In situ mechanochemical synthesis of nitrones followed by 1,3-dipolar cycloaddition: A catalyst-free, "green" route to cis-fused chromano[4,3-c]isoxazoles

Article abstract of DOI:10.1039/c5ra21044e

An efficient and catalyst-free method for the synthesis of cis-fused chromano[4,3-c]isoxazoles via intramolecular 1,3-dipolar nitrone cycloaddition involving hand-grinding in a mortar-pestle has been developed. The mechanochemical agitation was sufficient

Full text of DOI:10.1039/c5ra21044e

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ARTICLE
In-situ mechanochemical synthesis of nitrones followed by 1,3-
dipolar cycloaddition: a catalyst-free, “green” route to cis-fused
chromano[4,3-c]isoxazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Zigmee T. Bhutia,a Geethika P.,a Anurag Malik,a Vikash Kumar,a Amrita Chatterjee,*a Biswajit
Gopal Royb and Mainak Banerjee*a
DOI: 10.1039/x0xx00000x
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An efficient and catalyst-free method for the synthesis of cis-fused chromano[4,3-c]isoxazoles via intramolecular 1,3-
dipolar nitrone cycloaddition involving hand-grinding in a mortar–pestle has been developed. The mechanochemical
agitation was sufficient for dehydrative nitrone formation by condensation of various O-allyl salicylaldehyde derivatives
and alkyl / aryl hydroxylamines. The corresponding nitrones undergo intramolecular 1,3-dipolar cycloaddition leading to
regioselective formation of cis-fused tetrahydrochromeno[4,3-c]isoxazole derivatives in high yields. The key features of
this new method are cleaner reaction profiles, catalyst-free condition, high yields, and short reaction times.
26 the presence of a catalyst.6a–c,7 Although few eco-friendly
27 methods for chromano-isoxazoles are available,8 such a
28 method can be turned more economical by avoiding use of
1
Introduction
2
3
4
5
6
7
8
9
Isoxazolidines,1 an important class of nitrogen containing
five-membered heterocycles, is ubiquitous structural motif
of a wide spectrum of organic molecules of both natural
origin and synthetic background, many of which are
29 catalysts, additional reagents and solvents.
30 Use of toxic chemicals and solvents for chemical
31 transformations is a serious environmental concern for last
32 few decades. At present, most of the chemical processes at
33 an industrial scale use toxic organic solvents for various
34 transformations which account for 80–90% of the waste
pharmaceutically
important.2
1,3-Dipolar
nitrone
cycloaddition is the most facile way for the construction of
these heterocycles as documented by different research
groups.3 In particular, intramolecular nitrone-olefin
35 generated in
a typical pharmaceutical/fine chemical
36 operational process.9 To counter this growing
37 environmental problem, significant research efforts have
38 been focused on solvent-free reactions,10 which are often
39 associated with several other advantages such as faster
40 reaction rates, lower energy consumption and easy
41 separation giving rise to products in higher yields and with
42 higher purities. One common technique employed in
43 solvent-free reactions is mechanical grinding,11 which has
44 gradually become a powerful tool in the paradigm of
45 synthetic organic chemistry.12 In a typical mechanochemical
46 process, reactions are initiated and progressed under
47 frictional force provided either by grinding in a mortar-
10 cycloadditions are often employed to achieve structurally
11 more complex bi- or tri-cyclic isoxazolidines of biological
12 significance and also to synthesize key intermediates of
13 several natural products.4 Notably, fused isoxazoles /
14 isoxazolidines with chromano moiety are known to possess
15 biomedical properties (Fig. 1) such as antidepressant,
16 antipsychotic and antianxiolytic activities.5 Due to the labile
17 nature of N-O bond chromanoisoxazoles are used as
18 synthetic
precursors
for
the
construction
of
19 pharmaceutically important amino alcohols.6 Surprisingly,
20 however, not many methods are available for the
21 construction of these pharmacologically important
22 heterocyclic systems.6a–c,7,8 Moreover, most of the existing
23 methods are based on conventional synthetic protocols
24 that use hazardous reagents, toxic solvents and / or
25 relatively harsh reaction conditions and are facilitated by
48 pestle or by milling in
a
ball-mill. Recently,
49 mechanosynthesis by “ball milling” has emerged as
50 effective technique for various organic transformations13,14
51 including aldol condensation,14a,b Michael additions,15c,d
52 Knoevenagel
condensation,14e
Morita–Baylis–Hillman
53 reactions,14f cross-coupling reactions,14h-k click reactions14l,m
54 etc. On the other hand, manual grinding15 with a mortar
55 and pestle is mostly limited to condensation reactions16
56 including Schiff’s base formation,16a-c oxime formation,16d
57 Knoevenagel condensation,16e with occasional exceptions.17
58 However, this a very useful method at laboratory scale due
59 to simple and hazardless experimental set-up and is found
aDepartment of Chemistry, Birla Institute of Technology and Science, Pilani- K. K.
