked the scope and limitations of this protocol by varying
the substrates as shown in Scheme 4.
As depicted in Scheme 4, substrates 9aa−9ac containing a
simple aryl/heteroaryl group in the styryl moiety afforded
products (7a−c) in very good yield (74−88%). Even after
introduction of an electron-donating group (viz. Me/OMe) in
the aryl ring (substrates 9ad/9af), the corresponding products
7d/7f were isolated with comparable yields (78−85%). In
contrast, an electron-withdrawing substituent (viz. CF3) at the
same position of the substrate (9ae) reduced the yield (52%) of
the product (7e). On the other hand, employing substrates 23a
and 23b having a SO2 moiety in place of carbonyl delivered the
desired products 8a and 8b, respectively, in moderate yield
(57% and 50%).
The structures of the products were confirmed by
spectroscopic analysis (1H NMR, 13C NMR, HRMS) and
further supported by single crystal X-ray diffraction of
compound 7d (see the SI).22
We next applied this methodology for synthesizing (Scheme
5) analogues of Luotonin F,24 a natural alkaloid extracted from
the aerial parts of Peganum nigellastrum Bunge, the plant which
finds applications in the Chinese system of medicines for the
treatment of rheumatism, inflammation, abscesses, and other
diseases.25 The total synthesis of Luotonin F itself applying our
methodology is presently underway.
Table 4. Optimization of the Reaction Conditions for the
Synthesis of 2-(α-Styryl)quinazolin-4(3H)-one 7a
c
entry
base
solvent
time
30 h
yield (%)
a
1
KOtBu
KOtBu
KOH
DBU
NaH
THF
28
40
60
0
a
2
DMF
DMF
DMF
DMF
CH3CN
5 min
5 min
38 h
a
3
a
4
b
5
30 min
38 h
88
b
6
NaH
60
a
b
Reaction conditions: 9aa (1.0 equiv), base (3.0 equiv). Reaction
conditions: 9aa (1.0 equiv), NaH (60% dispersion in mineral oil, 5.0
c
equiv). Yield of isolated pure product.
promoted reaction in THF at rt remained mostly incomplete
(TLC), even after extending the reaction to 30 h, and yielded
only 28% of the desired product 7a along with the recovery
(58%) of the reactant 9aa (Table 4, entry 1). Gratifyingly, the
reaction was complete within 5 min on replacing the solvent by
DMF and the yield also improved somewhat (40%), though
several side products (TLC) were generated (Table 4, entry 2).
Thereafter, the use of KOH instead of KOtBu increased the
yield to 60% (Table 4, entry 3), but the product 7a was still
accompanied by side products (TLC) in minor amounts.
Though a strong organic base like DBU proved to be ineffective
for this reaction (Table 4, entry 4), the use of NaH (5 equiv)
was beneficial, leading to the formation of 7a (88% yield)
CONCLUSION
■
In conclusion, we have successfully developed a facile and mild
method for the general synthesis of 2-(α-styryl)-2,3-dihydro-
quinazolin-4-ones 9 via palladium-catalyzed cyclocondensation
of aryl/heteroaryl (or vinyl) iodide 11 with allenamides 13−15
at room temperature. This reaction can easily be extended for
bis-heteroannulation and the use of phenyl substituted
allenamide as well. Besides, the scope of this method has
been extended to the synthesis of 3-(α-styryl)-3,4-dihydro-
1,2,4-benzothiadiazine-1,1-dioxides 23 by varying the substrate
(22) and tweaking the temperature (i.e., 60 °C). A base-
E
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a b c
, ,
Scheme 5. Application of the Methodology for the Synthesis of Luotonin F Analogues
a
b
Reaction conditions: 2.0 equiv of KOtBu was used for 10/21 (1.0 equiv), but 3.0 equiv of the same base was used for 24 (1.0 equiv). Reaction
c
conditions: 13/25 (1.0 equiv), 26 (1.0 equiv), Pd(OAc)2 (0.05 equiv), PPh3 (0.12 equiv), K2CO3 (4.0 equiv). For 1.0 equiv of 27a and 27c, 5.0
equiv of NaH (60% dispersion in mineral oil) was used; while, for 27b (1.0 equiv), 2.0 equiv of the same base was used.
purified by silica gel (100−200 mesh) column chromatography using
12% ethyl acetate−petroleum ether (v/v) as eluent.
promoted reaction of the products (9a, 23) provided an easy
access to 2-(α-styryl)quinazolinones 7 and 3-(α-styryl)-1,2,4-
benzothiadiazine-1,1-dioxide 8, a novel class of compounds.
This methodology has also been applied in the generation of a
few analogues of Luotonin F. As 2-(β-styryl)quinazolinones
have already proved to be potent inducers of apoptosis and
possess other remarkable phamacological activities, their 2-(α-
styryl) variants are also anticipated to possess potent medicinal
value. Work in this direction is currently in progress and will be
reported in due course.
N-Methyl-N-(prop-2-yn-1-yl)-2-(2,2,2-trifluoroacetamido)-
benzamide (S1). Pale yellow amorphous solid (130 mg, 86% yield);
1
mp 90−92 °C; H NMR (CDCl3, 300 MHz) δ 10.32 (brs, 1H), 8.29
(d, J = 8.4 Hz, 1H), 7.54−7.48 (m, 2H), 7.28−7.23 (m, 1H), 4.25 (m,
2H), 3.18 (s, 3H), 2.37 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.7,
155.1 (q, J = 37.2 Hz), 134.8, 131.6, 127.9, 125.0, 124.0, 122.9, 115.6
(q, J = 286.7 Hz), 77.6, 73.4, 42.4, 36.9 ppm; HRMS (ESI+) m/z
calculated for C13H11F3N2O2Na [M + Na]+ 307.0670, found 307.0672.
Procedure for Conversion of 10, S1, S2 to Allenamides 13,
14, 15. N-Methyl-2-[(4-methylphenyl)sulfonamide]-N-(propa-1,2-
dien-1-yl)benzamide (13). To a stirred solution of acetylene 10
(100 mg, 0.29 mmol) in dry DMF was added KOtBu (66 mg, 0.58
mmol); the reaction was found to be completed within 5 min. (TLC).
It was then quenched with water (5 mL) and extracted with EtOAc (3
× 20 mL). The combined organic extracts were dried over Na2SO4
and concentrated in vacuo. The resulting residue was purified by silica
gel (100−200 mesh) column chromatography using 20% EtOAc−
petroleum ether (v/v) as eluent to furnish the product 13 as a white
EXPERIMENTAL SECTION
■
General. Melting points are uncorrected. Analytical thin-layer
chromatography (TLC) was performed on Silica gel 60-F254
aluminum TLC sheets. Visualization of the developed chromatogram
was performed by UV absorbance or iodine exposure. For purification,
column chromatography was performed using 100−200 mesh silica
1
gel. H and 13C NMR spectra were recorded at 298 K on a 300, 400,
1
amorphous solid (85 mg, 85%); mp 108−109 °C; H NMR (CDCl3,
500, or 600 MHz spectrometer using tetramethylsilane (TMS) as
internal standard. Chemical shifts (δ) are given from TMS (δ = 0.00)
in parts per million (ppm) with reference to the residual nuclei of the
600 MHz) δ 8.41 (brs, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (brs, 2H),
7.41 (t, J = 7.2 Hz, 1H), 7.21−7.12 (m, 4H), 5.98 (s, 1H), 5.45−5.35
(m, 2H), 2.97 (s, 2H), 2.47 (s, 1H), 2.33 (s, 3H); 13C NMR (CDCl3,
150 MHz) δ 201.3, 168.9, 145.6, 137.9, 137.7, 133.1, 131.0, 130.6,
129.4, 128.6, 127.2, 126.1, 104.5, 101.0, 88.9, 37.1, 32.9, 31.2, 23.0
ppm. HRMS (EI+) m/z calculated for C18H18N2O3S [M]+ 342.1038,
found 342.1034.
1
deuterated solvent used [CDCl3: H NMR δ = 7.26 ppm (s); 13C
NMR δ = 77.0 ppm]. Coupling constants (J) are expressed in hertz
(Hz), and spin multiplicities are given as s (singlet), d (doublet), dd
(double doublet), t (triplet), m (multiplet), and br (broad). All 13C
NMR spectra were obtained with broad-band proton decoupling. To
assign the structures under consideration, the following 1D and 2D
experiments were employed: 1H selective NOESY 2D: COSY and
1H−13C gradient selected HSQC and HMBC in a 600 MHz NMR
N-Methyl-N-(propa-1,2-dien-1-yl)-2-(2,2,2-trifluoroacetamido)-
benzamide (14). To a well-stirred solution of acetylene S1 (100 mg,
0.35 mmol) in dry DMF was added KOtBu (316 mg, 2.82 mmol), and
the reaction was continued for another 10 min until completion
(TLC). Then, the reaction was quenched with water (5 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo; the resulting
residue was purified by silica gel (100−200 mesh) column
chromatography using 10% ethyl acetate−petroleum ether (v/v) as
eluent to furnish the product 14 as a pale yellow amorphous solid (89
mg, 91%); mp 82−84 °C; 1H NMR (CDCl3, 300 MHz) δ 10.39 (brs,
1H), 8.35 (d, J = 8.4 Hz, 1H), 7.55−7.50 (m, 2H), 7.29−7.24 (m,
1H), 6.80 (brs, 1H), 5.46 (brs, 2H), 3.19 (brs, 3H); 13C NMR
(CDCl3, 75 MHz) δ 200.3, 167.9, 155.1 (q, J = 37.5 Hz), 135.2, 131.8,
124.8 (two carbon signals merged probably), 122.8 (two carbon
signals merged probably), 115.6 (q, J = 286.9 Hz), 103.0, 87.6, 31.9
ppm. HRMS (ESI+) m/z calculated for C13H12F3N2O2 [M + H]+
285.0851, found 285.0841.
machine. Mass spectra were performed using ESI-TOF, EI or FAB
ionization mode.
