Organocatalytic Synthesis of Oxazolines and Dihydrooxazines from Allyl-Amides: Bypassing the Inherent Regioselectivity of the Cyclization

Article abstract of DOI:10.1002/adsc.201701386

A selective and efficient methodology for the construction of either oxazolines or dihydrooxazines from the corresponding allyl-amides is reported. Bypassing the inherent selectivity of the cyclization and depending on the substitution pattern of the substrate, a selective epoxidation-cyclization was developed leading to either the five-membered or the six-membered ring, upon simple and complementary reaction conditions. The cyclization products were obtained in good to excellent yields and high selectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201701386

Title: Organocatalytic Synthesis of Oxazolines and Dihydrooxazines
from Allyl-Amides: Bypassing the Inherent Regioselectivity of the
Cyclization
Authors: Alexis Theodorou, Ierasia Triandafillidi, and Christoforos
Kokotos
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Synthesis of Oxazolines and Dihydrooxazines
from Allyl-Amides: Bypassing the Inherent Regioselectivity of
the Cyclization
Alexis Theodorou,a Ierasia Triandafillidia and Christoforos G. Kokotosa*
a
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens,
Panepistimiopolis 15771, Athens, Greece
Fax.: (+30) 2107274761; Phone: (+30) 2107274281; email: ckokotos@chem.uoa.gr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A selective and efficient methodology for the complementary reaction conditions. The cyclization
construction of either oxazolines or dihydrooxazines from products were obtained in good to excellent yields and high
the corresponding allyl-amides is reported. Bypassing the selectivities.
inherent selectivity of the cyclization and depending on the
substitution pattern of the substrate, a selective epoxidation-
cyclization was developed leading to either the five-
membered or the six-membered ring, upon simple and
Keywords: Organocatalysis, Oxidation, Green chemistry,
Oxazolines, Dihydrooxazines
Introduction
Oxazolines and dihydrooxazines are heterocycles
that are commonly encountered in a variety of natural
products, pharmaceuticals and chiral ligands. In
particular, oxazoline is an important scaffold, which
is present in numerous natural products,[1] molecules
of biological importance exhibiting antitumor,[2a]
anticancer,[2b] antidepressant[2c] and antibacterial
properties.[2d]
Furthermore,
oxazolines
and
dihydrooxazines play a pivotal role in protecting
groups,[3] chiral ligands and auxiliaries.[4] Due to their
significant importance, a variety of routes have been
reported for their syntheses, starting from
aldehydes,[5] carboxylic acids and their derivatives,[6]
olefins[7] and hydroxy-amides.[8] Among the most
important synthetic routes to construct either
oxazolines or dihydrooxazines is the cyclization of
allyl-amides (Scheme 1).
The most common reaction pathway constitutes the
halocyclization of allyl-amides (Scheme 1, A).[9-11]
Firstly, the bromination reaction was explored,[10a]
while later a variety of asymmetric approaches were
developed for the corresponding chlorination,[9]
bromination[10] and iodination.[10b,11] However, in all
cases, there is an inherent regioselectivity for the
cyclization step that cannot be suppressed. When a
1,1-disubstituted alkene is employed, the oxazoline
derivative IA is obtained and no dihydrooxazine IIA
can be produced (Scheme 1, A top).
Scheme 1. Approaches for the synthesis of oxazolines and
dihydrooxazines from allyl-amides.
1
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions.
The cyclization follows Baldwin’s empirical
cyclization rules. In addition, when the alkene is 1,2-
disubstituted, the corresponding dihydrooxazine IIA
is produced and no oxazoline IB is observed (Scheme
1, A bottom). In this case, cyclization occurs on the
carbon atom, where additional stabilization is favored
via the neighboring groups, leading selectively to the
six-membered ring. Thus, there is a gap in literature
reports regarding the selective synthesis of these
substrates from the same starting material. In an
effort to bridge this gap, Nicewicz and Morse
reported an alternative approach employing
Entry Catalyst Solvent
(mol%)
Yield
1aa
Yield
2a
Yield
3a
(%)a)
(%)a)
(%)a)
17
35
16
tBuOH
MeCN
AcOEt
MeCN
5
12
7
1
2
10
10
10
20
65
48
65
PhotoOrganocatalysis
for
the
photoredox
3
hydrofunctionalization of allyl-amides (Scheme 1,
B).[12] They reported a single example transforming a
1,1-disubstituted alkene into dihydrooxazine IIB, not
observing any oxazoline IC (Scheme 1, B top).