Birla, Goa Camps, Goa- 403 726, India.Fax: +91-832-255-7031; Tel.: +91-832-
2580-347 (M.B.), +91-832-2580-320 (A.C.); Email: mainak@goa.bits-pilani.ac.in
(M.B.); amrita@goa.bits-pilani.ac.in (A.C.).
bDepartment of Chemistry, Sikkim University, 6th Mile, Tadong, Gangtok, Sikkim-
737102, India
†Electronic Supplementary Information (ESI) available: Spectral data, IR studies,
selected spectra of compounds, etc. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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2
3
4
5
6
7
8
9
to be equally effective for the construction of heterocyclic
compounds of biological interest in last few years.18 In this
purview, we envisaged, development of an environment
friendly and a catalyst-free mechanochemical route to
chromano-isoxazoles is a worthy pursuit. As per our current
research focus of exploring the scope of hand-grinding
techniques for organic transformation,18b herein, we report
a one-pot process for nitrone formation followed by its
intarmolecular cycloaddition to afford a variety of cis-fused
34 Table 1. Optimization of the reaction condition for chromano[4,3-c]isoxazoles
Ph
Ph
O
O
N
N
O
CHO
ꢀ
grinding
rt
+
PhNHOH
O
O
1a
2a
3a
4a
Entry
1
Solvent
Neat
Temp
Time (h)a
(%) 3ab
(%) 4ab
10 tetrahydrochromeno [4,3-c] isoxazole derivatives in high
(°C)
Rt
11 yields.
0.25
2
100
70
Nil
20
86
84
Nil
26
Nil
18
Nil
25
12
13
O
12
Nil
HN
MeO
MeO
60
Rt
1.5
0.25
2
Nil
N
O
2
3
4
CHCl3
EtOH
100
57
NH
O
N
O
Rt
Rt
0.17
2
100
70
Antipsychotic and anxiolytic
activity
α2-Adrenoceptor antagonists
CH3CN
0.34
2
100
64
MeO
N
O
MeO
N
35 aReactions were ground for 10-120 min followed by heating, bRatio of
36 and 4
was obtained from 1H NMR of reaction mixture.
3
N
O
Serotonin inhibitors
14
37
15 Fig. 1. Chemical structures of few bioactive chromano[4,3-c]isoxazoles.
38 TLC after every 5 min. It was observed that grinding for 15
39 min in neat condition is sufficient for complete conversion
40 of aldehyde (1a) and hydroxylamine (2a) to corresponding
41 nitrone (3a). It is noteworthy to mention that rate of the
42 reaction is dependent on the force applied for grinding the
43 reaction mixture. As a matter of fact, fast and relentless
44 grinding of the same reaction led to nitrone (3a) formation
45 with about two third reduction in the reaction time (10
46 min). Since the nitrone formation is relatively fast even by
47 gentle grinding the remaining reactions were carried out by
48 gentle grinding only. However, intramolecular cycloaddition
49 of nitrone to obtain chromano isooxazoles was bit slower.
50 Only 20% of product (4a) was obtained even after 2 h of
51 grinding of the intermediate nitrone (Table 1, entry 1).
