A direct access to isoxazoles from ynones using trimethylsilyl azide as amino surrogate under metal/catalyst free conditions

Article abstract of DOI:10.1039/c6cc02047j

A general method for isoxazoles from readily available ynones using trimethylsilyl azide as an amino surrogate, likely via an unprecedented hydroazidation of the alkyne and denitrogenative cyclization, is demonstrated. The method neither required any cata

Full text of DOI:10.1039/c6cc02047j

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DOI: 10.1039/C6CC02047J
A Direct Access to Isoxazoles from Ynones using Trimethylsilyl
Az-ide as Amino Surrogate under Metal/Catalyst free Conditions
Gadi Ranjith Kumar, Yalla Kiran Kumaraa and Maddi Sridhar Reddy*
A general access to isoxazoles from readily available ynones is described with outstanding functional group compatibility
using trimethylsilyl azide as amino surrogate under exceptionally simple conditions.

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DOI: 10.1039/C6CC02047J
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A Direct Access to Isoxazoles from Ynones using Trimethylsilyl Az-
ide as Amino Surrogate under Metal/Catalyst free Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Gadi Ranjith Kumar, a,b† Yalla Kiran Kumaraa† and Maddi Sridhar Reddya,b
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general method for isoxazoles from readily available ynones using
trimethylsilyl azide as amino surrogate, likely via an unprecedented
hydroazidation of alkyne and denitrogenative cyclization, is demonstrated.
The method neither required any catalyst nor demanded the unusual
conditions to afford the products with outstanding functional group
compatibility.
Cyclization via inter- and/or intramolecular functionalization of
alkynes has become extensively sought after approach in modern
chemistry for the synthesis of wide range of hetero- and carbocycles
with vast new patterns of substitutions.1 Soft modes of activation
together with the ready accessibility of alkyne intermediates led to
their frequent use as the precursors. Possibility of tandem couplings,
rearrangements, isomerizations, etc. renders it a highly amenable
pathway for otherwise difficult outcomes. On the same line, Larock
et al. reported an elegant approach for the synthesis of isoxazoles,2a-b
highly privileged scaffolds in drug discovery (valdecoxib: COX-2
inhibitor; sulfamethoxazole: anti-bacterial; sulfafurazole: PABA
antagonist; cloxacillin: β-lactam antibiotic; isoxaflutole: 4-
hydroxyphenylpyruvate dioxygenase inhibitor; danazol: for treating
endometriosis; leflunomide: antirheumatic drug),3 from oxime ethers
of ynones via electrophilic halocyclization (Scheme 1B).
Subsequently, several groups disclosed various metal mediated
cyclizations of the same substrates (oximes or oxime ethers of
ynones) for variety of substituted isoxazoles (Scheme 1A & 1B).2c-k
The latter included the highly useful tendem cyclization/coupling
pathways for highly substituted isoxazoles.
Scheme 1. Synthesis of isoxazoles from ynones.
We began our studies with the optimization of reaction conditions
for the conversion of 1aa to 2aa (Table 1). Initially, when we treated
1aa with 2 equivalents of TMSN3 in presence of 10 mol% of AgCO3
in DMSO (entry 1), the desired product 2aa was obtained only in
10% yield along with the simple triazole as the major product.5
Elevation of reaction temperature (entry 2) or change of silver
catalyst (entries 3-5) brought in no improvement in the outcome.
Change of solvent to DMF slightly improved the yield, but still the
triazole was found to be the major adduct (entry 6). No reaction
occurred when other solvents like 1,2-dichloroethane (DCE), MeCN,
THF or toluene were employed (entries 7-10). Dramatically, when
we switched the solvent to trichloroethylene (TCE), the only desired
product 2aa was cleanly formed in 80% (entry 11). Surprisingly, a
control experiment revealed that the reaction indeed did not require
the assistance of the silver catalyst (entry 12). Thus, stirring of a
mixture of 1aa and TMSN3 in TCE at room temperature cleanly
furnished the product in 82% yield. Noteworthy is that the reaction
was performed under open atmosphere. In fact, the reaction was
almost halted under anhydrous conditions (entry 13), indicating that
the presence of water is necessary. Thinking that the presence of
nitrogen along with pressure (balloon) might have affected the
In continuation of interest in uncovering new activities of
functionalized alkynes,4 we herein present a direct access to
isoxazoles from ynones using TMSN3 as amino surrogate (Scheme
1C). This new method is step economical and it does not require (1)
assistance of any metal/catalyst, (2) harsh reaction conditions, and