Furthermore, 1,2-disubstituted allyl-amides were
transformed selectively to oxazolines ID (Scheme 1,
B bottom). Although this elegant contribution
provided a complementary solution, the problem of
overcoming the inherent regioselectivity of the
cyclization still stands unsolved. Herein, we would
like to report our efforts into providing a general,
easily executable and unified solution bypassing this
inherent regioselectivity of the cyclization (Scheme 1,
C). Our protocol involves the selective epoxidation of
allyl-amides, employing hydrogen peroxide as the
green oxidant and an organocatalyst to activate
hydrogen peroxide, followed by selective cyclization
to either the five-membered ring oxazoline or the six-
membered ring dihydrooxazine.
4b)
>99
-
-
The conversion was calculated by 1H-NMR.
The
a)
b)
oxidation step was left stirring for 4 h instead of 18 h.
oxazolines and dihydrooxazines, bypassing the
inherent regioselectivity encountered in the
cyclization step.
We began our investigation by employing allyl-
amide 1a in our general reaction conditions for the
epoxidation (Table 1, entry 1). Interestingly, although
epoxide 1aa was the major product, both oxazoline
2a and dihydrooxazine 3a were formed. This result
intrigued us in finding the appropriate reaction
conditions to provide either 2a or 3a. Simple
alteration of the solvent did not improve the
selectivity of the reaction (Table 1, entries 1-3).
Increasing the catalyst loading and carefully studying
the reaction conditions led to a quantitative yield of
epoxide 1aa (Table 1, entry 4).
We then turned our attention into bypassing the
inherent regioselectivity of the reaction, which leads
to the formation of the five-membered ring 2a,
according to literature reports and Baldwin’s
empirical rules (Table 2). Having previous experience
in imposing anti-Baldwin cyclizations[15] and
hypothesizing that an interaction of the intermediate
epoxide with a Lewis acid could alter the cyclization
towards the six-membered ring, a variety of acidic
conditions were tested (Table 2, entries 1 and 2).
From a variety of choices, the use of cheap and
extremely common trifluoroacetic acid (TFA) and
camphorsulfonic acid (CSA) provided a quantitative
yield of dihydrooxazine 3a. The use of common
Bronsted acids was preferred, in order to provide a
more general and cheap protocol. We then turned our
attention into identifying the appropriate basic
additive to provide a protocol for the synthesis of
oxazoline 2a (Table 2, entries 3-6). From some
common bases, tBuOK afforded a quantitative yield
in short reaction time at slightly elevated temperature.
Performing the reaction at room temperature required
prolonged reaction time to reach to the same
Results and Discussion
Previously, we were engaged in developing a novel
organocatalytic oxidative protocol that could employ
hydrogen peroxide as the oxidant.[13] Hydrogen
peroxide is a green and environmentally friendly
oxidant, since its only byproduct is water. However,
its poor oxidation power requires its activation by a
catalyst. Normally, this is realized by the use of a
metal catalyst, which is associated with high toxicity
and waste production. A few years ago, we identified
2,2,2-trifluoroacetophenone as the appropriate
organocatalyst for hydrogen peroxide activation. We
initially demonstrated its use in the oxidation of
heteroatoms, like silanes,[13a] tertiary amines and
azines,[13b,c] sulfides[13d] and anilines, where we
studied also the reaction mechanism, excluding the
possibility of the involvement of a dioxirane
intermediate.[13e] Also, we have employed this
oxidative protocol in the oxidation of alkenes and
cyclization reactions.[14] In this work, our
environmentally friendly protocol provides a new,
cheap and easy to perform synthetic pathway to
2
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
Table 2. Optimization of the reaction conditions.a)
desired product (Table 3, entries 6 and 7). The only
isolated product was the epoxide, which even after
prolonged reaction time and/or heating did not lead to
the dihydrooxazine. The electron density of the aryl
substituent of the allyl moiety was of great
importance for the outcome of the reaction, since the
strongly electron rich para-methoxy group led to a
selective ring opening-six-membered ring formation,
upon the epoxidation reaction conditions (Table 3,
entry 10). All attempts to isolate the intermediate
epoxide met with failure. This did not leave any room
for selective manipulation on the cyclization step.