52 Cycloaddition was complete only after standing the mixture
53 for 12 h at room temperature with intermittent grinding
54 (Table 1, entry 1). However, gentle heating of the reaction
55 mixture at 60 °C was helpful in almost 10 fold reduction of
56 the reaction time. On the other hand, LAG effect was
57 studied using three polar solvents viz. chloroform, ethanol
58 and acetonitrile (0.5 mL per 1 mmol of substrate) in which
59 all the starting materials, intermediates and products are
60 freely soluble. Although nitrone formation was as fast as
61 the neat reaction, there was practically no difference in the
62 rate of conversion of nitrone (3a) into the chromano-
63 isooxazole (4a) in each case of LAG. In addition, solvent got
64 evaporated after sometimes and time to time addition of
65 solvent (0.5 mL per 1 mmol of substrate each time) was
66 required to continue LAG. Therefore, “neat grinding” was
16 Results and discussion
17
R5
O
N
O
R1
CHO
O
R4
R1
grinding
rt
R4
+ R5NHOH
R3
R3
R2
R2
2a,b
1a-t
R5
3a-z
O
N
9b
R4
H
R1
3a
R3
H
*
60 ο
C
*
R1 = H, CH3, OMe, F, Cl, Br, NO2 or CN; R2 = OMe;
R3 = R4 = H or CH3; R5 = Ph or CH3.
O
R2
4a-z
19 Scheme 1. Mechanochemical route to cis-fused chromano[4,3-c]isoxazoles.
18
20
At first, we focused our attention on optimizing the
21 reaction conditions. Thus, a model reaction was conducted
22 between equimolar mixture of O-allyl salicylaldehyde (1a
)
23 and phenylhydroxylamine (2a) in an Agate mortar by
24 manual grinding at room temperature to examine whether
25 grinding under neat condition is useful or liquid assisted
26 grinding (LAG)19 is more effective. The first reaction was
27 conducted in neat condition. The reaction produced a
28 viscous liquid after 5 min of gentle grinding. Although out of
29 the two reactants N-phenylhydroxylamine is solid (m.p. 79-
30 80 °C) the reaction mixture forms a melt phase presumably
31 because of the transient heat generated during frictional
32 force. The formation of nitrone was monitored by taking
33
67 preferred
over
LAG
for
the
synthesis
of
68 tetrahydrochromeno[4,3-c]isoxazole derivatives unless all
69 the reactants are solid; in such cases, little amount of EtOH
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2
3
4
5
6
7
8
9
or 50% EtOH-H2O was used to form a paste which was
ground further. It is noteworthy to mention that the
reaction undergoes spontaneously without addition of any
catalyst or additive making this a highly atom-efficient
method for the synthesis of cis-fused chromano
isooxazoles. In a separate study, the necessity of grinding
58 Na2CO3 making release of N-methylhydroxylamine easy.
59 The products derived from N-methylhydroxylamine (2b
)
60 were taken in ethyl acetate and washed with water to
61 remove sodium carbonate if any and then purified either by
62 crystallization or by column chromatography. All the
1
63 chromano[4,3-c]isoxazoles were characterized by H NMR,
for smooth formation of intermediate nitrone (
3) was
64 13C NMR, ESI-MS and CHN analysis. The spectra of known
65 compounds were in well agreement with the reported
66 values.7b,c,8b Notably, Jadav et al.7b and we8b separately
67 demonstrated that 1,3-dipolar cycloaddition of nitrones
68 derived from O-allyl salicylaldehyde derivatives preferably
69 form chromano[4,3-c]isoxazoles with cis-stereochemistry at
70 the junction of six- and five-membered rings. The expected
71 cis stereochemistry was verified by comparing the coupling
established by carrying out the same reaction in
conventional ways (see ESI for details). It was observed that
10 nitrone formation is very sluggish in solution phase. At the
11 same time, just mixing the reactants under neat condition
12 without “grinding” is also not very effective. The nitrone
13 formation was not complete even after 48 h. The formation
14 of intermediate nitrone (3a) and the cyclized product (4a
)
15 was monitored by recording IR spectra of the reaction
16 mixture at regular interval (see ESI for details). It was
17 observed that the characteristic stretching bands of starting
18 materials like carbonyl of aromatic aldehyde at 1682 cm-1
19 and phenylhydroxylamine O-H and N-H bands at 3240 cm-1
20 and 3118 cm-1 almost disappeared after 10 min of hand
21 grinding and a new peak at 1545 cm-1 (presumably, C=N
22 stretching band of intermediate nitrone) appeared in the IR
23 spectrum. The same band significantly diminished after
24 gentle heating of the reaction mixture for 1.5 h indicating
25 conversion of intermediate nitrone to chromano
26 isooxazoles.
