2-Oxo Driven Unconventional reactions: Microwave Assisted Approaches to Tetrahydrofuro[3,2- d ]oxazoles and Furanones

Article abstract of DOI:10.1021/acs.orglett.5b01271

A highly efficient, novel, microwave-assisted, metal-free, diastereoselective synthesis of tetrahydrofuro[3,2-d]oxazole is disclosed. The synthesis of napthoxazoles is achieved for the first time without the aid of an external catalyst. On the contrary, o

Full text of DOI:10.1021/acs.orglett.5b01271

Letter
pubs.acs.org/OrgLett
2‑Oxo Driven Unconventional reactions: Microwave Assisted
Approaches to Tetrahydrofuro[3,2‑d]oxazoles and Furanones
Narsaiah Battini,†,‡ Satyanarayana Battula,†,‡ Raju Ranjith Kumar,§ and Qazi Naveed Ahmed*,†,‡
†Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu-180001, India
‡Academey of Scientific and Innovative Research (AcSIR), 2-Rafi Marg, New Delhi, India
§Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai-625021, India
S
* Supporting Information
ABSTRACT: A highly efficient, novel, microwave-assisted,
metal-free, diastereoselective synthesis of tetrahydrofuro[3,2-
d]oxazole is disclosed. The synthesis of napthoxazoles is achieved
for the first time without the aid of an external catalyst. On the
contrary, our reactions generated naphthofuranones when
treated in the presence of metals in microwave/thermal
conditions. The unusual behavior of our reactions has further
been explored in the generation of furanones from tetrahydro-
furo[3,2-d]oxazole through the use of metals.
n several cases, the aldehyde group of 2-Oxoaldehydes (OA)
Scheme 1. Summary of this Work
I
has shown a difference in reactivity in comparison to normal
aldehydes. This unusual behavior of OA is possibly due to the
existence of an electron-withdrawing ketone group that
promotes the reactivity of the aldehyde.1 Even though reactions
through an aldehyde group of OA with different nucleophiles
are well understood in diverse ways, the direct role of the α-
carbonyl group toward cyclization reactions with various
nucleophiles in the presence of a secondary amine is not well
explored. Our continued interest to unravel the unusual
behavior of OA has helped to explore a few novel concepts
that can find applications in diverse directions. Recently, we
established an unprecedented reactivity of OA toward various
nucleophiles in the presence of a secondary amine as a
catalyst.1c In addition to the basic concept, we developed the
mildest possible methods for α-ketoamides.1d On the basis of
recent findings regarding the iminium ion and literature
precedent, we developed a novel, mild, metal-free method for
tetrahydrofuro[3,2-d]oxazole. In addition, we successfully
established the unusual behavior of the same reaction in the
presence of a metal that resulted in generation of naphthofur-
anones under microwave/thermal conditions. On basis of the
latter method, we established the first report for the direct
conversion of tetrahydrofuro[3,2-d]oxazole to furanones
through the use of metals (Scheme 1).
Fused oxazole in general and tetrahydrofuro[3,2-d]oxazole in
particular represent a diverse set of natural products,2 modified
sugar derivatives, and important bioactive molecules. The
synthesis of some rare sugars and antisense oligonucleotides has
also been achieved by exploiting the tetrahydrofuro[3,2-
d]oxazole motif as a versatile biomimetic synthetic precursor.3
In literature, these structures have been explored as prodrugs of
caspase inhibitors with apoptotic-regulating activity (Figure 1).4
As a result, different groups worldwide are interested in the
Figure 1. Reterosynthetic strategy for tetrahydrofuro[3,2-d]oxazoles.
synthesis of such a skeleton from simple starting materials in a
sustainable and atom-economical fashion.5 Herein, we primarily
Received: May 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01271
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Organic Letters
Letter
report a novel synthetic strategy for tetrahydrofuro[3,2-
d]oxazole 4 through a Betti base as an intermediate. A general
approach for 4 is proposed, taking advantage of recent
developments in chemistry regarding 2-oxoaldehydes, wherein
the 2-oxo group can direct the reaction between 2-oxoaldehyde
1, pyrrolidine 2, and β-naphthol 3 in an unconventional way
(Figure 1). Since β-naphthols 3 are better nucleophiles than
simple phenols and pyrrolidines 2 were found to be the reagent
of choice for iminium promoted chemistry, we primarily
focused on their application toward the generation of 4.
