Consecutive reactions between methyl 3-dehydroshikimiate, amines and 1,2-dichloroalkanes under microwave conditions: A practical, one-pot construction of N-substituted dihydrobenzoxazines

Article abstract of DOI:10.1039/c3ra47221c

A biomass-involved, one-pot, two-step protocol for the synthesis of N-substituted 3,4-dihydro-2H-1,4-benzoxazines has been developed. A wide range of new compounds have been efficiently synthesized in moderate to excellent yields via the three-component consecutive reactions between methyl 3-dehydroshikimiate (3-MDHS), amines and 1,2-dichloroalkanes in short reaction times under microwave conditions.

Full text of DOI:10.1039/c3ra47221c

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PAPER
Consecutive reactions between methyl 3-
dehydroshikimiate, amines and 1,2-dichloroalkanes
under microwave conditions: a practical, one-pot
construction of N-substituted
Cite this: RSC Adv., 2014, 4, 10022
dihydrobenzoxazines†
Ensheng Zhang,ad Tianlong Xu,ad Dejian Wang,ad Tongkun Huang,a Mu Yuan,b Jun Lic
a
*
and Yong Zou
A biomass-involved, one-pot, two-step protocol for the synthesis of N-substituted 3,4-dihydro-2H-1,4-
benzoxazines has been developed. A wide range of new compounds have been efficiently synthesized in
moderate to excellent yields via the three-component consecutive reactions between methyl 3-
dehydroshikimiate (3-MDHS), amines and 1,2-dichloroalkanes in short reaction times under microwave
conditions.
Received 2nd December 2013
Accepted 30th January 2014
DOI: 10.1039/c3ra47221c
www.rsc.org/advances
benzoxazines using an aliphatic to aromatic protocol in a metal-
free, one-pot manner has not yet been reported. In addition,
Introduction
from sustainable chemistry perspective, the unremitting exca-
vation and utilization of biofeedstocks to replace limited fossil
oil as resources for chemical and pharmaceutical industries
represents one of the most fundamental tasks for chemists.11
Over recent years, ndings from Belotti,12 Yoshikai,13 Deng,14
Rodrigues,15 Saito,16 and Jiang17 groups have shown that the
aromatization of cyclohexenones induced by amines through
enamine intermediates in presence of palladium, iodine or even
p-TsOH constitutes an effective tool for constructing N-arylani-
lines or N-alkylanilines. Our group has also recently disclosed
the effectiveness of a special type of biomass-derived cyclo-
hexenone, the methyl 3-dehydroshikimiate (3-MDHS, 1), in the
facile and metal-free synthesis of polyfunctionalized diaryl-
amines and arylalkylamines via the tandem cross-coupling and
N-substituted 3,4-dihydro-1,4-benzoxazines are an attractive
class of nitrogen-containing compounds prevalent in pharma-
ceuticals, agrochemicals and bioactive molecules.1 Their
usefulness can be reected in the great value of the antibiotic
levooxacin2 and the herbicide safener benoxacor.3 Recent
studies also showed that the N-substituted 3,4-dihydro-1,4-
benzoxazines have emerged as intriguing building blocks for
biologically interesting molecules such as human URAT-1
inhibitor,4 a tumor-driven angiogenesis inhibitor,5 and PPAR
a/g agonist4 (Fig. 1). The N-substituted 3,4-dihydro-1,4-benzox-
azines are generally constructed by reactions of o-amino-
phenol,6 o-nitrophenol,7 o-halogenated phenol8 or o-
halogenated aniline9 with bifunctional components such as
chloroacetone, chloroacetyl chloride or chloroethanol, followed
by stepwise annulations and N-substitutions using Pd- or Ni-
containing catalyst and phosphine or bidentate nitrogen
ligands.10 Although much progress has been made, these
approaches still suffer from multistep procedures, preformed
substrates and relatively low yields in some cases. To the best of
our knowledge, the synthesis of N-substituted 3,4-dihydro-1,4-
aGuangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, 510650,
P. R. China. E-mail: zou_jinan@163.com; Fax: +86 (20)8523 1119; Tel: +86 (20)8523
1309
bGuangzhou Medical University, Guangzhou, 510182, P. R. China
cSecond Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang 310009,
P. R. China
dUniversity of Chinese Academy of Sciences, Beijing, 100039, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47221c
Fig. 1 Examples of biologically active 3,4-dihydro-2H-1,4-benzox-
azine derivatives.