72 constant (JH3a-H9b) of ring junction protons of the
73 compounds synthesized using the current method with
74 chromano[4,3-c]isoxazoles that are previously reported by
75 our group.8b A relatively small coupling constant (see Table
76 S2 of ESI) between ring junction protons of all the
77 chromano isoxazoles clearly indicate that the five- and six-
78 membered rings adopt a cis-fused twisted structure.7b,8b
79 In general, the method worked well with both aliphatic and
80 aromatic hydroxylamines and had been applied to a variety
81 of O-allyl salicylaldehydes with same efficacy. Noticeably,
82 substituents in the aromatic ring of the O-allyl
83 salicylaldehyde derivatives did not pose any significant
84 effect on the yield of chromano[4,3-c]isoxazoles. However,
85 yields of chromano[4,3-c]isoxazoles derived from N-
86 methylhydroxylamine (2b) (Table 2, entry 7, 19, 23 etc.)
27
28 To test the generality of this method, the phenolic –OH
29 group of several salicylaldehyde derivatives were first
30 alkylated with allyl group or prenyl group adopting reported
31 procedure.20 Next, a series of O-allyl/prenyl derivatives of
87 were slightly less than that of N-phenylhydroxylamine (2a
)
88 (Table 2, entry 5, 17, 21 etc.). It was also observed that the
89 nitrone formation for a particular O-allyl salicylaldehyde
32 salicylaldehyde
(1a-t) were ground with N-substituted
33 hydroxylamines (2a,b) in an Agate mortar and pestle for
34 several minutes to afford corresponding nitrones (Table 2).
35 Once nitrone formation was complete (as revealed by TLC),
36 the reaction mixture was heated on a sand bath at 60 °C for
37 several hours to afford racemic cis-fused 1-aryl-1,3a,4,9b-
90 derivative was little faster with N-phenylhydroxylamine (2a)
91 (Table 2, entry 1, 2, 5, 18 etc.) as compared to N-
92 methylhydroxylamine (2b) (Table 2, entry 3, 4, 7, 19 etc.).
93 Moreover, the intramolecular cycloaddition was generally
94 faster for nitrones derived from N-phenylhydroxylamine
38 tetrahydro-3H-chromano[4,3-c]isoxazoles
(
4a-z,aa
)
in
95
(2a) (Table 2, entry 1, 5, 20, 21 etc.) than that of N-
39 excellent yields via in situ intramolecular cycloaddition in a
40 stereoselective manner (Table 2). It is worthy to mention
96 methylhydroxylamine (2b) (Table 2, entry 3, 7, 19 etc.).
97 Presumably, the electron donation ability of the methyl
98 group makes the 1,3-dipolarophile less reactive, whereas,
99 phenyl group acts as an electron pulling unit to make
100 nitrone more reactive. Again, doubly substituted allyl
101 moiety (i.e. prenyl group) although did not influence the
41 that all the intermediate nitrones (
3) underwent complete
42 conversion into chromano[4,3-c]isoxazoles (
4) and the
43 crude products were found to be sufficiently pure. Most of
44 the crude products were purified by recrystallization from a
45 mixture of ethyl acetate and petroleum ether. Only few of
46 the final products, which were obtained as viscous liquid,
47 were purified by passing them through a short bed of silica
48 gel. It is noteworthy to mention that N-
102 yield of
4 but slowed down the reaction due to steric
103 reason (Table 2, entry 2, 4, 6, 18 etc.).