The substituent on the aryl moiety on the allyl
component of the starting material proved to be of
quite crucial importance, since the corresponding
para-nitro and para-chloro derivatives were insoluble
in the reaction mixture and failed to provide the
reaction. In an effort to gain further mechanistic
insight of the reaction sequence, E- and Z-
trisubstituted allyl-amides 1k and 1l were tested,
respectively (Table 3, entries 11 and 12). Under the
basic conditions of the oxazoline synthesis, 1k
afforded oxazoline 2k as a single diastereomer,
verifying our hypothesis and literature knowledge,
that after the regioselective epoxidation, a common
SN2 reaction mechanism for the ring opening-
cyclization occurs, according to Baldwin’s
cyclization rules. In accordance with this, Z-allyl-
amide 1l afforded oxazoline 2l, the diastereomer of
2k. Under the acidic conditions of the dihydrooxazine
synthesis, there are a number of alternative proposed
cyclization mechanisms that could be in place. For
instance, if the epoxide intermediate is activated by
the Bronsted acid, with an interaction, similar to
Lewis acid activation of epoxides, one could assume
a stable benzylic carbocation is formed, which upon
cyclization can lead to the same product, no matter of
the nature of the double bond (E-, Z- or mixture) of
the starting material. This is not the case, since a
different diastereomer of the dihydrooxazine was
obtained (3k and 3l, respectively). It seems that
activation of the epoxide with the Bronsted acid
occurs, and then a simultaneous ring opening-
cyclization (SN2-type) takes place to afford the TFA
salt of the dihydrooxazine, which upon wash with aq.
NaHCO3 affords the desired dihydrooxazine.[17] In the
former case, only dihydrooxazine 3k was obtained in
high yield (Table 3, entry 11). In the latter case, a
mixture of dihydrooxazine 3l and oxazoline 2l was
isolated (Table 3, entry 12). We believe that the
stereochemical hindrance on 3l (hydroxy group is cis
to the phenyl ring) is the limiting factor for the
selective synthesis of dihydrooxazine (anti-Baldwin)
and in retrospect leads to cyclization via the Baldwin-
selective 5-exo-tet to oxazoline 2l. Unfortunately,
moving to 1,1-disubstituted allyl-amides, like 1m,
Entry Solvent
Acid/
Base
T (oC),
Time
(h)
Yield
Yield
2a
3a
(%)b)
-
(%)b)
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
CSA
TFA
Cs2CO3
NaH
DBU
tBuOK
rt, 18
rt, 1.5
rt, 18
rt, 18
rt, 18
50, 1.5
>99
>99
31
-
14
30
0
-
0
-
>99
a)
1a (0.30 mmol) in MeCN, PhCOCF3 (0.06 mmol), aq
buffer and H2O2 at rt for 4 h, then solvent, acid/base. b) The
conversion was calculated by 1H-NMR.
outcome. In this manner, we could provide two direct
manifolds starting from an allyl-amide and depending
on the reaction conditions adopted to impose the
mode of cyclization that is preferred.
Having established the optimum reaction
conditions, we turned our attention to the exploration
of the substrate scope (Table 3). Starting from allyl-
amide 1a, oxazoline 2a was isolated in 78% yield,
while the dihydrooxazine 3a was isolated in 74%
yield (Table 3, entry 1). No other product (starting
material or epoxide) was observed in either case. It
has to be noted that in order to be certain for both the
regioselectivity of the cyclization step, as well as the
relative stereochemistry of the product, structures 2a
and 3a were analyzed with literature precedent (syn-
derivatives), whose structures have been proven via
X-ray crystallography.[16] Changing the substitution
pattern and the electron density of the aromatic
moiety of the amide did not alter the inherent
selectivity of the cyclization step leading to five-
membered oxazolines 2b-e, 2h and 2i in good to high
yields (Table 3, entries 2-5, 8 and 9). Bypassing this
selectivity, the acidic conditions after the epoxidation
step led to six-membered dihydrooxazines 3b-e, 3h
and 3i (Table 3, entries 2-5, 8 and 9). Moving from
aromatic substituents to aliphatic moieties on the
amide required additional base and elevated reaction
temperature to ensure cyclization. Indeed, oxazolines
2f and 2g were prepared in moderate yields (Table 3,
entries 6 and 7). Unfortunately, all attempts for the
synthesis of dihydrooxazines failed to deliver the
3
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
Table 3. Substrate scope of the organocatalytic synthesis of oxazolines or dihydrooxazines from allyl-amides.a)
Entry
Product
Yield
(%)b)
Starting Material
Product
Yield