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Table 1 Optimization of reaction conditionsa
aromatization reactions.18 In the course of our study, we envi-
sioned that this aliphatic to aromatic methodology could
further be extended for the assembly of N-substituted 3,4-
dihydro-1,4-benzoxazines through a cascade process by using
the readily accessible 3-MDHS, primary amines and a bifunc-
tional substrate like 1,2-dichloroethane or 1,2-dichloropropane
as the reactant. In continuation of our work on biomass
conversion and utilization,18 we describe herein a 3-MDHS-
based, metal- and ligand-free, one-pot method for access to N-
substituted 3,4-dihydro-1,4-benzoxazines, providing a practical
and efficient alternative to traditional stepwise approaches.
Entry Solvent
Base
T1/T2 (ꢁC) t1/t2 (min) Yieldb (%)
1
2
3
4
Ethanol
DMF
NMP
DMAC
1,4-Dioxane Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
78/78
30/30
8/6
7/5
7/7
15/16
8/7
8/7
8/7
8/5
8/12
8/12
8/12
8/12
8/12
8/12
8/12
8/12
8/12
8/30
15/15
5/3
NDc,d
72
84
74
Trace
40
40
55
92
85
Trace
Trace
Trace
62
60
65
Trace
Trace
NDc,d
82
80
78
110/120
110/120
110/120
90/90
Results and discussion
5
6
7
8
9
PEG-200
PEG-400
Glycol
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
Et3N
Pyridine 110/120
NaOH
KOH
110/120
110/120
110/120
110/120
110/120
110/120
110/120
In recent years, (ꢀ)-shikimic acid has become abundantly
available and cost-effective either through biomass extraction
from fruits of Chinese star anise (Illicium verum Hook. f.) or
through bioengineering production starting from glucose
mediated by E. coli.19 (ꢀ)-shikimic acid could then be readily
transformed to 3-MDHS (1) based on our previous ndings18a
and the recent improved procedures (see the ESI† for detail).
Therefore, 3-MDHS has become an easily accessible platform
compound deserve further transformation studies.
10
11
12
13
14
15
16
17
18
19
20
110/120
110/120
CH3ONa 110/120
DBU
110/120
110/120
110/120
90/110
150/180
110/120
Our research was initiated by investigating the three-
component reaction between 3-MDHS (1, 1.1 mmol), aniline
(2a, 1.0 mmol), and 1,2-dichloroethane (3a, 1.5 ml) in a one-pot,
DMAP
—
Cs2CO3
Cs2CO3
Cs2CO3
two-step manner. p-TsOH was used as the catalyst for step-one 21
22e
240/360
and a base was used as additive for step-two, both under
a
microwave conditions (Table 1). Although the intermediate A
Reaction conditions: 1 (1.1 mmol), 2a (1.0 mmol), solvent (5 ml), DCE
(1.5 ml), p-TsOH (0.05 mmol) at T1 ꢁC (240 W) for t1 min, then base (3
mmol) was added and reacted at T2 ꢁC (240 W) for t2 min. All
reactions were carried out in a ask connected with a condenser.
was detected in the reaction mixture, no desired product 4a
could be found when using ethanol as the solvent, 5 mol% p-
TsOH as the catalyst, and Cs2CO3 (3 mmol) as the base (Table 1,
entry 1). This might be due to the relatively high reaction
temperature needed for initiating step-two cannot be reached
with ethanol in an open vessel. Accordingly, solvents with
higher boiling-points such as DMF, NMP, DMAC, 1,4-dioxane,
b
c
d
Isolated yields based on aniline. ND: no desired product. Only
e
intermediate A was obtained. Reaction was carried out in an oil bath
for a total of 600 min (t1 + t2).
DMSO, PEG-200, PEG-400 and glycol were tested. We were DMSO at 110 ꢁC for step one, followed by the addition of Cs2CO3
pleased to nd that the expected product 4a could substantially (3 mmol) and reacted at 120 ꢁC for step two, both under
be obtained in most of these solvents, whereas DMSO proved to microwave conditions (Table 1, entry 9).