104
49 methylhydroxylamine
(
2b
)
was
generated
from
105 Conclusion
50 corresponding hydrochloride salt in situ by addition of
51 sodium carbonate to the reaction mixture. For these
52 reactions few drops of 50% EtOH-water was added at the
53 beginning and the resulting paste was ground thoroughly
54 with portionwise addition of Na2CO3. It was observed that
55 the nitrone formation was much faster in the presence of
56 little amount of solvent than at neat condition. Most likely,
57 EtOH-water mixture dissolves a part of CH3NHOH.HCl and
106
107 In conclusion, we have developed a catalyst-free method
108 for the synthesis of cis-fused chromano[4,3-c]isoxazoles via
109 intramolecular 1,3-dipolar nitrone cycloaddition reaction
110 involving hand-grinding in mortar-pestle. A series of O-allyl
111 salicylaldehyde derivatives were successfully condensed
112 with alkyl / aryl hydroxylamines to produce corresponding
113 chromano[4,3-c]isoxazoles in high yields. Most of the
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Table 2. Mechanochemical synthesis of chromano[4,3-c]isoxazoles
R5
R5
O
N
O
O
N
R4
R3
H
R1
CHO
O
R1
R4
R1
R4
grinding
rt
+
R3
R5NHOH
H
R3
O
R2
R2
R2
1a-t
2a,b
3a-z
4a-z
Entry
1
Salicyaldehyde derivatives
1a: R1 = R2 = R3 = R4 = H
R5
Ph
Ph
CH3
CH3
Ph
Ph
CH3
Ph
Ph
Ph
Ph
CH3
Ph
Ph
Ph
Ph
Ph
Ph
CH3
Ph
Ph
Ph
CH3
Ph
Time (min)a Nitrone
Time (h)b Product
Product
4a
4b
4c
% Yieldc
86
79
71
70
80
87
68
88
90
89
91
70
83
88
82
87
84
87
69
84
83
85
63
91
Ref.
15
15
20
20
15
15
20
30
30
30
30
40
10
20
15
15
10
10
15
10
10
15
20
20
1.5
3.0
3.0
4.0
2.0
2.5
3.0
4.0
4.0
3.0
4.5
2.5
2.5
4.0
2.0
4.0
1.5
3.0
3.0
1.0
1.0
1.5
3.0
1.0
8(b)
2
1b: R1 = R2 = H, R3 = R4 = CH3
1a: R1= R2 = R3 = R4 = H
8(b),7(b)
3
7(c)
4
1b: R1 = R2 = H, R3 = R4 = CH3
1c: R1 = Br, R2 = R3 = R4 = H
1d: R1 = Br, R2 = H, R3 = R4 = CH3
1c: R1 = Br, R2 = R2 = R3 = H
1e: R1 = OMe, R2 = R3 = R4 = H
4d
4e
4f
–
5
8(b)
6
8(b),7(b)
7
4g
4h
4i
–
8
–
9
1f: R1 = OMe, R2 = H, R3 = R4 = CH3
1g: R1 = H, R2 = OMe, R3 = R4 = H
1h: R1 = H, R2 = OMe, R3 = R4 = CH3
1g: R1 = H, R2 = OMe, R3 = R4 = H,
1i: R1 = Cl, R2 = R3 = R4 = H
1j: R1 = Cl, R2 = H, R3 = R4 = CH3
1k: R1 = CH3,, R2 = R3 = R4 = H
1l: R1 = CH3, R2 = H, R3 = R4 = CH3
1m: R1 = F, R2 = R3 = R4 = H
1n: R1 = F, R2 = H, R3 = R4 = CH3
1m: R1 = F, R2 = R3 = R4 = H
1o: R1 = NO2, R2 = R3 = R4 = H
1q: R1 = CN, R2 = R3 = R4 = H
1r: R1 = CN,R2 = H, R3 = R4 = CH3
1q: R1 = CN, R2 = R3 = R4 = H
1s: 2-(allyloxy)naphthalene-1-
carbaldehyde
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4j
8(b)
4k
4l
8(b),7(b)
–
–
4m
4n
4o
4p
4q
4r
–
–
–
–
–
4s
–
4t
8(b)
–
4u
4v
4w
4x
–
–
–
25
26
1t: 2-(3-methylbut-2-
enyloxy)naphthalene-1-
carbaldehyde
Ph
30
30
1.0
2.0
4y
4z
94
79
–
–
1s: 2-(allyloxy)naphthalene-1-
carbaldehyde
CH3
aReactions were ground for 10-40 minutes for intermediate nitrone formation, bthe reaction mixtures were heated on a sand bath for several hours, call
yields refer to isolated product, characterised by 1H-NMR,13C-NMR, ESI-MS.