Synthesis of Allenamides 13−15 from Corresponding
Acetylene Compounds 10, S1, S2. Synthesis of the Acetylenic
Substrate N-Methyl-N-(prop-2-yn-1-yl)-2-(2,2,2-trifluoroacet-
amido)benzamide (S1). The acetylene compounds 2-amino-N-
methyl-N-(prop-2-yn-1-yl)benzamide (S2) and N-methyl-2-[(4-
methylphenyl)sulfonamide]-N-(prop-2-yn-1-yl)benzamide (10) were
prepared by a known literature procedure.20a N-Methyl-N-(prop-2-yn-
1-yl)-2-(2,2,2-trifluoroacetamido)benzamide (S1) was prepared by
adding trifluoroacetic anhydride (223 mg, 1.06 mmol) and triethyl-
amine (81 mg, 0.80 mmol) in the solution of S2 (100 mg, 0.53 mmol)
in THF (5.0 mL) at 0 °C, followed by stirring at room temperature for
3 h. After completion of reaction (TLC), the solvent was evaporated in
vacuo; the residue was washed with aqueous NaHCO3 solution and
partitioned between EtOAc and brine. The organic layer was dried
over Na2SO4 and concentrated in vacuo. The crude product was then
2-Amino-N-methyl-N-(propa-1,2-dien-1-yl)benzamide (15). To a
well-stirred solution of acetylene S2 (100 mg, 0.53 mmol) in dry DMF
was added KOH (179 mg, 3.19 mmol). The reaction was found to be
F
DOI: 10.1021/acs.joc.6b01242
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
completed within 2 min (TLC). It was then quenched with water (5
mL) and extracted with EtOAc (3 × 20 mL). Combined organic
extracts were dried over Na2SO4 and concentrated in vacuo. The
resulting residue was purified by silica gel (100−200 mesh) column
chromatography using 10% EtOAc−petroleum ether (v/v) as eluent
mg, 74% yield); mp 178−179 °C; 1H NMR (CDCl3, 600 MHz) δ 7.86
(dd, J = 7.8 Hz, 1.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.50 (td, J = 7.8
Hz, 1.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.40−7.39 (m, 1H), 7.36
(td, J = 7.5 Hz, 1.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 8.4
Hz, 2H), 6.45 (t, J = 1.5 Hz, 1H), 5.38 (d, J = 1.2 Hz, 1H), 4.99 (d, J =
1.8 Hz, 1H), 2.95 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3, 150 MHz)
δ 161.4, 144.9, 141.9, 141.0, 135.2, 133.8, 132.8, 130.3 (q, J = 32.0
Hz), 129.6, 127.7, 127.7, 127.3, 127.0, 126.9, 125.5, 125.4 (q, J = 3.7
Hz), 124.0 (q, J = 270.6 Hz), 118.9, 73.7, 33.8, 21.6 ppm; HRMS
(EI+) m/z calculated for C25H21F3N2O3S [M]+ 486.1225, found
486.1216.
1
to afford 15 as a yellow gum (55 mg, 55%); H NMR (CDCl3, 300
MHz) δ 7.22−7.17 (m, 3H), 6.75−6.71 (m, 2H), 5.41−5.39 (m, 2H),
4.43 (brs, 2H), 3.12 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 201.7,
169.3, 146.2, 131.2, 128.9, 118.4, 117.2, 116.8, 99.9, 86.9, 32.4 ppm.
HRMS (ESI+) m/z calculated for C11H12N2ONa [M + Na]+ 211.0847,
found 211.0847.
General Procedure for Palladium-Catalyzed Synthesis of 2-
(α-Styryl)-2,3-dihydroquinazolin-4-ones 9a,b (Table 2). To a
well-stirerd solution of Pd(OAc)2 (0.05 equiv) and PPh3 (0.12 equiv)
in dry DMF (4 mL) was sequentially added iodo compound 11 (1
equiv), K2CO3 (4 equiv), and allene 13/14/15 (1 equiv) under an
argon atmosphere. The whole reaction mixture was allowed to stir at
room temperature for the requisite time (see Table 2) until
completion (TLC). DMF was removed in vacuo. The resulting
mixture was extracted with EtOAc (3 × 20 mL) and washed with
water (10 mL). The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. The crude residue was then
purified by (silica gel 100−200 mesh) column chromatography using
10−50% ethyl acetate−petroleum ether (v/v) as eluent to afford the
desired products (9a, 9b).
3-Methyl-2-(1-phenylvinyl)-1-tosyl-2,3-dihydroquinazolin-4(1H)-
one (9aa). Pale brown crystalline solid (68.9 mg, 94% yield); mp
192−193 °C; 1H NMR (CDCl3, 300 MHz) δ 7.86 (dd, J = 7.5 Hz, 1.5
Hz, 1H), 7.49 (td, J = 7.5 Hz, 1.5 Hz, 2H), 7.42−7.33 (m, 7H), 7.26−
7.22 (m, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.45 (s, 1H), 5.31 (d, J = 1.5
Hz, 1H), 4.89 (d, J = 2.1 Hz, 1H), 2.93 (s, 3H), 2.35 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 161.5, 144.7, 142.6, 137.4, 135.3, 133.9,
132.6, 129.5, 128.4, 128.2, 127.5, 127.0, 126.9, 125.6, 117.3, 73.8, 33.7,
21.6 ppm (two C signals seemed to overlap with other aromatic
carbons); HRMS (EI+) m/z calculated for C24H22N2O3S [M]+
418.1351, found 418.1352.
3-Methyl-2-[1-(pyridin-3-yl)vinyl]-1-tosyl-2,3-dihydroquinazolin-
4(1H)-one (9ab). Pale yellow solid (53.7 mg, 73% yield); mp 181−182
°C; 1H NMR (CDCl3, 300 MHz) δ 8.61 (d, J = 4.5 Hz, 1H), 8.47 (brs,
1H), 7.88 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.56−7.50 (m,
1H), 7.45−7.35 (m,3H), 7.28−7.24 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H),
6.41 (s, 1H), 5.40 (s, 1H), 5.03 (d, J = 1.2 Hz, 1H), 2.97 (s, 3H), 2.38
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 161.3, 149.4, 148.2, 144.9,
139.9, 135.1, 134.1, 133.8, 133.2, 132.9, 129.6, 127.8, 127.7, 126.9,
126.9, 125.4, 123.1, 118.7, 73.6, 33.8, 21.6 ppm; HRMS (FAB+) m/z
calculated for C23H22N3O3S [M + H]+ 420.1382, found 420.1377.
3-Methyl-2-[1-(thiophen-2-yl)vinyl]-1-tosyl-2,3-dihydro-
quinazolin-4(1H)-one (9ac). White amorphous solid (49.1 mg, 66%
yield); mp 182−184 °C; 1H NMR (CDCl3, 300 MHz) δ 7.84 (dd, J =
7.6 Hz, 1.3 Hz, 1H), 7.62−7.57 (m, 2H), 7.52 (td, J = 7.6 Hz, 1.3 Hz,
1H), 7.36 (td, J = 7.5 Hz, 1.1 Hz, 1H), 7.26−7.23 (m, 3H), 7.14 (d, J =
8.4 Hz, 2H), 7.09−7.06 (m, 1H), 6.39 (s, 1H), 5.47 (s, 1H), 4.73 (s,
1H), 2.89 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 161.4,
144.9, 139.7, 135.3, 135.1, 133.6, 132.8, 129.5, 127.8, 127.8, 127.5,
127.4, 127.1, 125.9, 125.6, 125.4, 115.6, 73.7, 33.5, 21.7 ppm; HRMS
(EI+) m/z calculated for C22H20N2O3S2 [M]+ 424.0915, found
424.0924.
3-Methyl-2-[1-(p-tolyl)vinyl]-1-tosyl-2,3-dihydroquinazolin-
4(1H)-one (9ad). Pale brown amorphous solid (55.3 mg, 73% yield);
mp 164−166 °C; 1H NMR (CDCl3, 300 MHz) δ 7.85 (dd, J = 7.5 Hz,
1.5 Hz, 1H), 7.51−7.46 (m, 1H), 7.43−7.40 (m, 1H), 7.34 (td, J = 7.4
Hz, 1.3 Hz, 2H), 7.28−7.21 (m, 3H), 7.18−7.11 (m, 4H), 6.43 (s,
1H), 5.28 (d, J = 1.2 Hz, 1H), 4.83 (d, J = 1.5 Hz, 1H), 2.92 (s, 3H),
2.37−2.35 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ 161.5, 144.7,
142.4, 138.1, 135.4, 134.5, 134.1, 132.7, 129.6, 129.1, 127.6, 127.5,
127.1, 127.0, 126.8, 125.7, 116.6, 73.9, 33.7, 21.7, 21.2 ppm; HRMS
(EI+) m/z calculated for C25H24N2O3S [M]+ 432.1508, found
432.1500.
2-[1-(4-Methoxyphenyl)vinyl]-3-methyl-1-tosyl-2,3-dihydro-
quinazolin-4(1H)-one (9af). Brown amorphous solid (58.2 mg, 74%
yield); mp 150−151 °C; 1H NMR (CDCl3, 300 MHz) δ 7.85 (dd, J =
7.8 Hz, 1.2 Hz, 1H), 7.52−7.41 (m, 2H), 7.37−7.31 (m, 3H), 7.26−
7.22 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.42
(s, 1H), 5.26 (d, J = 0.9 Hz, 1H), 4.80 (d, J = 1.5 Hz, 1H), 3.84 (s,
3H), 2.92 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 161.4,
159.4, 144.6, 141.7, 135.3, 133.9, 132.5, 129.6, 129.4, 128.0, 127.4,
126.9, 126.9, 125.6, 115.8, 113.7, 73.8, 55.1, 33.6, 21.5 (one carbon
signal has probably merged with other aromatic carbon signals) ppm;
HRMS (EI+) m/z calculated for C25H24N2O4S [M]+ 448.1457, found
448.1453.