Maycock et al. and Chandan et al. described elegant methods
employing a metal catalyzed cyclization approach to oxazines.6
Both of these methods used Betti bases as starting materials
(previous work, Scheme 1). In our case, we successfully
employed the precursor of the Bitti base, intermediate A, in two
diverse ways. In one approach, under metal-free conditions, we
generated tetrahydrofuro[3,2-d]oxazoles 4, which otherwise
was suppose to give the Betti base as the final product.7 In
contrast, under Maycock and Chandan conditions, we
exclusively isolated furanones 5, instead of 1,3-benzaoxazines.6
We commenced our study with a reaction of phenylglyoxal
1a (0.746 mmol), pyrrolidine 2 (0.895 mmol), and β-naphthol
3 (0.746 mmol) at room temperature (Table 1, entry 1).
phenylglyoxal 1a (0.746 mmol), β-naphthol 3 (0.746 mmol),
and pyrrolidine 2 (0.895 mmol) at 100 °C under microwave
conditions (entry 7). Yet, when the same reaction was
conducted in the presence of copper(II) acetate (10 mol %)
at room temperature, we obtained exclusively 2-hydroxy-2-
phenylnaphtho[2,1-b]furan-1(2H)-one 5a in 65% yield (enter
10). Later we performed a few reactions between 1a, 2, and 3
under microwave conditions (entries 11−14). To our delight,
we isolated 5a in 92% yield within 15 min under microwave
conditions with 10 mol % copper catalyst (entry 12).The same
reaction when tried with 20 mol % of pyrrolidine 2 at 50 W
generated the desired product in comparable yields (entry 13).
This perhaps was the best suitable set of conditions for
generation of 5 for maximum yields.
In order to investigate the substrate scope of the former
reaction with respect to various 2-oxoaldehydes 1, we primarily
focused on the synthesis of different tetrahydrofuro[3,2-
d]oxazoles 4 (Scheme 2). In general, all the reactions tested
Scheme 2. Scope of the Tetrahydrofuro[3,2-d]oxazoles
a
Synthesis
Table 1. Optimization of Reaction Conditions
c
yields (%)
additive
(mol %)
condition (μw)
(°C)
time
(min)
entry 2 (equiv)
4a
5a
1
2
3
4
5
6
7
8
9
1
−
−
−
−
−
−
−
−
−
rt
180
180
5
52
44
53
60
80
75
85
85
85
−
25
25
−
−
−
−
−
−
−
1
100
1
50 W, 80
50 W, 100
50 W, 100
50 W, 120
50 W, 100
50 W, 100
100 W, 100
rt
1
5
1
10
10
10
10
15
180
1
a
1.2
1.5
1.2
1.2
10
Cu(OAc)2
(10)
65
11
12
13
14
1.2
1.2
0.2
0.2
″
″
″
″
80
60
15
15
15
−
−
−
−
86
92
92
90
50 W, 100
50 W, 100
100 W, 100
b
a
1a (0.746 mmol), 2 (0.895 mmol), and 3 (0.746 mmol) in toluene (1
b
mL) at 100 °C in μW (50 W), 10 min for 4a. 1a (0.746 mmol), 2
(0.149 mmol), β-naphthol 3 (0.746 mmol) and Cu(OAc)2.H2O (10
mol %) in toluene (1 mL) at 100 °C in μW (50 W), 15 min for 5a.
a
Reaction condition: 1a (0.746 mmol), 2 (0.895 mmol), and β-
naphthol 3 (0.746 mmol) in toluene (1 mL) at 100 °C using a μW (50
W) source for 10 min.
c
Isolated yields.
Surprisingly, we could isolate a mixture of two products 4a
(52%) and 5a (25%) after 3 h. In order to attain better yields
and product selectivity, the same reaction was conducted at 100
°C (entry 2). However, no improvement was seen in the nature
of the reaction. Further different reactions were monitored
under microwave radiation at different time intervals/temper-
atures with varied concentrations of pyrrolidine 2 (entries 3−
9). We discovered 4a could be achieved exclusively in 85% yield
in 10 min when the reaction was conducted between
generated the desired product in good yields (entry 4a−4o).
However, reactions with 2-oxoaldehydes bearing electron-
withdrawing groups at the ortho position, i.e., 2-Cl (4e) and
2-CF3 (4m), para position, viz., −F (4b), −Cl (4c), −Br (4d),
−CF3 (4f), and meta position, for example −CF3 (4g), −NO2
(4h), produced slightly lower yields than those of unsubstituted
4a and ones containing a donating group, 4i, 4l, and 4n. In
addition our reaction worked well with different aliphatic/
naphthal 2-oxoaldehydes (4j, 4k, and 4o). In general, we
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Organic Letters
Letter
observed that napthoxazoles 4 attained diastereoselectivity.
However, the reaction with OA containing hindered ortho/
meta groups such as CF3 (4m) and CH3 (4n and 4l) failed to
conserve diastereoselectivity.