(%)b)
1
2
X: H 2a, 78%
X: H 3a, 74%
X: p-Br 2b,
85%
X: p-Br 3b, 80%
3
4
5
X: p-CF3 2c,
85%
X: p-NO2 2d,
55%
X: o-Cl 2e,
83%
X: p-CF3 3c,
84%
X: p-NO2 3d,
73%
X: o-Cl 3e, 84%
6c)
7d)
R Bn 2f, 46%
R Bn 3f, -
R: n-C7H15 2g,
X: n-C7H15 3g, -
65%
8
9
X: p-MeO 2h,
80%
X: 2,4-diMe 2i,
55%
X: p-MeO 3h,
84%
X: 2,4-diMe 3i,
62%
10e)
2j, -
3j, 57%
3k, 72%
11
12
2k, 83%
2l, 78%
3l+2l, 77%
(42:58)
13
14
2m, 87%
2n, 90%
2m, 97%
3n+2n, 86%
(60:40)
15
R : H 5a, 99%
R : Ac 5b, 71%
R : H 5a, 99%
16f)
-
a)
1a (0.30 mmol) in MeCN (0.24 mL), PhCOCF3 (0.06 mmol), aq. buffer (0.24 mL, 0.6M K2CO3 – 4 x 10-4M EDTA
disodium salt), acetonitrile (0.30 mL) and 30% aqueous H2O2 (0.84 mL) at rt for 4 h, then for oxazolines: dry THF (3
mL), KΟtBu (0.45 mmol) at 50 oC for 90 min; for dihydrooxazines: dry CH2Cl2 (3 mL), TFA (0.60 mmol) at rt for 90 min,
then wash with aq. NaHCO3. b) Isolated yield. c) KΟtBu (1.20 mmol) at 70 oC for 90 min. d KΟtBu (0.60 mmol) at 70 oC for
e
f
90 min. Cyclization occurred during the oxidation step. EtOAc instead of THF was used as the solvent for the
cyclization step.
4
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
and although the intermediate epoxide was formed,
under both acidic or basic conditions, oxazoline 2m
was the sole product obtained (Table 3, entry 13). In
the former case, an almost quantitative yield was
obtained. The outcome of the reaction was expected,
although it did not provide the possibility for
selection of the reaction pathway. Under basic
conditions, the Baldwin rules were followed, as well
as ring opening at the most hindered side. Under the
acidic conditions, the ring opening and cyclization
occurs at the side, where the slightly positive charge
is stabilized. When trisubstituted allyl-amide 1n was
employed, oxazoline 2n was obtained in high yield
(Table 3, entry 14). Under acidic conditions, the
desired dihydrooxazine 3n was formed, albeit as a
mixture with oxazoline 2n (Table 3, entry 14). As
before, the additional steric hindrance of the gem-
methyl substituents next to the hydroxy group (one
methyl is cis and the other is trans) apparently
increases the energy required for cyclization and thus,
oxazoline 2n was also formed. This result also hints
that the cyclization and the selectivity observed in the
cases of aromatic substituted allyl-amides (for
example, 3k vs 3n) are controlled by the stabilization
of the benzylic “quasi” carbocation. Moving to
another example of 1,1-disubstituted olefin, allyl-
amide (vinylphenyl amide) (4a), under both reaction
conditions, the same product (5a) was isolated in a
quantitative yield (Table 3, entry 15). As expected,
under acidic conditions the six-membered ring was
formed. However, under basic reaction conditions,
the attack on the less hindered face of the epoxide
that would lead to an unfavorable seven-membered
ring was not followed, and thus, the more
thermodynamically stable six-membered ring was
formed. Interestingly, when EtOAc was employed as
the solvent for the cyclization step, acetylated product
5b was formed (Table 3, entry 16).
Scheme 2. Proposed reaction mechanism.
Finally, attempts were made to provide an
asymmetric manifold. Since all our efforts to
introduce
a
chiral catalyst for this protocol
(employing hydrogen peroxide) proved unsuccessful,
we turned our attention into the well-established
dioxirane chemistry.[18] Utilizing Shi’s catalyst and
Oxone as the oxidant, we were able to render the
process asymmetric (Scheme 3). In unoptimized
reaction conditions, oxazoline 2a was obtained in
71% yield and 60% ee, while 3a was obtained in 40%
yield and 50% ee.
Based on our previous studies[14] and current
experiments, a proposed reaction mechanism is
shown in Scheme 2. In the aqueous environment of
the reaction, 2,2,2-trifluoroacetophenone affords diol
I. Then, and in the appropriate pH, MeCN reacts with
H2O2 to afford II, which in conjunction with H2O2
oxidizes I to perhydrate IV.[14] Another molecule of
II reacts with IV affording V, which can be or
provide the active oxidant of the protocol, which
epoxides the allyl-amide.[13e] Under basic conditions,
Baldwin’s cyclization rules are followed and
cyclization at the least hindered position leads to the
formation of oxazolines. Under acidic conditions,
activation of the epoxide, leads to the simultaneous
ring opening-cyclization on the side that stabilizes
better the formed carbocation leading to
dihydrooxazines.
Scheme 3. Asymmetric variant.