Methyl 4-[1-(3-Methyl-4-oxo-1-tosyl-1,2,3,4-tetrahydro-
quinazolin-2-yl)vinyl]benzoate (9ag). White amorphous solid (71.8
mg, 86% yield); mp 198−200 °C; 1H NMR (CDCl3, 300 MHz) δ 8.06
(d, J = 8.7 Hz, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.54−7.48 (m, 1H), 7.43
(d, J = 8.4 Hz, 2H), 7.40−7.35 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H),
7.15(d, J = 8.1 Hz, 2H), 6.48 (s, 1H), 5.41 (d, J = 0.9 Hz, 1H), 4.99 (d,
J = 1.5 Hz, 1H), 3.96 (s, 3H), 2.97 (s, 3H), 2.37 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 166.7, 161.4, 144.8, 142.2, 141.9, 135.2, 133.9,
132.8, 129.8, 129.7, 129.6, 127.6, 127.6, 127.0, 126.9, 125.5, 118.6,
73.6, 52.1, 33.8, 21.6 ppm (one carbon signal is expected to merge
with other aromatic carbon signals); HRMS (EI+) m/z calculated for
C26H24N2O5S [M]+ 476.1406, found 476.1397.
2-[1-(3-Methyl-4-oxo-1-tosyl-1,2,3,4-tetrahydroquinazolin-2-yl)-
vinyl]benzaldehyde (9ah). Pale yellow amorphous solid (58.7 mg,
75% yield); mp 156−157 °C; 1H NMR (CDCl3, 300 MHz) δ 9.80 (s,
1H), 7.91−7.87 (m, 2H), 7.58−7.50 (m, 3H), 7.44−7.35 (m, 2H),
7.21 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.2 Hz,
1H), 6.38 (s, 1H), 5.11 (d, J = 0.9 Hz, 1H), 5.06 (d, J = 1.2 Hz, 1H),
3.02 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 192.6,
161.3, 144.7, 142.5, 139.8, 135.5, 134.2, 133.8, 133.7, 132.8, 130.7,
129.7, 128.6, 127.7, 127.4, 126.8, 126.5, 125.1, 118.8, 73.7, 33.4, 21.6
ppm; HRMS (ESI+) m/z calculated for C25H23N2O4S [M + H]+
447.1378, found 447.1421.
3-Methyl-2-[1-(4-nitrophenyl)vinyl]-1-tosyl-2,3-dihydro-
quinazolin-4(1H)-one (9ai). Pale yellow amorphous solid (53.6 mg,
66% yield); mp 216−217 °C; 1H NMR (CDCl3, 300 MHz) δ 8.26 (d,
J = 9 Hz, 2H), 7.90−7.87 (m, 1H), 7.56−7.50 (m, 3H), 7.42−7.37 (m,
2H), 7.28−7.23 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.49 (s, 1H), 5.47
(d, J = 1.2 Hz, 1H), 5.09 (d, J = 1.5 Hz, 1H), 2.98 (s, 3H), 2.38 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 161.2, 147.5, 145.1, 143.9, 141.4,
134.9, 133.6, 132.9, 129.6, 127.9, 127.8, 127.7, 126.9, 126.8, 125.3,
123.7, 119.9, 73.5, 33.8, 21.6 ppm; HRMS (ESI+) m/z calculated for
C24H21N3O5SNa [M + Na]+ 486.1100, found 486.1096.
2-[1-(2,4-Dimethoxypyrimidin-5-yl)vinyl]-3-methyl-1-tosyl-2,3-
dihydroquinazolin-4(1H)-one (9aj). White amorphous solid (75.0
mg, 89% yield); mp 182−184 °C; 1H NMR (CDCl3, 300 MHz) δ 7.86
(d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.54−7.49 (m, 1H), 7.41 (d, J = 8.1
Hz, 1H), 7.38−7.33 (m, 1H), 7.26−7.21 (m, 2H), 7.13 (d, J = 8.1 Hz,
2H), 6.51 (s, 1H), 5.15 (d, J = 1.2 Hz, 1H), 5.01 (d, J = 1.8 Hz, 1H),
4.14 (s, 3H), 4.03 (s, 3H), 2.94 (s, 3H), 2.35 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 167.8, 165.4, 161.3, 157.6, 144.7, 138.2, 135.3,
134.1, 132.8, 129.6, 127.6, 127.5, 126.9, 126.8, 125.4, 119.3, 113.1,
72.9, 54.9, 54.3, 33.8, 21.6 ppm; HRMS (EI+) m/z calculated for
C24H24N4O5S [M]+ 480.1467, found 480.1469.
2-(Buta-1,3-dien-2-yl)-3-methyl-1-tosyl-2,3-dihydroquinazolin-
4(1H)-one (9ak). Brown amorphous solid (25.2 mg, 39% yield); mp
152−154 °C; 1H NMR (CDCl3, 300 MHz) δ 7.83 (dd, J = 7.5 Hz, 1.5
3-Methyl-1-tosyl-2-{1-[4-(trifluoromethyl)phenyl]vinyl}-2,3-
dihydroquinazolin-4(1H)-one (9ae). Yellow amorphous solid (63.0
G
DOI: 10.1021/acs.joc.6b01242
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.53 (td, J = 7.6 Hz, 1.3 Hz, 1H),
7.35 (t, J = 7.2 Hz, 1H), 7.26−7.23 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H),
6.28 (dd, J = 17.8 Hz, 11.2 Hz, 1H), 6.20 (s, 1H), 5.88 (d, J = 18 Hz,
1H), 5.31 (d, J = 11.4 Hz, 1H), 5.17 (s, 1H), 4.69 (s, 1H), 2.82 (s,
3H), 2.36 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 163.0, 146.4,
140.6, 136.9, 135.4, 135.4, 134.2, 131.1, 129.2, 129.0, 128.9, 128.6,
127.1, 119.4, 118.9, 74.1, 34.9, 23.2 ppm; HRMS (EI+) m/z calculated
for C20H20N2O3S [M]+ 368.1195, found 368.1185.
General Procedure for One-Pot Bis-heteroannulation
(Scheme 2). To a stirred solution of diiodo compound 16a (38.6
mg, 0.12 mmol) [or 16b (39.3 mg, 0.12 mmol)] in dry DMF (3 mL)
were added K2CO3 (129.1 mg, 0.94 mmol) and allenamide 13 (80.0
mg, 0.23 mmol) sequentially. After stirring for a few minutes,
Pd(OAc)2 (2.6 mg, 0.01 mmol) and PPh3 (7.4 mg, 0.03 mmol) were
added, and the whole reaction mixture was allowed to stir at rt under
an argon atmosphere for the requisite time (see Scheme 2). After
completion of the reaction (TLC), DMF was evaporated under
reduced pressure and the resulting mixture was extracted with ethyl
acetate (3 × 20 mL). The combined organic extracts were washed with
water (15 mL), dried over Na2SO4, and concentrated in vacuo. The
crude residue was purified by silica gel (100−200 mesh) column
chromatography using 40% ethyl acetate−petroleum ether (v/v) to
afford the desired product 17a (or 17b).
2,2′-[1,4-Phenylenebis(ethene-1,1-diyl)]bis[3-methyl-1-tosyl-2,3-
dihydroquinazolin-4(1H)-one] (17a). White crystalline solid (44.3
mg, 50% yield); mp 264−265 °C; 1H NMR (CDCl3, 300 MHz) δ 7.86
(d, J = 8.1 Hz, 2H), 7.56−7.51 (m, 2H), 7.47 (d, J = 7.2 Hz, 2H),
7.41−7.34 (m, 6H), 7.27−7.25 (m, 4H), 7.15 (d, J = 8.1 Hz, 4H), 6.49
(s, 2H), 5.40 (s, 2H), 4.93 (s, 2H), 2.96 (s, 6H), 2.37 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 161.5, 144.7, 142.2, 137.2, 135.3, 133.9,
132.8, 129.5, 127.6, 127.5, 127.2, 126.9, 125.6, 117.3, 73.7, 33.8, 21.6
ppm; HRMS (ESI+) m/z calculated for C42H39N4O6S2 [M + H]+
759.2311, found 759.2304.
2,2′-[Thiophene-2,5-diylbis(ethene-1,1-diyl)]bis[3-methyl-1-tosyl-
2,3-dihydroquinazolin-4(1H)-one] (17b). Brown amorphous solid
(49.2 mg, 55% yield); mp 236−238 °C; 1H NMR (CDCl3, 300 MHz)
δ 7.89 (d, J = 7.5 Hz, 2H), 7.54−7.49 (m, 8H), 7.39−7.34 (m, 4H),
7.29−7.26 (m, 4H), 6.65 (s, 2H), 4.79 (s, 2H), 4.69 (d, J = 1.2 Hz,
2H), 2.89 (s, 6H), 2.41 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 161.4,
144.9, 139.6, 135.2, 134.8, 133.6, 132.8, 129.5, 127.8, 127.5, 127.2,
126.7, 125.6, 116.2, 73.5, 33.5, 21.6 ppm; HRMS (ESI+) m/z
calculated for C40H36N4O6S3Na [M + Na]+ 787.1695, found 787.1693.