be the most optimal (92% isolated yield, Table 1, compare entry
With the optimized conditions in hand, we next examined
9 to entries 2–8). A survey of different bases showed that Cs2CO3 the scope for this three-component consecutive reaction using
was superior to other bases such as K2CO3, Na2CO3, Et3N, various arylamines. As shown in Table 2, a variety of N-aryl-3,4-
pyridine, NaOH, KOH, CH3ONa, DBU and DMAP (Table 1, dihydro-2H-1,4-benzoxazines were readily obtained in good to
entries 9–18). Moreover, no desired product 4a but only inter- excellent yields. In general, arylamines containing an electron-
mediate A could be obtained in absence of a base (Table 1, entry donating group are more reactive than those bearing an elec-
19). In addition, temperature studies indicated that a 110/ tron-withdrawing group. For example, substituted arylamines
120 ꢁC combination of step-one and step-two, respectively, was with a Me or OMe group provided high yields (Table 2, entries 2
more favourable for the formation of 4a, whereas lower or and 3), whereas substrates with an electron-withdrawing group
higher temperature modes gave lower yields (Table 1, entries 9, such as Ac, NO2 or CF3 gave moderate yields (Table 2, entries 8,
20 and 21). Also, it could be found that the reaction time was 9, 18 and 20). We were disappointed to note that no desired
greatly shortened under microwave conditions comparing with product was detected when 2,4-dinitroaniline was used as the
conventional heating, for this two-step reaction took only 13 substrate, probably due to the insufficient nucleophilicity of the
min (t1 + t2) to go to completion under microwave irradiation, amino group (Table 2, entry 17). A comparison of the reaction
whereas 600 min (t1 + t2) was needed to gave a 78% yield in an yields indicated that the reactivity of halo-substituted aryl-
oil bath (Table 1, entry 9 vs. 22). Thus, the optimized reaction amines decreased in the order I > Br > Cl > F (Table 2, entries
conditions were: 3-MDHS (1, 1.10 mmol), aniline (2a, 1.0 4–7). Results also showed that arylamines with substituents on
mmol), 1,2-dichloroethane (3a, 1.5 ml), p-TsOH (0.05 mmol) in the 2,6-positions gave relative lower yields, which might be due
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Table 2 Scope of the one-pot synthesis of N-aryl-3,4-dihydro-2H- Table 2 (Contd.)
1,4-benzoxazinesa
Entry
Arylamine
t1/t2 (min)
Products
Yieldb (%)
Entry
1
Arylamine
t1/t2 (min)
Products
Yieldb (%)
9
8/10
84
8/5
92
2
3
8/5
8/5
96
95
10
8/8
85
11
12
13
8/9
80
82
87
8/10
8/8
4
8/5
88
5
6
8/6
8/6
85
83
14
8/12
75
15
16
8/12
8/10
65
61
7
8
8/7
8/6
78
82
17
20/20
NDc
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Table 2 (Contd.)
Entry
18
Arylamine
t1/t2 (min)
Products
Yieldb (%)
10/10
72
Scheme 1 Cascade reactions of 3-MDHS, 1,2-dichloroethane with
benzidine, 1-naphthylamine and benzophenone hydrazone.
19
20
10/8
10/8
92
78
the electron-rich (entries 2 and 3) and the electron-poor (entries
5–7) arylamines were applicable to this tandem reactions and
the molar ratios of 7/8 were ranging from 0.9–1.5, which showed
somewhat selectivity for generating 7 over 8 (entries 1–7).
Interestingly and unexpectedly, we have found that the use of
other bifunctional substrates like 1,3-dichloropropane (3c),
epichlorohydrin (3d) and propargyl chloride (3e) could afford
21
10/8
82
Table 3 Scope for the one-pot synthesis of N-alkyl-3,4-dihydro-2H-
1,4-benzoxazinesa
a
Reaction conditions: 1 (1.1 mmol), 2 (1.0 mmol), p-TsOH (0.05 mmol)
in DMSO (5 ml) and 3a (1.5 ml) stirred for t1 min at 110 ꢁC (240 W), then
Cs2CO3 (3 mmol) was added and stirred for t2 min at 120 ꢁC (240 W). All
reactions were carried out in a ask connected with a condenser.
b
Isolated yields. c ND: not detected.
Entry
1
Alkylamine
t1/t2 (min)
Product
Yieldb (%)
to the steric hindrance of the substrates (Table 2, entries 15 and
16). It is gratifying to mention that mutisubstituted or polycyclic
(pseudo)arylamines such as benzidine (2v, molar ratio: 1/2v ¼
2/1), 1-naphthylamine (2w) and benzophenone hydrazone (2x)
proceeded smoothly in this cascade coupling reaction to afford
the corresponding N-aryl-3,4-dihydro-2H-1,4-benzoxazines
4v–4x in satisfactory yields (Scheme 1).