reactions were conducted under solvent-free condition and
Experimental
in few cases, minimum volume of ethanol-water was used
for proper mixing of reactants. The approach is “greener”
and more advantageous over existing methods because of
drastic reduction in the use of organic solvents
accompanied with clean reaction profile, high yields, and
short reaction times.
General Information
All the reagents were procured from commercial sources
and were used without further purification. All solvents
were obtained from local suppliers and were of research
grade. 1H NMR and 13C NMR spectra were recorded on
Bruker Avance (300 or 400 MHz, respectively) with TMS or
4 | J. Name., 2012, 00, 1-3
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8-Chloro-3,3a,4,9b-tetrahydro-1-phenyl-1H-chromeno[4,3-
c]isoxazole (4m): Light yellow solid, m.p.: 103-105
C; 1H
NMR (400 MHz, CDCl3): (ppm) 3.04-3.10 (m, 1H), 4.05 (dd,
solvent peak as internal standard. The chemical shifts are
reported in parts per million (ppm) units. Mass spectra
were recorded on Agilent 6220 Accurate-Mass TOF LC-MS
using ESI as the ion source. IR spectra were recorded in KBr
pellets with IR Affinity 1, Shimadzu. CHN data were
recorded using Vario MICRO elementar CHNS analyzer.
Melting points of the compounds were determined using
Melting Point Apparatus, Bio Techniques, India. The
reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25-mm silica gel on aluminium plates
(60F-254) using UV light (254 or 365 nm). Column
chromatography was performed on silica gel (60–120 mesh,
Merck).
°
δ
J1 = 5.6 Hz, J2 = 8.0 Hz, 1H), 4.23 (dd, J1 = 5.2 Hz, J2 = 11.6 Hz,
1H), 4.26 (dd, J1 = 3.6 Hz, J2 = 11.6 Hz, 1H), 4.33 (t, J = 8.4
Hz, 1H), 4.84 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 7.09
(t, J = 7.4 Hz, 1H), 7.17-7.22 (m, 3H), 7.36-7.40 (m, 2H), 7.49
(d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ (ppm) 40.6,
63.2, 65.5, 68.2, 115.3, 118.7, 123.1, 124.0, 126.8, 129.2,
129.4, 129.9, 150.7, 154.6; IR (KBr): 3068, 2887, 1593, 1481,
1245, 1096, 1026 cm-1; ESI-MS (m/z): 310 [M + 23]+ (major
peak, for 35Cl), 312 [M + 23]+ (minor peak, for 37Cl); Anal.
Calcd for C16H14ClNO2: C, 66.79; H, 4.90; Cl, 12.32; N, 4.87.
Found: C, 66.89; H, 4.97; N, 4.81.
3,3a,4,9b-Tetrahydro-8-methyl-1-phenyl-1H-
1
chromeno[4,3-c]isoxazole (4o): m.p.: 134-136 °C; H NMR
General procedure for chromano[4,3-c]isoxazoles: synthesis of
4h.