Synthesis of Internal Alkyne 18: Reaction of Phenyl
Substitute Allenamide 19 with Iodo Compound 11g (Scheme
3). A mixture of iodobenzene (63 mg, 0.31 mmol), Pd(PPh3)2Cl2 (4
mg, 0.006 mmol), CuI (2 mg, 0.012 mmol), and Et3N (74 mg, 0.73
mmol) in dry DMF (3.0 mL) was stirred under an argon atmosphere
for a few minutes. To a well-stirred solution of this reaction mixture
was added terminal alkyne 10 (100 mg, 0.29 mmol) slowly, and
stirring was continued for 1 h. After completion of reaction (TLC), the
solvent was evaporated under reduced pressure and the resulting
residue was extracted with EtOAc (3 × 20 mL). The combined
organic extracts were washed with water (10 mL), dried over Na2SO4,
and concentrated in vacuo. The crude residue was then purified by
silica gel (100−200 mesh) column chromatography using 17% ethyl
acetate−petroleum ether (v/v) as eluent to afford the internal alkyne
18.
1,3-Dimethyl-5-[1-(3-methyl-4-oxo-1-tosyl-1,2,3,4-tetrahydro-
quinazolin-2-yl)vinyl]pyrimidine-2,4(1H,3H)-dione (9al). Brown
1
amorphous solid (53.0 mg, 63% yield); mp 160−162 °C; H NMR
(CDCl3, 300 MHz) δ 7.92 (d, J = 8.1 Hz, 1H), 7.62−7.54 (m, 2H)
7.42−7.36 (m, 1H), 7.32−7.28 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.99
(s, 1H), 6.58 (s, 1H), 5.28 (s, 1H), 4.93 (d, J = 1.2 Hz, 1H), 3.44−3.43
(m, 6H), 2.88 (s, 3H), 2.38 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
161.9, 161.0, 151.2, 144.8, 140.8, 136.7, 135.2, 133.8, 132.6, 129.6,
127.6, 127.4, 126.9, 126.5, 124.9, 118.9, 110.9, 71.7, 37.0, 33.2, 27.9,
21.5 ppm; HRMS (ESI+) m/z calculated for C24H24N4O5SNa [M +
Na]+ 503.1365, found 503.1357.
3-Methyl-2-(1-phenylvinyl)-2,3-dihydroquinazolin-4(1H)-one
(9ba). Yellow gum (41.0 mg, 74% yield from 14; 50.5 mg, 60% yield
1
from 15); H NMR (CDCl3, 300 MHz) δ 7.93 (d, J = 7.5 Hz, 1H),
7.37 (brs, 5H), 7.28−7.22 (m, 1H), 6.88−6.83(m, 1H), 6.46 (d, J =
7.8 Hz, 1H), 5.59 (s, 1H), 5.43 (s, 1H), 5.24 (s, 1H), 4.30 (brs, 1H),
3.15 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 163.6, 144.8, 144.4,
137.9, 133.2, 128.8, 128.3, 127.1, 119.3, 116.2, 114.4, 73.4, 32.8 ppm
(two carbon signals probably have merged with other aromatic
carbons); HRMS (ESI+) m/z calculated for C17H17N2O [M + H]+
265.1341, found 265.1371.
3-Methyl-2-{1-[4-(trifluoromethyl)phenyl]vinyl}-2,3-dihydro-
quinazolin-4(1H)-one (9bb). Dark brown amorphous solid (40.7 mg,
1
58% yield); mp 128−130 °C; H NMR (CDCl3, 300 MHz) δ 7.90
(dd, J = 7.8 Hz, 1.2 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.4
Hz, 2H), 7.28−7.22 (m, 1H), 6.87−6.82 (m, 1H), 6.47 (d, J = 7.8 Hz,
1H), 5.58 (d, J = 1.8 Hz, 1H), 5.48 (s, 1H), 5.34 (d, J = 0.6 Hz, 1H),
4.26 (brs, 1H), 3.11 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 163.6,
144.6, 143.9, 141.6, 133.4, 130.2 (q, J = 32.2 Hz), 128.3, 127.7, 125.6
(q, J = 3.7 Hz), 123.9 (q, J = 270.5 Hz), 119.4, 118.1, 116.0, 114.5,
73.6, 32.6 ppm; HRMS (EI+) m/z calculated for C18H15F3N2O [M]+
332.1136, found 332.1144.
2-[1-(4-Methoxyphenyl)vinyl]-3-methyl-2,3-dihydroquinazolin-
4(1H)-one (9bc). Brown amorphous solid (31.1 mg, 50% yield from
14; 46.0 mg, 49% yield from 15); mp 113−115 °C; 1H NMR (CDCl3,
300 MHz) δ 7.91 (d, J = 6.3 Hz, 1H), 7.34−7.31 (m, 2H), 7.22 (dd, J
= 7.6 Hz, 1.0 Hz, 1H), 6.90−6.80 (m, 3H), 6.45 (d, J = 8.1 Hz, 1H),
5.56 (s, 1H), 5.38 (s, 1H), 5.16 (s, 1H), 4.27 (brs, 1H), 3.82 (s, 3H),
3.10 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 163.6, 159.6, 145.0,
143.7, 133.2, 130.0, 128.3, 128.2, 119.1, 116.0, 115.2, 114.4, 114.1,
73.7, 55.3, 32.5 ppm; HRMS (ESI+) m/z calculated for C18H18-
N2O2Na [M + Na]+ 317.1266, found 317.1258.
N-Methyl-2-[(4-methylphenyl)sulfonamide]-N-(3-phenylprop-2-
yn-1-yl)benzamide (18). Brown amorphous solid (93 mg, 76%); mp =
Methyl 4-[1-(3-Methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)-
1
93−95 °C; H NMR (CDCl3, 300 MHz) δ 8.47 (s, 1H), 7.71−7.62
vinyl]benzoate (9bd). Brown crystalline solid (56.5 mg, 83% yield
1
(m, 3H), 7.47−7.34 (m, 6H), 7.26−7.14 (m, 4H), 4.45 (brs, 1H), 3.65
(brs, 1H), 3.05−2.67 (m, 3H), 2.34 (brs, 3H); 13C NMR (CDCl3, 75
MHz) δ 169.0, 143.5, 136.4, 136.3, 135.9, 131.7, 131.1, 129.4, 128.7,
128.3, 127.1, 125.9, 124.5, 124.3, 83.0, 82.9, 40.1, 36.7, 32.8, 21.3 ppm.
HRMS (ESI+) m/z calculated for C24H22N2O3SNa [M + Na]+
441.1249, found 441.1244.
from 14; 82.2 mg, 80% yield from 15); mp 156−158 °C; H NMR
(CDCl3, 300 MHz) δ 8.03 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 7.8 Hz,
1H), 7.45 (d, J = 8.1 Hz, 2H), 7.28−7.23 (m, 1H), 6.86 (t, J = 7.5 Hz,
1H), 6.46 (d, J = 7.8 Hz, 1H), 5.61 (s, 1H), 5.51 (s, 1H), 5.33 (s, 1H),
4.28 (brs, 1H), 3.95 (s, 3H), 3.13 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 166.6, 163.5, 144.7, 144.1, 142.6, 133.3, 129.9, 129.8, 128.2,
127.2, 119.3, 117.7, 116.1, 114.5, 73.4, 52.2, 32.7 ppm; HRMS (EI+)
m/z calculated for C19H18N2O3 [M]+ 322.1317, found 322.1321.
2-[1-(2,4-Dimethoxypyrimidin-5-yl)vinyl]-3-methyl-2,3-dihydro-
quinazolin-4(1H)-one (9be). Brown amorphous solid (57.2 mg, 55%
yield); mp 150−152 °C; 1H NMR (CDCl3, 300 MHz) δ 7.91 (s, 1H),
7.85 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.25−7.19 (m, 1H), 6.83−6.78 (m,
1H), 6.47−6.44 (m, 1H), 5.48 (s, 1H), 5.31 (s, 1H), 5.23 (s, 1H), 4.38
(brs, 1H), 4.01 (s, 3H), 3.98 (s, 3H), 3.15 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 168.9, 166.2, 164.1, 159.2, 145.3, 140.4, 134.2, 129.1,
120.4, 119.4, 117.5, 115.4, 114.3, 73.2, 55.9, 55.3, 34.1 ppm; HRMS
(ESI+) m/z calculated for C17H18N4O3Na [M + Na]+ 349.1277, found
349.1257.
KOtBu (47 mg, 0.42 mmol) was added to the solution of acetylene
18 (90 mg, 0.21 mmol) in dry DMF (5 mL), and the stirring was
continued at rt under an argon atmosphere. The reaction was found to
be completed within 15 min (TLC) and quenched with water (3 mL).
It was then extracted with EtOAc (3 × 15 mL), and the combined
organic extracts were washed with water (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Without further
purification, the resulting crude compound obtained was used directly
for the next palladium-catalyzed cyclization. To a stirred solution of
Pd(OAc)2 (2 mg, 0.01 mmol), and PPh3 (7 mg, 0.02 mmol) in dry
DMF were added 4-iodomethylbenzoate 11g (55 mg, 0.21 mmol),
K2CO3 (116 mg, 0.84 mmol), and allene 19 (0.21 mmol) sequentially
H
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The Journal of Organic Chemistry
Article
at room temperature under an argon atmosphere, and the whole
reaction mixture was allowed to stir at room temperature for 5 h. After
completion of reaction (TLC), DMF was evaporated under reduced
pressure and the resulting mixture was extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with water, dried
over Na2SO4, and concentrated in vacuo. The crude residue was
purified by silica gel (100−200 mesh) column chromatography using
17% ethyl acetate−petroleum ether (v/v) as eluent to afford the
desired product 20.
