Functionalization of an sp3 C-H bond via a redox-neutral domino reaction: Diastereoselective synthesis of hexahydropyrrolo[2,1-b]oxazoles

Article abstract of DOI:10.1039/c4cc00454j

A diastereoselective synthesis of pyrrolidinooxazolidines was achieved by a metal-free, base-promoted reaction of pyrrolidine and aromatic aldehydes under microwave irradiation. The rare functionalization of an sp³ C-H bond probably results from an in situ generated azomethine ylide that undergoes cycloaddition with aldehydes.

Full text of DOI:10.1039/c4cc00454j

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Functionalization of an sp3 C–H bond via a
redox-neutral domino reaction: diastereoselective
synthesis of hexahydropyrrolo[2,1-b]oxazoles†
Cite this: Chem. Commun., 2014,
50, 2951
Received 19th January 2014,
Accepted 28th January 2014
Matiur Rahman, Avik Kumar Bagdi, Subhajit Mishra and Alakananda Hajra*
DOI: 10.1039/c4cc00454j
www.rsc.org/chemcomm
A diastereoselective synthesis of pyrrolidinooxazolidines was achieved
by a metal-free, base-promoted reaction of pyrrolidine and aromatic
aldehydes under microwave irradiation. The rare functionalization of
an sp3 C–H bond probably results from an in situ generated azo-
methine ylide that undergoes cycloaddition with aldehydes.
Functionalization of C–H bonds into C–C and/or C–X bonds (X = O,
N, halogen, etc.) is an important area of organic synthesis for the
construction of biologically active complex molecules.1 Direct for-
mation of a C–heteroatom bond via sp3 C–H bond activation is a
challenging task due to the strength of the sp3 C–H bond, and it is
difficult for a metal to form a sterically hindered C–H bond.2 In this
context, some promising catalytic systems for the selective functiona-
lization of sp3 C–H bonds have been developed during the last few
years.3 Generally functionalizations of sp3 C–H bonds are carried out
either by transition metal catalysis or by internal redox processes
under thermal conditions. Recently much attention has been
focussed on redox-neutral reactions for the formation of a fused ring
as no external oxidant is required for this transformation.4 However,
the utilities of redox-neutral domino reactions in stereoselective
syntheses of bioactive molecules have not been extensively explored
so far. Recently, Seidel et al. reported a few redox-neutral approaches
for the a-functionalization of secondary amines (Scheme 1).5
Pyrrolidinooxazolidines are the key intermediates in synthetic as
well as in pharmaceutical chemistry and are important building
blocks for the syntheses of various biologically active nitrogen contain-
ing heterocycles.6 In addition, these are the core structures of some
naturally occurring alkaloids.7 As a consequence, substantial attention
has been paid to develop efficient methods for their syntheses.8 One
notable strategy for the construction of this scaffold is the cycloaddi-
tion reaction between aldehyde and the in situ generated azomethine
ylide from L-proline through decarboxylation.8a,b But the formation of
Scheme 1 Example of the redox-neutral approach.
azomethine ylide from the inactivated secondary amine is not easy
due to the strong sp3 C–H bonds. So the replacement of L-proline with
pyrrolidine is a challenging task.
The development of an efficient method for the stereo-controlled
construction of fused heterocycles from basic chemicals is a demand-
ing task in synthetic chemistry. The domino reaction is one of the
major strategies for the construction of novel heterocycles from easily
available starting materials.9 It also offers more advantages over the
step-wise reaction as there is no need for isolation of the intermedi-
ate. Microwave-assisted organic synthesis (MAOS) has drawn tremen-
dous attention in recent times and has a great impact on C–H
functionalization as microwave irradiation often enables the rapid
attainment of high temperature necessary for inert C–H bond
activation.10 Taking a clue from the work of Seidel5 we thought that
the pyrrolidinooxazolidines could be synthesized by employing the
iminium ion under suitable conditions (Scheme 2). Based on our
previous experiences in microwave-assisted syntheses11 and C–H
functionalization,12 herein we present a new diastereoselective syn-
thesis of hexahydropyrrolo[2,1-b]oxazole through a redox-neutral
Department of Chemistry, Visva-Bharati, Santiniketan-731235, India.
E-mail: alakananda.hajra@visva-bharati.ac.in
† Electronic supplementary information (ESI) available. CCDC 950404. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc00454j
Scheme 2 Strategy for the synthesis of hexahydropyrrolo[2,1-b]oxazole.
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Table 2 Substrate scopes of the reactiona
Scheme 3 Synthesis of hexahydropyrrolo[2,1-b]oxazole.
domino reaction under microwave irradiation (Scheme 3). The overall
process becomes redox-neutral due to the combination of reductive
N-alkylation and oxidative a-functionalization.
Initially we started our work by using pyrrolidine (1 equiv.) and
4-chlorobenzaldehyde (2 equiv.) as the model substrates under
microwave irradiation for 15 min (optimized, see ESI†) in toluene.
We noticed the formation of the expected product in 26% yield
(Table 1, entry 1) as a single diastereomer in which two phenyl groups
are in a trans arrangement and the structure of this diastereomer was
confirmed by nOe experiments as well as by comparing the NMR
result with the literature value.8a We felt that the base could accelerate
the yield. When 20 mol% DABCO was used, the yield was increased to
62% (Table 1, entry 2). Next we tried to optimize the reaction
conditions by varying the bases, solvents and temperature. Among