(400 MHz, CDCl3):
δ (ppm) 2.33 (s, 3H), 3.05-3.08 (m, 1H),
4.06-4.13 (m, 2H), 4.25 (dd, J1 = 3.6 Hz, J2 = 11.6 Hz, 1H),
4.33 (t, J = 8.4 Hz, 1H), 4.87 (d, J = 8.0 Hz, 1H), 6.84 (d, J =
8.0 Hz, 1H), 7.04-7.10 (m, 2H), 7.25 (dd, J1 = 0.8 Hz, J2 = 8.4
Hz, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.36-7.40 (m, 2H); 13C NMR
2-(Allyloxy)-5-methoxybenzaldehyde (1e, 192 mg, 1 mmol)
and phenylhydroxylamine (2a, 115 mg, 1.05 mmol) was
taken in a Agate mortar and the mixture was ground
thoroughly by a pestle for 30 min. The complete conversion
of starting materials to nitrone (3h) was monitored by TLC.
Next, the mortar was placed in a sand bath and the reaction
mixture was heated at 60 °C for 4 h. The crude product was
recrystallized from 20% EtOAc in petroleum ether to afford
corresponding chromeno[4,3-c]isoxazole, 4h in pure form
(248 mg, 88%).
(100 MHz, CDCl3):
δ (ppm) 20.9, 41.1, 63.5, 65.4, 68.3,
115.4, 117.0, 122.1, 122.8, 129.3, 129.9, 130.4, 131.4,
151.2, 153.8; IR (KBr): 3033, 2875, 1593, 1491, 1296, 1219,
1088 cm-1; ESI-MS (m/z): 268 [M + H]+; Anal. Calcd for
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.26; H,
6.49; N, 5.28.
Selected spectral data of new entries
3,3a,4,9b-Tetrahydro-3,3-dimethyl-1-phenyl-1H-
chromeno[4,3-c]isoxazole-8-carbonitrile (4v): Light yellow
3,3a,4,9b-Tetrahydro-8-methoxy-1-phenyl-1H-
chromeno[4,3-c]isoxazole (4h): Light brown solid, m.p.:
solid, m.p.: 78-81 °C; 1H NMR (400 MHz, CDCl3): δ (ppm)
1.38 (s, 3H), 1.39 (s, 3H), 2.68-2.73 (m, 1H), 4.23 (dd, J1 =
8.8 Hz, J2 = 11.2 Hz, 1H), 4.42 (dd, J1 = 4.8 Hz, J2 = 11.6 Hz,
1H), 4.60 (d, J = 6.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.12 (td,
J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 7.19-7.26 (m, 3H), 7.33-7.37 (m,
2H), 7.46 (dd, J1 = 2.2 Hz, J2 = 8.6 Hz, 1H); 13C NMR (100
113-115 °C; 1H NMR (300 MHz, CDCl3):
δ (ppm) 3.00-3.06
(m, 1H), 3.78 (s, 3H), 4.03-4.10 (m, 2H), 4.22 (dd, J1 = 3.6 Hz,
J2 = 11.4 Hz, 1H), 4.29 (t, J = 8.4 Hz, 1H), 4.84 (d, J = 7.8 Hz,
1H), 6.80-6.88 (m, 2H), 6.99 (d, J = 3.2 Hz, 1H), 7.08 (t, J =
6.9 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.35-7.40 (m, 2H); 13C
MHz, CDCl3):
δ (ppm) 22.5, 29.8, 47.8, 62.1, 65.0, 82.6,
NMR (75 MHz, CDCl3):
δ (ppm) 41.0, 55.7, 63.6, 65.5, 68.1,
104.6, 117.9, 118.2, 119.1, 122.4, 124.3, 129.2, 133.0,
135.5, 150.6, 158.8; IR (KBr): 3069, 2937, 2219, 1596, 1489,
1245, 1138, 1082 cm-1; ESI-MS (m/z): 307 [M + H]+; Anal.
Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C,
74.60; H, 6.01; N, 9.07.
113.6, 115.4, 115.9, 117.9, 122.7, 122.8, 129.2, 149.9,
150.9, 154.4; IR (KBr): 3060, 2883, 1594, 1492, 1252, 1214,
1091 cm-1; ESI-MS (m/z): 306 [M + 23]+; Anal. Calcd for
C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.94; H,
6.11; N, 4.89.