Methyl (E)-4-[1-(3-Methyl-4-oxo-1-tosyl-1,2,3,4-tetrahydro-
quinazolin-2-yl)-2-phenylvinyl]benzoate (20). Brown amorphous
solid (65.4 mg, 55% yield); mp 180−181 °C; 1H NMR (CDCl3,
600 MHz) δ 8.02 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.89 (dd, J = 7.8 Hz,
1.2 Hz, 1H), 7.53−7.50 (m, 2H), 7.36−7.34 (m, 1H), 7.23 (dd, J = 6.9
Hz, 1.5 Hz, 2H), 7.14−7.11 (m, 4H), 7.06−7.05 (m, 1H), 7.02−6.99
(m, 2H), 6.73−6.71 (m, 2H), 6.28 (d, J = 1.8 Hz, 1H), 6.27 (brs, 1H),
3.94 (s, 3H), 2.99 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3, 150 MHz)
δ 168.4, 162.9, 146.3, 143.2, 137.1, 136.0, 135.9, 135.7, 134.4, 132.1,
131.7, 131.2, 131.2, 130.9, 130.7, 129.6, 129.5, 129.3, 129.1, 128.5,
128.4, 126.8, 77.8, 53.7, 35.5, 23.2 ppm; HRMS (FAB+) m/z
calculated for C32H29N2O5S [M + H]+ 553.1797, found 553.1804.
General Procedure for Synthesis of 3-α-Styryl-3,4-dihydro-
1,2,4-benzothiadiazine-1,1-dioxide 23 (Table 3). Synthesis of
Starting Acetylene Compound 21. The acetylene was synthesized in
three steps from commercially available o-nitrobenzenesulfonyl
chloride.
Synthesis of N-Methyl-2-nitro-N-(prop-2-yn-1-yl)benzene-
sulfonamide (S3). To a stirred solution of o-nitrobenzenesulfonyl
chloride (1 g, 4.51 mmol) and Et3N (548 mg, 5.41 mmol) in dry
dichloromethene (10 mL) was added N-methylpropargylamine (468
mg, 6.77 mmol) at 0 °C, and the whole reaction mixture was allowed
to stir at room temperature for 2 h until completion (TLC). The
solvent was evaporated under reduced pressure, and the resulting
mixture was extracted with dichloromethane (3 × 20 mL). The
combined organic extract was washed with water (15 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by silica gel (100−200 mesh) column chromatography using
15% ethyl acetate−petroleum ether (v/v) as eluent to afford the
product S3 as a white solid (848 mg, 74%). The spectral data of the
product were in accordance with the reported26 data. 1H NMR
(CDCl3, 300 MHz) δ 8.05−8.02 (m, 1H), 7.73−7.69 (m, 2H), 7.65−
7.62 (m, 1H), 4.16 (d, J = 2.4 Hz, 2H), 3.01 (s, 3H), 2.21 (t, J = 2.5
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 148.2, 133.9, 131.6, 131.4,
130.8, 124.0, 76.4, 74.1, 39.6, 34.3 ppm. MS (ESI+) m/z 277.03 [M +
Na]+.
and the whole reaction mixture was allowed to stir at rt for overnight.
The solvent was evaporated under reduced pressure, and the mixture
obtained was extracted with dichloromethane. The crude residue
obtained was purified by silica gel (100−200 mesh) column
chromatography using 15% ethyl acetate−petroleum ether (v/v) as
eluent to afford 21 as a white amorphous solid (560 mg, 83%); mp
1
92−94 °C; H NMR (CDCl3, 300 MHz) δ 9.23 (s, 1H), 7.86 (d, J =
8.4 Hz, 2H), 7.76 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 7.71 (d, J = 8.1 Hz,
1H), 7.54−7.48 (m, 1H), 7.35−7.31 (m, 2H), 7.19−7.14 (m, 1H),
4.03 (d, J = 2.1 Hz, 2H), 2.88 (s, 3H), 2.45 (s, 3H), 2.19 (t, J = 2.5 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 144.5, 136.5, 136.2, 134.6, 130.3,
129.9, 127.3, 123.9, 123.3, 119.1, 75.6, 74.6, 39.6, 34.3, 21.6 ppm.
HRMS (EI+) m/z calculated for C17H18N2O4S2 [M]+ 378.0708, found
378.0711.
Generation of Allenesulphonamide 22 from Acetylene 21
and Subsequent Reactions with Iodo Compounds 11 To
Synthesize 3-(α-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine-
1,1-dioxides 23. KOtBu (35.6 mg, 0.32 mmol) was added to the
solution of acetylene 21 (60.0 mg, 0.16 mmol) in dry DMF at rt under
an argon atmosphere; the reaction was found to be complete within 2
min (TLC). The reaction was quenched with water (5 mL) and
extracted with ethyl acetate. The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. The crude product
obtained was used directly in the next step without further purification.
To a stirred solution of Pd(OAc)2 (1.8 mg, 0.008 mmol) and PPh3
(5.0 mg, 0.02 mmol) in dry DMF (5 mL) were added iodo compound
11 (0.16 mmol), K2CO3 (87.6 mg, 0.64 mmol), and crude
allenesulphonamide 22 (0.16 mmol) sequentially, and the whole
reaction mixture was heated at 60 °C for the requisite time (see Table
3) under an argon atmosphere. After completion of reaction (TLC),
DMF was evaporated under reduced pressure and the resulting residue
was extracted with EtOAc (3 × 20 mL). The combined organic
extracts were washed with water (15 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude mixture was purified by
silica gel (100−200 mesh) column chromatography using 9−40%
ethyl acetate−petroleum ether (v/v) as eluent to afford the pure
product 23.
2-Methyl-3-(1-phenylvinyl)-4-tosyl-3,4-dihydro-2H-benzo[e]-
[1,2,4]thiadiazine-1,1-dioxide (23a). White amorphous solid (48.3
mg, 67% yield); mp 154−155 °C; 1H NMR (CDCl3, 300 MHz) δ 7.77
(dd, J = 8.4 Hz, 0.9 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.50−
7.41 (m, 4H), 7.33−7.26 (m, 3H), 7.23−7.18 (m, 2H), 7.10 (d, J = 8.1
Hz, 2H), 6.60 (d, J = 1.2 Hz, 1H), 5.62 (d, J = 0.9 Hz, 1H), 5.58 (d, J
= 1.5 Hz, 1H), 2.56 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 144.9, 143.7, 137.8, 135.5, 134.5, 133.5, 129.9, 129.6, 128.7,
128.6, 128.2, 126.7, 126.0, 125.9, 125.7, 118.9, 77.3, 34.1, 21.7 ppm;
HRMS (EI+) m/z calculated for C23H22N2O4S2 [M]+ 454.1021, found
454.1016.
2-Methyl-3-[1-(pyridin-3-yl)vinyl]-4-tosyl-3,4-dihydro-2H-benzo-
[e][1,2,4]thiadiazine 1,1-dioxide (23b). White amorphous solid (44.8
mg, 62% yield); mp 162−164 °C; 1H NMR (CDCl3, 300 MHz) δ 8.71
(d, J = 1.8 Hz, 1H), 8.60−8.59 (m, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.70
(d, J = 7.8 Hz, 1H), 7.59−7.52 (m, 3H), 7.34−7.26 (m, 2H), 7.22 (d, J
= 8.1 Hz, 2H), 6.64 (s, 1H), 5.73−5.72 (m, 2H), 2.71 (s, 3H), 2.38 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 149.5, 147.8, 145.2, 140.8, 134.9,
134.3, 134.2, 133.6, 133.5, 129.6, 129.2, 128.1, 126.0, 125.9, 125.0,
123.4, 120.4, 76.9, 34.4, 21.7 ppm; HRMS (ESI+) m/z calculated for
C22H21N3O4S2Na [M + Na]+ 478.0871, found 478.0866.
2-Methyl-3-[1-(thiophen-2-yl)vinyl]-4-tosyl-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine-1,1-dioxide (23c). Yellow amorphous
solid (29.2 mg, 40% yield); mp 107−108 °C; 1H NMR (CDCl3,
600 MHz) δ 7.93 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 7.8 Hz, 1.2 Hz,
1H), 7.59−7.56 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.32−7.26 (m,
3H), 7.18 (d, J = 8.4 Hz, 2H), 7.04−7.03 (m, 1H), 6.58 (s, 1H), 5.84
(s, 1H), 5.64 (s, 1H), 2.60 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3,
150 MHz) δ 144.9, 140.1, 137.2, 135.4, 133.9, 133.6, 129.8, 129.4,
128.2, 127.6, 126.0, 125.9, 125.9, 125.5, 125.1, 116.9, 76.9, 33.4, 21.6
ppm; HRMS (EI+) m/z calculated for C21H20N2O4S3[M]+ 460.0585,
found 460.0578.
2-Amino-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (S4).
Saturated aqueous NH4Cl (1.15 g, 21.50 mmol) solution was added
to the solution of S3 (840 mg, 3.31 mmol) in MeOH (10 mL).
Thereafter, activated Zn (1.075 g, 16.53 mmol) was added to the
mixture at room temperature, and the whole reaction mixture was
stirred for 2.5 h under an argon atmosphere. After completion of the
reaction (TLC), the reaction mixture was then filtered through a
sintered funnel and the filtrate was concentrated in vacuo. The
resulting mixture obtained was diluted with 2N NaOH solution (8
mL) and extracted with EtOAc (3 × 20 mL). The combined organic
extracts were washed with water (10 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude material was purified by
silica gel (100−200 mesh) column chromatography using 15% ethyl
acetate−petroleum ether (v/v) as eluent to afford pure S4 as a yellow
1
liquid (422 mg, 57%); H NMR (CDCl3, 300 MHz) δ 7.60 (dd, J =
8.1 Hz, 1.5 Hz, 1H), 7.33−7.26 (m, 1H), 6.76 (d, J = 6.9 Hz, 1H), 6.71
(d, J = 8.1 Hz, 1H), 5.05 (brs, 1H), 4.02 (d, J = 2.7 Hz, 2H), 2.87 (s,
3H), 2.16 (t, J = 2.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 146.3,
134.3, 130.3, 118.4, 117.7, 117.2, 73.7, 73.7, 39.6, 34.3 ppm. HRMS
(ESI+) m/z calculated for C10H12N2O2SNa [M + Na]+ 247.0517,
found 247.0505.