(3) exclusion of air or moisture.
a.Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-
10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India. E-
mail: msreddy@cdri.res.in.
b.Academy of Scientific and Innovative Research, New Delhi 110001, India.
† Contributed equally.
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
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the products (2aj-ak) in 65-88% yields. Enynone 1al with two
progress of the reaction by reducing the rate of denitrogenation step
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DOI: 10.1039/C6CC02047J
terminals (β and δ) for initial azide addition showed no interference
(vide infra, see mechanism), we conducted a reaction with a CaCl2
from olefin portion to deliver the desired adduct 2al in 85% yield.
Next we tested the scope of the reaction toward aliphatic
substitution. Pleasingly, the substrates with both acyclic (1am) and
cyclic (1an-ao) alkyl substitution passed through the reaction
smoothly to afford the products in excellent yields (71-91%).
Furthermore, the reaction proceeded well with the substrates derived
from protected propargyl-alcohol (1ap) and –amine (1aq-ar).
Remarkably, substrate 1as with free propargyl hydroxyl showed
hassle-free participation in the reaction to deliver the corresponding
adduct 2as in 62% yield. Subsequently, we verified the scope of the
reaction with respect to substitution on carbonyl terminal of ynone.
The results are summarized in Table 3. Initially we screened various
aryl ynones through the standard conditions. Thus, similar to the
basic substrate 1aa, methyl- and isopropyl- substituted phenyl
ynones 1ba-bb afforded the corresponding adducts 2ba-bb in
Table 1. Optimization of reaction conditions.a
Table 2. Synthesis of isoxazoles from ynones.a
aReaction conditions: 1 mmol of 1 and 2 mmol of TMSN3 in 5 mL of
c
solvent in open air at rt for 12 h. bIsolated yields. Simple triazole
d
e
was major product. Starting material recovered as such. Reaction
conducted in inert atmosphere (N2 balloon). fCaCl2 guard tube
instead of a N2 balloon.
guard tube (entry 14) which maintains the anhydrous atmosphere
without any external pressure. The result was same as in presence of
nitrogen suggesting that the hydroazidation (with the help of water),
and not azidosilylation, of alkyne was only the feasible reaction.
However, addition of 2 equivalents of water (entry 15) to the
reaction did not increase the rate of the reaction but slightly affected
the yield demonstrating that the addition of water must be very slow
(atmosphere) along with the reaction over 12 h. Further, we did an
experiment in presence of 2 equiv. of TEA to see if any trace of HCl
in the solvent was responsible for the reaction (entry 16). But it
could not affect the reaction, producing the product as good as in a
base free reaction.
With these observations, we next headed to evaluate the generality
of this new and direct access to isoxazoles from ynones. We first
studied the reaction scope against the change of substitution at the
alkyne terminal. As is evident from table 2, the reaction showed no
bias in accommodating substrates with disparate electron properties.
Thus, the substrates with phenyl ring on alkyne terminal with
substitution ranging from simple alkyl (1ab-ac) or phenyl (1ad) to
halo (1ae-ah) or methoxy (1ai) all produced the corresponding
products (2ab-ai) in excellent yields (66-86%). The smooth
aReaction conditions: 1 mmol of 1 and 2 mmol of TMSN3 in 5 mL of
trichloroethylene in open air at rt for 12 h. bIsolated yields.
90-92% yields. Bromo- and chloro-phenyl substituents in 1bc-bd
were comfortably accommodated to yield the adducts with ready
handles for further functionalization. Electron rich alkoxy and amino
substituted substrates 1be-bg were found to be highly productive
(70-89% of 2be-bg; 2bg unstable in open air) whereas its electron
formation of bromo adduct 2ah shows that the ortho substituents on deficient nitro and cyano substituted counterparts 1bh-bi were
slightly reluctant to reaction (43-52% of 2bh-bi; partial
decomposition) likely due to reduced nucleophilicity of carbonyl
group (vide infra, reaction mechanism in Scheme 3). Next, naphthyl
and pyridyl adducts (2bj-bk) were obtained smoothly (72-78%).
the benzene moiety display no apparent effect on the outcome.
Heteroaryl (pyridyl and thiophenyl) substituted ynones (1aj-ak)
were found to be equally viable substrates for the reaction to furnish
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Very interestingly, enynone 1bl with two Michael acceptor terminals
selectively underwent the desired transformation to deliver the
corresponding product 2bl in 83% yield. Similarly, diynone 1bm
yielded the acetylynic isoxazole 2bm but in a low yield of 36%.