3,3a,4,9b-Tetrahydro-8-methoxy-3,3-dimethyl-1-phenyl-
1H-chromeno[4,3-c]isoxazole (4i): Light brown solid, m.p.:
3,3a,4,9b-Tetrahydro-3,3-dimethyl-1-phenyl-1H-
benzo[f]chromeno[4,3-c]isoxazole (4y): Yellow solid, m.p.:
1
C; H NMR (400 MHz, CDCl3):
130-133
1.55 (s, 3H), 2.63-2.68 (m, 1H), 4.37 (dd, J1 = 4.0 Hz, J2
° δ (ppm) 1.52 (s, 3H),
C; 1H NMR (400 MHz, CDCl3):
66-68
°
δ
(ppm) 1.37 (s, 3H),
1.42 (s, 3H), 2.70-2.75 (m, 1H), 3.65 (s, 3H), 4.11 (dd, J1 =
9.6 Hz, J2 = 11.2 Hz, 1H), 4.39 (dd, J1 = 4.8 Hz, J2 = 11.2 Hz,
1H), 4.64 (d, J = 6.8 Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 6.80
(dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 7.09
(t, J = 7.0 Hz, 1H), 7.27-7.38 (m, 4H); 13C NMR (100 MHz,
=
11.6 Hz, 1H), 4.50 (dd, J1 = 6.8 Hz, J2 = 11.6 Hz, 1H), 5.38 (d,
J = 6.0 Hz, 1H), 7.01-7.06 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H),
7.19-7.32 (m, 6H), 7.51 (d, J = 8.4 Hz, 1H), 7.74-7.77 (m, 2H);
13C NMR (100 MHz, CDCl3):
δ (ppm) 23.7, 31.3, 47.5, 60.2,
CDCl3):
δ (ppm) 22.3, 29.6, 48.8, 55.7, 62.8, 64.9, 82.7,
63.9, 83.4, 111.0, 117.9, 118.6, 123.25, 123.28, 123.5,
126.6, 128.5, 129.0, 129.6, 130.5, 133.5, 150.5, 153.8; IR
(KBr): 3053, 2965, 1594, 1488, 1228, 1116 cm-1; ESI-MS
(m/z): 332 [M + H]+; Anal. Calcd for C22H21NO2: C, 79.73; H,
6.39; N, 4.23. Found: C, 79.87; H, 6.36; N, 4.34.
114.3, 116.0, 117.5, 117.7, 122.0, 123.3, 129.0, 149.3,
151.7, 153.9; IR (KBr): 3050, 2961, 1593, 1505, 1261, 1217,
1162, 1022 cm-1; ESI-MS (m/z): 312 [M + H]+; Anal. Calcd for
C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.16; H,
6.87; N, 4.39.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C5RA21044E
ARTICLE
Journal Name
D. Lucas, A. Díaz, J. Fernández, L. M. Font, L. Iturrino, C.
Lafuente, S. Martínez, M. H. Bakker, I. Biesmans, L. I.
Heylen and A. A. Megens, Bioorg. Med. Chem. Lett., 2004,
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Alvarez, J. M. Cid, A. I. D. Lucas, J Fernández, S.Martínez,
C Nieto, J Pastor, M. H. Bakker, I Biesmans, L. I. Heylen
Acknowledgments
M.B. thanks CSIR (India) (project No. 02(0075)/12/EMR-II) for
financial support. Z.T.B. is thankful to DST India for INSPIRE
fellowship and V.K. is indebted to CSIR, India for SRFship.
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DOI: 10.1039/C5RA21044E
R5
O
N
R1
CHO
O
R1
R4
grinding
rt
R4
R NHOH
5
+
R3
O
R3
2a,b
R2
R2
1a-t
3a-z
R5
O
N
R4
H
R1
60 ο
C
R3
H
*
*
O
R2
4a-z
R1 = H, CH3, OMe, F, Cl, Br, NO2 or CN;
R2 = OMe; R3 = R4 = H or CH3; R5 = Ph or CH3.
Total 26 entries, yield:
An efficient, catalyst free mechanochemical route to cis-fused chromano[4,3-c]isoxazoles has been developed via a simple
mortar–pestle grinding method.