N-Methyl-2-[(4-methylphenyl)sulfonamide]-N-(prop-2-yn-1-yl)-
benzenesulfonamide (21). To a stirred and cooled (0 °C) solution of
S4 (400 mg, 1.79 mmol) in dry dichloromethane were added pyridine
(169 mg, 2.14 mmol) and TsCl (349 mg, 1.84 mmol) sequentially,
I
DOI: 10.1021/acs.joc.6b01242
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The Journal of Organic Chemistry
Article
2-Methyl-3-[1-(p-tolyl)vinyl]-4-tosyl-3,4-dihydro-2H-benzo[e]-
[1,2,4]thiadiazine-1,1-dioxide (23d). White amorphous solid (46.8
mg, 63% yield); mp 201−202 °C; 1H NMR (CDCl3, 600 MHz) δ 7.88
(d, J = 8.4 Hz, 1H), 7.69 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 7.57−7.53 (m,
3H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.20−7.18 (m,
4H), 6.68 (s, 1H), 5.69 (s, 1H), 5.61 (d, J = 1.2 Hz, 1H), 2.63 (s, 3H),
2.38 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 144.8,
143.3, 138.4, 135.5, 134.7, 134.4, 133.4, 129.6, 129.4, 129.3, 128.1,
126.4, 125.9, 125.8, 125.5, 118.0, 77.1, 33.9, 21.6, 21.2 ppm; HRMS
(EI+) m/z calculated for C24H24N2O4S2 [M]+ 468.1177, found
468.1172.
added NaH (60% oil suspension) (28.0 mg, 0.70 mmol), and the
whole reaction mixture was allowed to stir at rt under an argon
atmosphere for 0.5 h. After complete consumption of the starting
material (TLC), the reaction was quenched with water (5 mL) and
extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated in vacuo.
The crude residue was purified by silica gel (100−200 mesh) column
chromatography using 13−80% ethyl acetate−petroleum ether (v/v)
to afford the pure product 7a.
3-Methyl-2-(1-phenylvinyl)quinazolin-4(3H)-one (7a). White
1
amorphous solid (33.1 mg, 88% yield); mp 106−108 °C; H NMR
2-Methyl-4-tosyl-3-{1-[4-(trifluoromethyl)phenyl]vinyl}-3,4-dihy-
(CDCl3, 600 MHz) δ 8.34−8.33 (m, 1H), 7.81−7.77 (m, 2H), 7.54−
7.51 (m, 1H), 7.37−7.35 (m, 5H), 6.05 (s, 1H), 5.71 (s, 1H), 3.36 (s,
3H); 13C NMR (CDCl3, 150 MHz) δ 162.4, 155.7, 147.4, 144.1,
135.9, 134.3, 129.1, 129.1, 127.6, 127.1, 126.7, 125.8, 120.8, 118.2, 32.6
ppm; HRMS (ESI+) m/z calculated for C17H15N2O [M + H]+
263.1184, found 263.1159.
dro-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide (23e). White amor-
1
phous solid (72.9 mg, 88% yield); mp 71−72 °C; H NMR (CDCl3,
300 MHz) δ 7.84 (d, J = 8.1 Hz, 1H), 7.70 (dd, J = 7.8 Hz, 1.5 Hz,
1H), 7.66−7.52 (m, 7H), 7.33−7.26 (m, 1H), 7.21 (d, J = 8.1 Hz,
2H), 6.67 (s, 1H), 5.75−5.73 (m, 2H), 2.68 (s, 3H), 2.38 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 145.1, 142.6, 141.2, 135.1, 134.2, 133.6,
130.4 (q, J = 32.0 Hz), 129.6, 129.2, 128.0, 127.0, 126.0, 125.9, 125.5
(q, J = 3.7 Hz), 125.1, 120.5, 76.9, 34.3, 21.6 ppm; HRMS (ESI+) m/z
calculated for C24H21F3N2O4S2Na [M + Na]+ 545.0792, found
545.0797.
3-Methyl-2-[1-(pyridin-3-yl)vinyl]quinazolin-4(3H)-one (7b). Yel-
1
low gum (27.8 mg, 74% yield); H NMR (CDCl3, 600 MHz) δ 8.73
(d, J = 1.8 Hz, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H),
7.81−7.77 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.56−7.53 (m, 1H),
7.32−7.30 (m, 1H), 6.13 (s, 1H), 5.83 (s, 1H), 3.39 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ 162.2, 154.5, 150.1, 147.3, 147.1, 141.2, 134.5,
133.1, 131.9, 127.6, 127.4, 126.8, 123.7, 120.8, 120.1, 32.7 ppm;
HRMS (ESI+) m/z calculated for C16H13N3ONa [M + Na]+ 286.0956,
found 286.0957.
3-[1-(4-Methoxyphenyl)vinyl]-2-methyl-4-tosyl-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine-1,1-dioxide (23f). Pale yellow solid (30.0
mg, 39% yield); mp 152−154 °C; 1H NMR (CDCl3, 300 MHz) δ 7.88
(d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H),
7.47 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 7.19 (d, J = 8.1 Hz,
2H), 6.91 (d, J = 8.7 Hz, 2H), 6.65 (s, 1H), 5.66 (s, 1H), 5.59 (s, 1H),
3.84 (s, 3H), 2.62 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ 159.8, 144.8, 142.8, 135.5, 134.3, 133.4, 133.1, 129.8, 129.4, 128.1,
127.7, 127.6, 125.9, 125.6, 117.3, 113.9, 77.2, 55.3, 33.8, 21.6 ppm;
HRMS (EI+) m/z calculated for C24H24N2O5S2 [M]+ 484.1127, found
484.1135.
Methyl 4-[1-(2-Methyl-1,1-dioxido-4-tosyl-3,4-dihydro-2H-benzo-
[e][1,2,4]thiadiazin-3-yl)vinyl]benzoate (23g). Brown crystalline
solid (42.2 mg, 52% yield); mp 142−144 °C; 1H NMR (CDCl3,
300 MHz) δ 8.04 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.68
(dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.57−7.51 (m, 5H), 7.32−7.26 (m, 1H),
7.20 (d, J = 8.1 Hz, 2H), 6.69 (s, 1H), 5.78 (s, 1H), 5.73 (d, J = 1.2
Hz, 1H), 3.94 (s, 3H), 2.66 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 166.7, 145.1, 142.9, 142.1, 135.1, 134.2, 133.6, 130.0,
129.9, 129.6, 129.4, 128.1, 126.7, 126.0, 125.9, 125.2, 120.4, 76.9, 52.2,
34.3, 21,7 ppm; HRMS (ESI+) m/z calculated for C25H24N2O6S2Na
[M + Na]+ 535.0973, found 535.0981.
3-[1-(4-Fluorophenyl)vinyl]-2-methyl-4-tosyl-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine-1,1-dioxide (23m). White amorphous
solid (47.0 mg, 63% yield); mp 172−174 °C; 1H NMR (CDCl3,
300 MHz) δ 7.85 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 7.8 Hz, 1.5 Hz,
1H), 7.57−7.46 (m, 5H), 7.32−7.26 (m, 1H), 7.19 (d, J = 8.1 Hz,
2H), 7.09−7.04 (m, 2H), 6.61 (s, 1H), 5.66−5.65 (m, 2H), 2.65 (s,
3H), 2.37 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 162.8 (d, J = 247.5
Hz), 144.9, 142.6, 135.3, 134.3, 133.7 (d, J = 3 Hz), 133.5, 129.5, 128.4
(d, J = 7.5 Hz), 128.1, 125.9 (d, J = 15 Hz), 125.4, 118.9, 115.6, 115.4,
77.2, 33.9, 21.6 ppm (one carbon signal has probably merged with
other aromatic carbon signals); HRMS (ESI+) m/z calculated for
C23H21FN2O4S2Na [M + Na]+ 495.0825, found 495.0832.
3-[1-(4-Bromophenyl)vinyl]-2-methyl-4-tosyl-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine-1,1-dioxide (23n). White amorphous solid
(51.5 mg, 61% yield); mp 206−208 °C; 1H NMR (CDCl3, 300 MHz)
δ 7.84 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.6 Hz, 1.0 Hz, 1H),7.56−7.49
(m, 4H), 7.37 (d, J = 8.4 Hz, 2H), 7.32−7.26 (m, 2H), 7.19 (d, J = 8.1
Hz, 2H), 6.61 (s, 1H), 5.69−5.66 (m, 2H), 2.65 (s, 3H), 2.37 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 145.2, 142.9, 136.8, 135.4, 134.5,
3-Methyl-2-[1-(thiophen-2-yl)vinyl]quinazolin-4(3H)-one (7c).
1
Brown gum (33.0 mg, 87% yield); H NMR (CDCl3, 600 MHz) δ
8.34 (d, J = 8.4 Hz, 1H), 7.79−7.77 (m, 2H), 7.55−7.52 (m, 1H), 7.30
(d, J = 5.4 Hz, 1H), 6.98−6.96 (m, 1H), 6.82 (d, J = 3.0 Hz, 1H), 5.95
(s, 1H), 5.51 (s, 1H), 3.51 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
162.3, 154.6, 147.3, 140.1, 137.9, 134.4, 127.9, 127.7, 127.3, 126.7,
126.5, 126.3, 120.9, 116.2, 32.7 ppm; HRMS (ESI+) m/z calculated for
C15H13N2OS [M + H]+ 269.0749, found 269.0734.