Conclusion
5
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
Acknowledgements
In conclusion, an efficient and selective protocol for
the synthesis of oxazolines or dihydrooxazines from
the corresponding allyl-amides was introduced.
Bypassing the inherent selectivity of the cyclization,
which depends on the substitution pattern of the
substrate, the selective epoxidation-cyclization was
performed leading to either the five-membered or the
six-membered ring, upon simple and complementary
reaction conditions. The cyclization products were
obtained in good to excellent yields and high
selectivities. Attempts to render the process
asymmetric, met with limited success.
The authors gratefully acknowledge the Operational Program
“Education and Lifelong Learning” for financial support through
the NSRF program “ΕΝΙΣΧΥΣΗ ΜΕΤΑΔΙΔΑΚΤΟΡΩΝ
ΕΡΕΥΝΗΤΩΝ” (PE 2431)” co-financed by ESF and the Greek
State. The authors would also like to thank Konstantinos Doukas
and Vassileios Mouchtouris for preliminary results and Dr.
Maroula Kokotou for her assistance in acquiring HRMS data. IT
would like to thank the Hellenic Foundation of Research and
Innovation (ΕΛΙΔΕΚ) for a PhD scholarship. Also, COST Action
C-H Activation in Organic Synthesis (CHAOS) CA15106 is
acknowledged for helpful discussions.
Experimental Section
References
General Procedure for the Organocatalytic Synthesis of
2-Oxazolines: Substrate (0.30 mmol) was placed in a
round bottom flask and dissolved in MeCN (0.24 mL).
2,2,2-Trifluoro-1-phenylethanone (8.7 mg, 0.05 mmol),
aqueous buffer solution (0.24 mL, 0.6M K2CO3 – 4 x 10-4
M EDTA disodium salt), acetonitrile (0.30 mL, 6.00
mmol) and 30% aqueous H2O2 (0.84 mL, 8.00 mmol) were
added consecutively. If the substrate is insoluble to the
reaction mixture, EtOAc (0.1 mL) was added as well. The
reaction mixture was left stirring for 4 hours at room
temperature. The reaction was diluted with CH2Cl2 (5 mL)
dried over Na2SO4, filtered and the solvent was evaporated
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o
under reduced pressure up to 30 C, to give the crude
epoxide intermediate. Then, the reaction mixture was
dissolved in dry THF (3 mL). KΟtBu (50 mg, 0.45 mmol)
was added and the reaction mixture was left stirring at 50
oC for 90 min. The solvent was evaporated, EtOAc (5 mL)
was added and the residue was filtered off. The filtrate was
then concentrated under reduced pressure and the crude
product was purified using flash column chromatography
(40% EtOAc in Pet. Ether) to afford the desired product.
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2760-2764.
Procedure for the Organocatalytic Synthesis of
Dihydro-1,3-Oxazines: Substrate (0.30 mmol) was placed
in a round bottom flask and dissolved in MeCN (0.24 mL),
2,2,2-Trifluoro-1-phenylethanone (8.7 mg, 0.05 mmol),
aqueous buffer solution (0.24 mL, 0.6M K2CO3 - 4x10-4M
EDTA disodium salt), acetonitrile (0.30 mL, 6.00 mmol)
and 30% aqueous H2O2 (0.84 mL, 8.00 mmol) were added
consecutively. If the substrate is insoluble to the reaction
mixture, EtOAc (0.1 mL) was added as well. The reaction
mixture was left stirring for 4 hours at room temperature.
The reaction was quenched with CH2Cl2 (5 mL) dried over
Na2SO4, filtered and the solvent was evaporated under
reduced pressure up to 30 oC, to give the crude
intermediate epoxide. Then, the reaction mixture was
dissolved in dry CH2Cl2 (3 mL). TFA (46 μL, 0.60 mmol)
was added and the reaction mixture was left stirring at
room temperature for 90 min. The solvent was evaporated,
EtOAc (10 mL) was added and the organic layer was
washed with aq. NaHCO3 (10 mL, 10% w/w). The organic
layer was dried (Na2SO4), filtered and concentrated and the
crude product was purified using flash column
chromatography (40% EtOAc in Pet. Ether) to afford the
desired product.
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6
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201701386
Advanced Synthesis & Catalysis
FULL PAPER
Organocatalytic Synthesis of Oxazolines and
Dihydrooxazines from Allyl-Amides: Bypassing
the Inherent Regioselectivity of the Cyclization
Adv. Synth. Catal. Year, Volume, Page – Page
Alexis Theodorou, Ierasia Triandafillidi,
Christoforos G. Kokotos*
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