the common bases such as DABCO, DBU, pyridine, K2CO3, KOAc,
NaOH, and Cs2CO3, KOAc was found to be the most efficient
affording 72% yield (Table 1, entries 2–8). No significant change in
the yield was observed when the amount of base was increased to
30 mol% (Table 1, entry 9). The choice of solvents was important as
the other solvents such as DCB, DMF, DMSO, and xylene were not so
effective (Table 1, entries 10–13). A lower amount of the desired
product was obtained when the temperature was decreased to 150 1C
(Table 1, entry 14). However, when the reaction was carried out with
conventional heating under refluxing conditions, only 24% of the
desired product was afforded even after 24 hours (Table 1, entry 15).
Finally, we chose the optimized reaction conditions as 20 mol% KOAc
in toluene at 180 1C under microwave irradiation (Table 1, entry 6).
a
b
Isolated yields. One enantiomer of the racemic product is presented.
With the optimized reaction conditions in hand we studied the
general applicability of the reaction (Table 2). Pyrrolidine efficiently
reacted with various aldehydes bearing electron-donating as well as
electron-withdrawing substituents to afford the corresponding
products under the optimized reaction conditions (3a–m) and in
each case the formation of a single diastereomer was observed.
Aldehydes with –Me, –OMe, –SMe functionalities gave products
with high yields (3c–e). Piperonal also reacted well to afford the
product in 68% yield (3f). A strong electron-donating substituent
like –N(Me)2 did not diminish the yield of the product (3g).
Aldehydes bearing halogens such as –F, –Cl, –Br were employed
and the desired products were obtained in moderate to high yields
(3h–j). A strong electron-withdrawing group like –NO2 in the phenyl
ring also successfully produced the product (3k, l). A substituent at
the ortho position of the phenyl ring also afforded the corre-
sponding product with a comparable yield (3j). Single crystal X-
ray diffraction analysis of 3k was carried out for further confirma-
tion of the stereochemistry of the product (Fig. 1).13 2-Thiophene
carboxaldehyde was compatible in this reaction to give the desired
product 3m without polymerization.
This protocol is applicable to piperidine also. Piperidine suc-
cessfully reacted with aldehydes through this domino reaction to
afford the corresponding 2,3-disubstituted hexahydrooxazolo-
[3,2-a]pyridines (Scheme 4). Both the products (5a, 5b) were
obtained in moderate yields which are difficult to prepare through
the conventional decarboxylative method. However, morpholine,
L-prolinol and aliphatic aldehydes did not afford the desired
product under the present reaction conditions.
Table 1 Optimization of reaction conditions
Entry
Base (mol%)
Solvent
Temperature (1C)
Yield (%)b
1
2
3
4
5
6
7
8
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCB
DMF
DMSO
Xylene
Toluene
Toluene
180
180
180
180
180
180
180
180
180
180
180
180
180
150
Refluxc
26
62
64
48
32
72
38
36
70
48
42
—
64
56
24
DABCO (20)
DBU (20)
Pyridine (20)
K2CO3 (20)
KOAc (20)
NaOH (20)
Cs2CO3 (20)
KOAc (30)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
9
10
11
12
13
14
15
a
b
Only one enantiomer of the racemic product is presented. Isolated
c
yields. In conventional heating under reflux for 24 h.
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In summary, we have developed a conceptually new method for
the direct functionalization of the unreactive sp3 C–H bond of a cyclic
amine via the redox-neutral domino reaction. Microwave-assisted
hexahydropyrrolo[2,1-b]oxazoles were synthesized diastereoselectively
in high yields. A simple operation, atom-efficient, transition metal-free
and environmentally benign reaction conditions are the attractive
features of this one-step protocol. Several aryl and heteroaryl aldehydes
were found to be suitable substrates for this base promoted transfor-
mation. Piperidine also reacted well under the present reaction
conditions. This present mechanistically different approach provides
a useful alternative to the existing decarboxylative method. We believe
that our present protocol will open up an expedient synthetic pathway
for the synthesis of bioactive fused oxazolidine analogues.
Fig. 1 The single crystal XRD structure of compound 3k.
A.H. acknowledges the financial support from CSIR, New
Delhi. A.K.B and S.M. thank CSIR and UGC for their fellowship.
We thank Dr T. K. Paine, IACS, Kolkata, for XRD analysis.
Notes and references
Scheme 4 Synthesis of 2,3-disubstituted-hexahydro-oxazolo[3,2-a]pyridine.
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Scheme 5 Synthesis of amino alcohol from the pyrrolidinooxazolidine.
Diastereoselective amino alcohol can be easily prepared from the
synthesized pyrrolidinooxazolidine. Reduction of 3a with NaBH4 gave
1,2-bis-(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethanol (6) in 87% yield as a
1
single diastereoisomer as determined by H and 13C NMR spectro-
scopy (Scheme 5).
A plausible reaction mechanism for this domino reaction is
outlined in Scheme 6. The first step is the formation of the iminium
ion (A) by the reaction between pyrrolidine and aldehyde. Then this
iminium ion A transformed into azomethine ylide B via iminium
a-deprotonation by the carboxylate anion.5a The [3+2] cycloaddition
reaction between another equivalent of the aldehyde and the
generated azomethine ylide B afforded the corresponding product
selectively8a in high yield.
´
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Scheme 6 A probable mechanism.
13 CCDC deposition code of compound 3k: 950404.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 2951--2953 | 2953