3-Methyl-2-[1-(p-tolyl)vinyl]quinazolin-4(3H)-one (7d). Pale yel-
low crystalline solid (29.9 mg, 78% yield); mp 124−126 °C; 1H NMR
(CDCl3, 600 MHz) δ 8.33 (d, J = 7.8 Hz, 1H), 7.80−7.77 (m, 2H),
7.54−7.51 (m, 1H), 7.26−7.24 (m, 2H), 7.16 (d, J = 7.8 Hz, 2H), 5.99
(s, 1H), 5.65 (s, 1H), 3.36 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3,
150 MHz) δ 162.4, 155.9, 147.4, 143.9, 139.1, 134.3, 133.1, 129.8,
127.6, 127.1, 126.7, 125.7, 120.8, 117.2, 32.6, 21.2 ppm; HRMS (ESI+)
m/z calculated for C18H16N2ONa [M + Na]+ 299.1160, found
299.1161.
3-Methyl-2-{1-[4-(trifluoromethyl)phenyl]vinyl}quinazolin-4(3H)-
one (7e). Pale yellow amorphous solid (21.0 mg, 52% yield); mp 184−
1
186 °C; H NMR (CDCl3, 300 MHz) δ 8.35 (d, J = 7.8 Hz, 1H),
7.81−7.80 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.58−7.49 (m, 3H), 6.15
(s, 1H), 5.85 (s, 1H), 3.37 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
162.2, 154.8, 147.2, 142.9, 139.4, 134.5, 131.0 (q, J = 32.5 Hz), 127.6,
127.4, 126.8, 126.2, 126.2−126.1 (m), 123.8 (q, J = 270.5 Hz), 120.8,
120.5, 32.6 ppm; HRMS (ESI+) m/z calculated for C18H14F3N2O [M
+ H]+ 331.1058, found 331.1054.
2-[1-(4-Methoxyphenyl)vinyl]-3-methylquinazolin-4(3H)-one (7f).
1
Yellow amorphous solid (33.2 mg, 85% yield); mp 156−157 °C; H
NMR (CDCl3, 600 MHz) δ 8.33 (d, J = 7.8 Hz, 1H), 7.80−7.78 (m,
2H), 7.54−7.51 (m, 1H), 7.30−7.28 (m, 2H), 6.89−6.87 (m, 2H),
5.93 (s, 1H), 5.58 (s, 1H), 3.81 (s, 3H), 3.38 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ 162.4, 160.2, 155.9, 147.4, 143.5, 134.3, 128.5,
127.6, 127.2, 127.1, 126.7, 120.8, 116.1, 114.4, 55.3, 32.6 ppm; HRMS
(ESI+) m/z calculated for C18H16N2O2Na [M + Na]+ 315.1109, found
315.1137.
Typical Procedure for the Synthesis of 2-Methyl-3-(1-
phenylvinyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide (8a).
To a well-stirred solution of 1,2,4-benzothiadiazine-1,1-dioxides 23a
(60.0 mg, 0.13 mmol) in dry DMF (5.0 mL) was added NaH (60% oil
suspension) (10.4 mg, 0.26 mmol), and the whole reaction mixture
was allowed to stir at rt for 1 h under an argon atmosphere. On
complete conversion of starting material (TLC), the reaction was
quenched with water (5 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic extracts were dried over anhydrous Na2SO4
133.6, 131.9, 129.8, 129.7, 128.5, 128.3, 126.1, 126.0, 125.5, 122.8,
119.5, 77.4, 34.2, 21.8 ppm; HRMS (ESI+) m/z calculated for
C23H21BrN2O4S2Na [M + Na]+ 555.0024, found 555.0026.
Synthesis of 2-(α-Styryl)-quinazolinones 7 and 3-(α-Styryl)-
1,2,4-benzothiadiazine-1,1-dioxide 8 (Scheme 4). Typical
Procedure for the Synthesis of 3-Methyl-2-(1-phenylvinyl)-
quinazolin-4(3H)-one (7a). To a well-stirred solution of dihydro-
quinazolinone 9aa (60.0 mg, 0.14 mmol) in dry DMF (2 mL) was
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Article
and concentrated in vacuo. The resulting crude residue was purified by
silica gel (100−200 mesh) column chromatography using 10−50%
ethyl acetate−petroleum ether (v/v) to afford the pure product 8a.
2-Methyl-3-(1-phenylvinyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-di-
oxide (8a). White amorphous solid, mp 116−118 °C; (22.3 mg, 57%
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 149.3, 147.9, 145.3, 141.0,
135.3, 134.5, 133.7, 133.3, 130.5, 130.0, 129.8, 129.6, 129.4, 128.5,
128.3, 127.6, 127.3, 126.2, 126.1, 125.3, 120.7, 77.4, 34.5, 21.8 ppm;
HRMS (ESI+) m/z calculated for C26H23N3O4S2Na [M + Na]+
528.1028, found 528.1029.
1
yield); H NMR (CDCl3, 300 MHz) δ 7.91 (dd, J = 7.9 Hz, 1.0 Hz,
3-Benzyl-2-[1-(quinolin-3-yl)vinyl]-1-tosyl-2,3-dihydroquinazolin-
4(1H)-one (27c). To a solution of Pd(OAc)2 (2.6 mg, 0.01 mmol) and
PPh3 (7.2 mg, 0.03 mmol) in dry DMF (5 mL) were added 3-
iodoquinoline 2627 (58.5 mg, 0.23 mmol), K2CO3 (126.8 mg, 0.92
mmol), and allene 25 (96 mg, 0.23 mmol) sequentially. The whole
reaction mixture was allowed to stir at rt under an argon atmosphere,
and the reaction completed after 1 h (TLC). DMF was removed under
reduced pressure, and the mixture was extracted with EtOAc (3 × 15
mL). The combined organic extracts were washed with water (10 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
residue was then purified by silica gel (100−200 mesh) column
chromatography using 25% ethyl acetate−petroleum ether (v/v) as
eluent to afford the product 27c as a white amorphous solid (75.1 mg,
60% yield); mp 103−105 °C; 1H NMR (CDCl3, 300 MHz) δ 8.70 (d,
J = 2.1 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H),
7.96−7.90 (m, 2H), 7.75 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H),
7.49−7.43 (m, 7H), 7.37−7.32 (m, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.81
(d, J = 8.1 Hz, 2H), 6.72 (s, 1H), 5.45 (s, 1H), 5.06 (s, 1H), 5.01 (d, J
= 13.8 Hz, 1H), 4.22 (d, J = 13.8 Hz, 1H), 2.27 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 161.4, 149.2, 147.5, 144.3, 139.6, 135.4, 135.0,
133.6, 133.5, 133.0, 130.2, 130.2, 129.8, 129.4, 129.0, 128.9, 128.5,
128.3, 128.0, 127.3, 127.3, 127.0, 125.9, 125.3, 119.5, 71.3, 49.9, 21.5
ppm; HRMS (ESI+) m/z calculated for C33H28N3O3S [M + H]+
546.1851, found 546.1847.
3-Methyl-2-[1-(quinolin-3-yl)vinyl]quinazolin-4(3H)-one (28a).
To a stirred solution of 27a (101.4 mg, 0.22 mmol) in dry DMF
was added NaH (60% oil suspension) (43.2 mg, 1.08 mmol), and the
whole reaction mixture was allowed to stir at rt under an argon
atmosphere for 1 h. Upon consumption of the starting material
(TLC), the reaction was quenched with water (5 mL) and extracted
with EtOAc (3 × 15 mL). The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. The crude product
was purified by silica gel (100−200 mesh) column chromatography
using 55% ethyl acetate−petroleum ether (v/v) as eluent to afford
product 28a as a yellow amorphous solid (36.0 mg, 53% yield);
(overall yield 39% after 3 steps); mp 180−182 °C; 1H NMR (CDCl3,
300 MHz) δ 9.15 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.13
(d, J = 8.7 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 3.6 Hz, 2H),
7.77−7.70 (m, 1H), 7.58−7.53 (m, 2H), 7.49−7.46 (m, 1H), 6.29 (s,
1H), 5.91 (s, 1H), 3.42 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
162.5, 154.9, 148.0, 147.4, 141.6, 134.7, 132.9, 132.2, 130.5, 129.5,
128.7, 128.6, 128.4, 127.9, 127.7, 127.6, 127.0, 121.1, 120.3, 32.9 ppm;
HRMS (ESI+) m/z calculated for C20H15N3ONa [M + Na]+ 336.1113,
found 336.1117.
2-Methyl-3-[1-(quinolin-3-yl)vinyl]-2H-benzo[e][1,2,4]thia-
diazine-1,1-dioxide (28b). Product 28b was synthesized adopting
the procedure of 28a; the only difference was that 2.0 equiv of NaH
(60% oil suspension) was used in this case instead of 5.0 equiv and the
reaction time was 1.5 h. Product 28b was eluted using 40% ethyl
acetate−petroleum ether (v/v) as a yellow gum (17.5 mg, 38% yield);
(overall yield 19% after 3 steps); 1H NMR (CDCl3, 300 MHz) δ 9.16
(s, 1H), 8.26−8.14 (m, 2H), 7.85−7.54 (m, 3H), 7.25−7.20 (m, 1H),
6.91−6.82 (m, 3H), 6.26 (s, 1H), 6.13 (s, 1H), 3.15 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 155.9, 148.2, 147.9, 142.6, 141.1, 134.1, 133.8,
130.7, 129.8, 129.1, 128.8, 128.5, 127.9, 127.8, 123.2, 121.4, 120.7,
115.5, 32.3 ppm; HRMS (ESI+) m/z calculated for C19H15N3O2SNa
[M + Na]+ 372.0783, found 372.0785.