8/5
82
To further investigate the synthetic utility of our protocol, a
range of alkylamines were subjected to the typical reaction
conditions (Table 3). Inspiringly, all of these substrates reacted
smoothly to afford the N-alkyl-3,4-dihydro-2H-1,4-benzoxazines
in acceptable to good yields. For example, benzylamine (5a)
reacted with 3-MDHS (1) and DCE (3a) to afford the corre-
sponding product 6a in 82% yield within 13 min (Table 3,
entry 1). Other alkylamines such as cyclohexylamine, n-butyl-
amine and ethylamine were all successfully converted into the
desired products 6b–6d in moderate yields (Table 3, entries 2–4).
The diversity of our protocol was further explored by using
1,2-dichloropropane 3b to react with 3-MDHS (1) and anilines
(Table 4, entries 1–7). As expected, these consecutive reactions
proceeded smoothly and gave the N-aryl-dihydrobenzoxazines
(7/8) as a regioisomeric mixture in good yields (Table 4). Both
2
3
8/5
60
8/6
8/6
62
65
4
a
Typical reaction procedure: 1 (1.1 mmol), 5 (1.0 mmol), p-TsOH (0.05
mmol) in DMSO (5 ml) and 3a (1.5 ml) stirred for t1 min at 110 ꢁC (240
W), then Cs2CO3 (3 mmol) was added and stirred for t2 min at 120 ꢁC
(240 W). b Isolated yields.
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Table 4 Expanding of substrate scope using 1,2-dichloropropane as
the bifunctional substratea
Entry Arylamine
t1/t2 (min) Ratio of productsb (7/8) Yieldc (%)
1
8/25
8/25
7a/8a ¼ 1.5
7b/8b ¼ 1.0
85
86
2
3
4
5
6
Scheme 2 Cascade reactions of methyl 3-dehydroshikimiate, aniline
with other bifunctional substrates.
8/25
8/30
8/30
7c/8c ¼ 0.9
7d/8d ¼ 1.0
7g/8g ¼ 1.0
86
74
70
8/35
8/35
7i/8i ¼ 1.3
68
61
Scheme 3 Plausible reaction pathway.
MDHS (1) reacted with a primary amine through the tandem
condensation/isomerization/dehydration process to afford the
N-substituted o-aminophenol (I), which could then be O-alky-
lated by 1,2-dichloroethane to afford the intermediate II
through nucleophilic substitution (Path A, whereas Path B can
be excluded because the N-alkylated intermediate III was not
observed).20 The intermediate II can then undergo an intra-
molecular SN2 cyclization to give the desired N-substituted 3,4-
dihydro-2H-1,4-benzoxazines (IV).
7
7n/8n ¼ 1.4
a
Typical reaction procedure: 1 (1.1 mmol), 2 (1.0 mmol), p-TsOH (0.05
mmol) in DMSO (5 ml) and 1,2-dichloropropane (2.0 ml) stirred for t1
min at 110 ꢁC (240 W), then Cs2CO3 (3 mmol) was added and stirred
b
for t2 min at 120 ꢁC (240 W). The ratio of products (7/8) were
detected by H NMR. c Isolated yields.
1
the corresponding O-alkylated products (9c–9e) in excellent
yields, whereas no N-alkylated products or N-phenyl dihy-
Conclusions
drobenzoxazines were obtained (Scheme 2). This and the above- In conclusion, a facile and efficient methodology for access to
mentioned results indicated that the O-alkylation process might N-substituted 3,4-dihydro-2H-1,4-benzoxazines starting from 3-
be more preferential than the N-alkylation process under these MDHS (1), primary amines and 1,2-dichloroalkanes via an
reaction conditions.
aliphatic to aromatic, cascade process has been established.
With the important intermediate II (R2 ¼ benzyl) being iso- The notable features include the use of the biomass-derived
lated from the reaction mixture of 3-MDHS (1), benzylamine platform compound 3-MDHS, metal- and ligand-free reaction
(5a) and DCE (3a), and as an overview of the experimental conditions, short reaction times, and operational simplicity
results, a plausible mechanism was postulated (Scheme 3). 3- that make it an interesting paradigm for biomass conversion
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and a practical strategy for the library synthesis of newer N-
substituted dihydrobenzoxazines with biological importance.
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Acknowledgements
This work was supported by the National Science Foundation of
China (no. 21272280, 81201716, 81301890), Science & Tech-
nology Program of Guangdong Province (S2013010014278,
2011A081401002, 2012B091100241), Zhejiang Province (LY1
3H160010, 2012ZQ017) and Guangzhou City (2012J4300097).
The authors are thankful to Prof. Ming Yan at Sun Yat-sen
University for helpful discussion and are also grateful to
Guangxi Wanshan Spice Co. Ltd. for giving high quality
(ꢀ)-shikimic acid as a gi.
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