Having successfully tested the method for conjugated substitution at
C5, we next aimed to synthesize 5-alkyl oxazoles. Thus methyl
adduct 2bn was obtained from corresponding alkyl ynone 1bn in
89% yield. Note that 2bn is the precursor of non-steroidal anti-
inflammatory drug veldicoxib.6 Finally, cyclohexyl and benzyl
ynones 1bo-bp were cleanly converted to 2bo-bp using the standard
protocol.
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Table 3. Synthesis of isoxazoles with varying substitution at C5.a
aReaction conditions: 1 mmol of 1 and 2 mmol of TMSN3 in 5 mL of
trichloroethylene in open air at rt for 12 h. bIsolated yields.
Likewise, leucine derived ynone 1ch was converted to 2ch in 42%
yield.
Next, we headed to verify the scope of the method towards the
substrate with aliphatic substitution on both terminals of the ynone,
i.e. ynone without any external activation. Pleasingly, 1da delivered
the expected 2da but in moderate yield of 60% (Scheme 2).
Scheme 2. Synthesis of isoxazoles from ynones.
Finally, we became curious to check the fate of ynoate 3 and alkynyl
sulfone 4 under the standard conditions (Scheme 3). Setting a
limitation, no reaction occurred perhaps the initiation step i.e.
Michael addition did not take place due to weak acceptor nature
unlike ynones.
aReaction conditions: 1 mmol of 1 and 2 mmol of TMSN3 in 5 mL of
trichloroethylene in open air at rt for 12 h. bIsolated yields.
To explore any further generality of the method, we next chose the
substrates like 1ca-ch with a nucleophile flanking nearby. They in
general readily undergo intramolecular electrophilic cyclization,
especially in the typical metal (or any acid) mediated conditions.7
Delightedly, when we subjected 1ca to the standard conditions, the
expected product 2ca was obtained in excellent yield of 82% without
any interference of NHBoc group. The reaction went equally well
with n-alkyl (1cb-cc) and cycloalkyl (1cd-ce) substitution at the
alkyne terminal of ynone. Similarly, o-methoxy variant 1cf too
showed high productivity (2cf in 92%). Very pleasingly, amino acid
(alanine) derived ynone 1cg also underwent the desired
transformation to yield the isoxazole (2cg) with a chiral substitution.
Scheme 3. Attempts for reaction of ynoate 3 and sulfonyl acetylene
4 with TMSN3.
A probable mechanism for the above direct access to isoxazole from
ynone is described in Scheme 4. The coordination of TMS group of
TMSN3 with ynone oxygen, which is electron rich due to
conjugation, reduced the barrier of Michael addition reaction and
hence enabled it (A) without the assistance of the activating catalyst.
Table 4. Synthesis of isoxazoles from ynones bearing nearby nucleophile.a
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S. Murarka and A. Studer, Org. Lett., 2011, 13, 2746-2749; (d) C.
Further, this coordination was responsible for the addition of azide
syn to the carbonyl group which is necessary for the subsequent
cyclization. The thus added azide group increased the nucleophilicity
of already nucleophilic (due to conjugation) enone carbonyl group
which hence readily underwent cyclization to form O-N bond
relieving the nitrogen molecule. Perhaps this nucleophilic nature is
reduced by the powerful withdrawing groups on the adjacent aryl
rings in case of 2bh and 2bi that hence showed low yielding. As the
literature supports the formation of azirine from vinyl azides,8 we
also propose an alternate route for 2 from A through azirine B
(azirine ring formation followed by ring opening to release the
strain).
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Praveen, A. Kalyanasundaram and P. T. Perumal, Synlett, 2010, 777-
DOI: 10.1039/C6CC02047J
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Scheme 4. Proposed mechanism.
In summary, we have illustrated a highly general and straightforward
method for the synthesis of isoxazoles from readily available ynones
using TMSN3 as amino surrogate. The reaction likely proceeds via
tandem azidation and denitrogenative cyclization (providing a new
set of disconnections), offering a single pot C-N and O-N bond Rogers, A. F. Shaffer, Y. Y. Zhang, B. S. Zweifel and K. Seibert, J.
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formation. The reaction mainly features: (1) step economy, (2) no
necessity of metal/catalyst, and (3) highly ambient conditions (under
open air and at room temperature). Further, a high reaction scope
with respect to both terminals of ynone together with excellent
product yields makes it a practical approach for the highly privileged
scaffold.
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GRK and YKK thank CSIR for the fellowships. We thank SAIF
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