3-Benzyl-2-[1-(quinolin-3-yl)vinyl]quinazolin-4(3H)-one (28c).
Product 28c was prepared adopting the procedure of 28a, and the
reaction time was 2 h. Product 28c was eluted using 45% ethyl
acetate−petroleum ether (v/v) as a yellow gum (33.2 mg, 62% yield);
(overall yield 36% after 3 steps); 1H NMR (CDCl3, 300 MHz) δ 9.06
(d, J = 2.1 Hz, 1H), 8.43−841 (m, 1H), 8.09 (d, J = 8.4 Hz, 1H),
7.86−7.80 (m, 3H), 7.74−7.68 (m, 1H), 7.66−7.57 (m, 2H), 7.54−
7.49 (m, 1H), 7.14−7.09 (m, 2H), 7.05−7.01 (m, 3H), 6.14 (s, 1H),
1H), 7.74−7.65 (m, 2H), 7.53−7.48 (m, 3H), 7.46−7.39 (m, 3H),
6.02 (s, 1H), 5.93 (s, 1H), 3.11 (s, 3H); 13C NMR (CDCl3, 150 MHz)
δ 155.6, 143.9, 142.7, 135.6, 133.5, 129.2, 129.1, 128.2, 127.3, 126.9,
126.4, 121.3, 121.1, 31.7 ppm; HRMS (ESI+) m/z calculated for
C16H15N2O2S [M + H]+ 299.0854, found 299.0848.
2-Methyl-3-[1-(pyridin-3-yl)vinyl]-2H-benzo[e][1,2,4]thiadiazine-
1,1-dioxide (8b). Yellow gum (19.7 mg, 50% yield); 1H NMR
(CDCl3, 600 MHz) δ 8.85 (d, J = 1.8 Hz, 1H), 8.65 (dd, J = 4.8 Hz,
1.2 Hz, 1H), 7.92 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 7.81 (dt, J = 7.8 Hz, 2.1
Hz, 1H), 7.74−7.72 (m, 1H), 7.65 (dd, J = 8.1 Hz, 0.9 Hz, 1H), 7.55−
7.52 (m, 1H), 7.38 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 6.11 (s, 1H), 6.07 (s,
1H), 3.13 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 154.5, 150.1,
147.6, 142.4, 141.0, 133.9, 133.6, 128.3, 127.7, 127.2, 123.8, 123.3,
121.2, 32.2 ppm (one carbon merged with other aromatic carbons);
HRMS (ESI+) m/z calculated for C15H14N3O2S [M + H]+ 300.0807,
found 300.0800.
Synthesis of Luotonin F Analogues 28 (Scheme 5). Synthesis
of N-Benzyl-2-[(4-methylphenyl)sulfonamide]-N-(propa-1,2-dien-1-
yl)benzamide (25). Precursor acetylene 24 (100.0 mg, 0.24 mmol)
synthesized by reported procedure20a was treated with KOtBu (80.5
mg, 0.72 mmol) in dry DMF (4 mL), and the whole reaction mixture
was stirred at rt under an argon atmosphere for 2 h. After completion
of the reaction (TLC), it was extracted with EtOAc (3 × 15 mL). The
combined organic extracts were washed with water (10 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude residue
was purified by silica gel (100−200 mesh) column chromatography
using 15% ethyl acetate−petroleum ether (v/v) as eluent.
N-Benzyl-2-[(4-methylphenyl)sulfonamide]-N-(propa-1,2-dien-1-
yl)benzamide (25). Yellow gum (96 mg, 96%); 1H NMR (CDCl3, 300
MHz) δ 8.39 (brs, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.39−7.26 (m, 9H),
7.15−7.11 (m, 1H), 6.89−6.85 (m, 2H), 5.77 (brs, 1H), 5.34−5.32
(m, 2H), 4.69 (brs, 2H), 2.23 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
200.1, 167.4, 143.8, 136.5, 131.7, 129.5, 129.2, 128.9, 128.5, 127.7,
126.9, 125.8, 125.2, 124.5, 101.8, 87.8, 77.2, 47.9, 21.4 ppm. HRMS
(ESI+) m/z calculated for C24H22N2O3SNa [M + Na]+ 441.1249,
found 441.1235.
3-Methyl-2-[1-(quinolin-3-yl)vinyl]-1-tosyl-2,3-dihydro-
quinazolin-4(1H)-one (27a). Intermediate 27a was synthesized from
13 (85 mg, 0.25 mmol) adopting the general procedure of the
synthesis of product 9 (Table 2) described earlier. The reaction time
was 1 h. The crude product was purified by silica gel (100−200 mesh)
column chromatography using 30% ethyl acetate−petroleum ether (v/
v) as eluent as a brown amorphous solid (100.2 mg, 86% yield); mp
174−176 °C; 1H NMR (CDCl3, 300 MHz) δ 8.88 (d, J = 2.1 Hz, 1H),
8.41 (brs, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.96−7.88 (m, 2H), 7.78 (t, J
= 7.3 Hz, 1H), 7.69−7.63 (m, 1H), 7.52−7.47 (m, 1H), 7.40−7.35 (m,
2H), 7.27−7.25 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 5.59
(s, 1H), 5.12 (s, 1H), 2.98 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 161.3, 148.8, 146.8, 145.0, 139.4, 135.1, 134.4, 133.7,
132.9, 130.3, 130.1, 129.7, 128.7, 128.5, 128.4, 127.8, 127.7, 127.5,
127.4, 127.0, 125.4, 119.3, 73.6, 33.9, 21.6 ppm; HRMS (ESI+) m/z
calculated for C27H23N3O3SNa [M + Na]+ 492.1358, found 492.1353.
2-Methyl-3-[1-(quinolin-3-yl)vinyl]-4-tosyl-3,4-dihydro-2H-benzo-
[e][1,2,4]thiadiazine-1,1-dioxide (27b). Intermediate 27b was
synthesized from 21 adopting the general procedure of product 23
(Table 3) described earlier. The reaction time was 1.5 h. The crude
product was purified by silica gel (100−200 mesh) column
chromatography using 35% ethyl acetate−petroleum ether (v/v) as
eluent as a white amorphous solid (66.8 mg, 50% yield); mp 184−186
°C; 1H NMR (CDCl3, 300 MHz) δ 9.02 (d, J = 2.4 Hz, 1H), 8.27 (d, J
= 2.1 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.89−7.83 (m, 2H), 7.77−
7.70 (m, 2H), 7.62−7.58 (m, 3H), 7.56−7.50 (m, 1H), 7.30 (td, J =
7.7 Hz, 1.0 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 1.2 Hz, 1H),
5.89 (d, J = 0.9 Hz, 1H), 5.83 (d, J = 1.5 Hz, 1H), 2.73 (s, 3H), 2.38
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5.61 (s, 1H), 5.20 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 162.5,
154.8, 147.7, 147.3, 140.6, 136.2, 134.9, 133.2, 130.4, 129.7, 129.2,
128.9, 128.6, 128.3, 127.9, 127.8, 127.5, 127.4, 126.7, 121.2, 120.8,
120.3, 115.6, 48.3 ppm; HRMS (ESI+) m/z calculated for C26H20N3O
[M + H]+ 390.1606, found 390.1602.
(8) (a) Mannhold, R. Med. Res. Rev. 2004, 24, 213. (b) de Tullio, P.;
Becker, B.; Boverie, S.; Dabrowski, M.; Wahl, P.; Antoine, M.-H.;
Somers, F.; Sebille, S.; Ouedraogo, R.; Hansen, J. B.; Lebrun, P.;
Pirotte, B. J. Med. Chem. 2003, 46, 3342. (c) Alemzadeh, R.; Langley,
G.; Upchurch, L.; Smith, P.; Slonim, A. E. J. Clin. Endocrinol. Metab.
1998, 83, 1911.
(9) For the synthesis of 1a, see a review: (a) Rohokale, R. S.;
Kshirsagar, U. A. Synthesis 2016, 48, 1253. (b) Connolly, D. J.; Cusack,
D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153. For
selected recent examples, see: (c) Yan, Y.; Xu, Y.; Niu, B.; Xie, H.; Liu,
Y. J. Org. Chem. 2015, 80, 5581. (d) Mohammed, S.; Vishwakarma, R.
A.; Bharate, S. B. J. Org. Chem. 2015, 80, 6915. (e) Cheng, R.; Guo, T.;
Zhang-Negrerie, D.; Du, Y.; Zhao, K. Synthesis 2013, 45, 2998.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01242.
Experimental procedures, copies of NMR (1H and 13C),
HRMS of representative compounds, 2D NMR data of
compound 20, and tables of crystal data of compounds
9aa, 9bd, 23g, and 7d (PDF)
X-ray crystallographic data for compounds 7d, 9aa, 9bd,
and 23g (ZIP)
́ ́
(f) Rocchi, D.; Gonzalez, J. F.; Menendez, J. C. Green Chem. 2013, 15,
511. (g) Farzipour, S.; Saeedi, M.; Mahdavi, M.; Yavari, H.;
Mirzahekmati, M.; Ghaemi, N.; Foroumadi, A.; Shafiee, A. Synth.
Commun. 2014, 44, 481. (h) Mhaske, S. B.; Argade, N. P. J. Org. Chem.
2004, 69, 4563.
(10) For the synthesis of 1b, see selected examples: (a) Majumdar, K.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chinmay@iicb.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.K. thanks UGC, New Delhi, India, and A.M. thanks CSIR,
New Delhi, India, for a fellowship. Financial support from the
CSIR network project (CSC 0108) is gratefully acknowledged.
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