Scheme 4. Controlled Experiments
The structures of all tetrahydrofuro[3,2-d]oxazoles 4 were
1
elucidated with the help of HRMS, H, 13C, and DEPT. The
structure of compound 4a was further confirmed by single
crystal X-ray diffraction studies (Figure 2; for details see
were indicative of generation of the desired product (5a)
predominantly by the amine catalytic pathway. Also, compound
4a on treatment with metal under microwave conditions gave
5a in 94% yield (experiment 3). However, almost 20 min were
required to complete the reaction. Since our latter reaction, as
described in Scheme 3, generated the desired product in
excellent yields with 20 mol % pyrrolidine in 10 min, we
presume that generation of 5 in general is a metal and/amine
catalyzed reaction. As an advantage, we established that
compound 5 can be transformmed to 4 through use of metal.
In this regard, the scope of this transformation was further
explored by changing the identity of tetrahydrofuro[3,2-
d]oxazoles. As shown in Scheme 5, a variety of oxazoles 4
could be used in our transformation regardless of their
substitution pattern or electronic nature.
Figure 2. ORTEP diagrams of compound 4a.
Supporting Information (SI)). Surprisingly, we could establish
that compound 4a had fixed stereochemistry (Figure 2). To
authenticate the result, we performed chiral HPLC, wherin we
successfully separated two isomers (see SI).
In continuation, different test reactions were performed with
various 2-oxoaldehydes 1 as per optimized conditions
mentioned in entry 13, Table 1 (Scheme 3). In general we
observed that irrespective of the nature of substitution, all the
tested reactions were efficiently transformed to 5 within 10 min
(81−92%, 5a−5l).
a
Scheme 3. Scope of the Furanones Synthesis Reaction
Scheme 5. Scope of the Conversion of Tetrahydrofuro[3,2-
a
d]oxazoles to Furanones
a
Reaction conditions: 4 (1.0 mmol), Cu(OAc)2.H2O (10 mol %) in
toluene (1 mL) at 100 °C using a μW (50 W) source for 20 min.
Based on the previous literature reports6−8 and the above-
mentioned results, we propose the mechanism of these
reactions as depicted in Figure 3. The initial step for the
synthesis of 4 and 5 involves reaction of 2-oxoaldehyde 1 and
pyrrolidne 2 to form 2-oxoiminium ion (intermediate A). This
intermediate behaves differently under metallic/nonmetallic
conditions. In the metal-free pathway (path A), intermediate A
isomerizes to I which can react with 3 in two possible ways. On
one hand, intermediate I can undergo an ene reaction with 3
which later undergoes O-cyclization to II. On the other hand,
intermediate A can undergo O-cyclization to a fused compound
III that can later generate II by undergoing ene cyclization with
3. However, The LC-ESI-MS analysis supported the former
a
Reaction conditions: 1 (0.746 mmol), 2 (0.149 mmol), 3 (0.746
mmol) and Cu(OAc)2.H2O (10 mol %) in toluene (1 mL) at 100 °C
using a μW (50 W) source for 15 min.
To gain insight into the mechanism of both of the reactions,
we conducted few additional experiments (Scheme 4). As
evident from experement 1, although compound 5a was
isolated in low yields (40%) with a copper catalyst, the best
results were obtained when treated with copper in the presence
of 20 mol % of amine 2 (experiment 2). These observations
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Organic Letters
Letter
Figure 3. Proposed mechanism.
mechanism, as we failed to trap the mass of III (SI, p 6). Later,
intermediate II on air oxidation generates desired tetracyclic
compound 4. In the case of the metal catalyzed reaction (path
B), intermediate A on reaction with 3 produces the Betti base,
which generates intermediate ammoniumyl radical cation B
through a single electron transfer (SET) to CuII. Radical B on
successive loss of an H radical (or a combination of electron
and H+) led to an iminium salt6,8a that is quite stabilized by the
adjacent 2-oxo group. The iminium intermediate ultimately on
cyclization undergoes hydrolysis to 5. The generation of 5
through the Betti base was well supported by LC-ESI-MS mass
analysis (SI, p 6). In addition, generation of 5 from 4 (path C)
can be predicted by involvement of CuII in the ring opening
and deamination reaction.8b
In conclusion, we have outlined a new strategy for the
generation of tetrahydrofuro[3,2-d]oxazoles 4 and naptho-
furanones 5 through 2-oxo directed nontraditional reactions. In
general, all the reactions were performed without the aid of
external additives or co-oxidants. The most imperative feature
of napthotetrahydrofuro[3,2-d]oxazoles synthesis can be the
diastereoselectivity. Further detailed mechanistic studies and
their application with other amines and phenols and biological
activities will be disclosed in due course.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical data for products, NMR
spectra of products. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01271.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: naqazi@iiim.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.B. and S.B. thank UGC and CSIR. The authors thank the
analytical department of IIIM. Finally, we are grateful to the
online network project BSC-0108, for funding this work. IIIM
Communication No. IIIM/1804/2015.
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DOI: 10.1021/acs.orglett.5b01271
Org. Lett. XXXX, XXX, XXX−XXX