5 and 6 Membered Heterocycle Synthesis

Michael Ko

English 363
































Abstract
The direct formation of heterocycles by reacting oximes with carbon groups provides an
efficient mean to synthesize diverse heterocycles. Transition metals and chemical reagents are used
to initiate the cyclization reactions. This review presents an overview of the metal screen yields and
oxime reactivity for various oximes used in the synthesis of heterocycles.
Introduction
Heterocycles are important for their biological activity in drug and natural product
synthesis
[4]
. For example, a drug called Mycobacterium tuberculosis phosphatase inhibitor is a drug
for tuberculosis
[4]
. It has an important heterocycle ring which contributes to its biologically active
state
[4]
. Previous studies focused on synthesizing these heterocyclic compounds by developing new
reaction mechanisms and pathways
[4]
. There are a few ways to produce these heterocycles and the
method of interest for many are the transition metal catalyzed reactions
[1]
. The reason for this is that
these metals can aid in the direct formation of very diverse heterocycles from common starting
materials under simple conditions
[1]
. Previous methods usually included intermediates and harsh
conditions which have poor atom economy
[1]
. There are two main processes for heterocyclic
synthesis which are carbon-carbon bond and carbon-R bond formation into heterocycles.
Oximes and oxime ethers synthesize into heterocycles because they contain an oxygen and a
nitrogen atom
[3]
. The oxygen and nitrogen atom make heterocycles different from other cyclic
derivatives because they behave differently in molecular interactions
[3]
. So far, studies focused on
using oxime and oxime ethers as the basis for heterocyclic synthesis using different transition metal
catalysts, while other studies used chemical reagents. This review observes how oxime and oxime
ethers form five or six membered heterocycles, especially focusing on the product yield and the
product reactivity.


5 Membered Heterocycles

Metal Catalyst Screen Yields
Isoxazoles are important heterocycles because of their five membered cyclic characteristics.
A great method to synthesize heterocycles involves using alkynes for the cycloaddition process to
attack the oxime group. Ueda, Ikeda, et al. reported the synthesis of disubstituted isoxazoles through
silver-catalyzed reaction using an alkynyl oxime ether
[4]
. Their metal catalyst screen revealed
AgBF4, with THF as the solvent, to be the most efficient combination for the highest yield (80%)
[5]
.
The next best catalyst combination, AgBF4, with AcOH as the solvent, only yielded 71% of the
product
[4]
.
While Ueda, Ikeda, et al. used silver as their metal catalyst, Ueda, Sato, et al. used gold as
their metal catalyst
[5]
. AuCl3 proved to be the most efficient catalyst producing yields of 90%
[5]
. The
best catalyst for synthesizing the disubstituted isoxazoles was AgBF4, but for the trisubstituted
isoxazole AgBF4 only produced 85% yield
[5]
.
While both groups mentioned above used metal catalyst to synthesize isoxazoles from oxime
ethers, Jawalekar, Reubsaet, et al. used a chemical reagent called phenyliodine bis(trifluoroacetate)
(PIFA) instead of a metal catalyst to from these isoxazole products
[3]
. Jawalekar, Reubsaet, et al.
changed the portions (1.5 molar equivalence) of PIFA to see if it affected the yields instead of
conducting a chemical reagent screen
[3]
. Their study revealed that three portions of PIFA addition
proved to be the best with 90% yields while one and two portions yielded only 65% and 70%
[3]
.
These three groups mentioned above use oxime ethers and alkynes in order to produce these
isoxazole products, but Faulkner, Race, et al.'s study uses oxime esters and alkenes in order to
produce the pyrrole product
[2]
. The study incorporates the use of metal catalysts, specifically copper
in order to catalyze the cyclization reaction and their metal catalyst screen revealed that Cu(2-
ethylhexanoate)2, with PhCN as the solvent, produced the highest yields (79%)
[2]
. Compared to the
other studies, the cooper catalyst have lower yield rates, and this can be due to one oxime being an
oxime ether, while the other is an oxime ester
[2]
. It is important to have good yields for reactions
because higher yields signify greater synthesis efficiency, but it is also important to understand the
product reactivity.
Oxime Ether Reactivity
After determining which transition metal catalyst proved to be the best in terms of percent
yield, various oxime ether derivatives were tested to analyze their reactivity. The reactivity of the
oxime ethers are also measured in yield, but the difference from the metal yield measurements above
is that different substrates and R groups are used to react with the oxime ethers. In a study from
Ueda, Ikeda, et al. scheme one shows the alkynyl oxime ether to undergo the Claisentype [3,3]
rearrangement forming the intermediate A
[4]
.
From the intermediate, the presence of a Bronsted
acid produced the [3,5] disubstituted isoxazoles
[4]
.
Table 1 shows the various alkynyl oxime ethers
tested
[4]
. The oxime ether's reactivity becomes
altered due to the different substrates and R groups used in the reaction, but table 1 shows that the
yields were all relatively high
[4]
. The oxime ether's substituents had chemical variety, such as
electron rich, electron poor, hydrogen and oxygen groups, but they were all accommodated
producing the disubstituted isoxazole
[4]
. While Ueda,
Ikeda, et al.'s study showed the R groups 4-CF3C6H4 and
CH2OAc with the highest isoxazole formation (86%),
Ueda, Sato, et al.'s study had different R groups that
produced the highest yield
[4]
.
[4]
[4]
From Ueda, Sato, et al.'s study, scheme two shows the alkynyl oxime ether undergo the [3,3]
Claisentype rearrangement and subsequent aromatization to produce the isoxazole
[5]
. Table 2 shows
the different R group combinations used to test the reactivity of the oxime ether
[5]
. All the R group
combinations produced great product yields forming the
isoxazole, but the R groups C6H4 and CH2OTBS produced the
highest yields (99%)
[5]
.
While the two studies
mentioned above use an
intramolecular type reaction, Jawalekar, Reubsaet, et al.'s study
uses an intermolecular reaction which changes the reactivity of the
oxime ether.
In Jawalekar, Reubsaet, et al.'s study scheme 3 shows the formation of the isoxazole by the
reaction of the oxime ether with alkyne nitrile oxide
[3]
. A variety of substrates was used to evaluate
the scope of isoxazole formation
[3]
. The R groups
CH3C6H4 and C4H9OH produced the highest yield
product (94%) seen in figure 1
[3]
.
In Faulkner, Race, et al.'s study scheme 4 shows the formation of the pyrrole by reacting the
oxime ester with alkenes
[2]
. Figure 2 shows the highest yielded pyrrole with the highest yielded
pyrrole with 82% product formation
[2]
.








[5]
[3]
[3]
[2]
[5]
[2]
6 Membered Heterocycles

Metal Catalyst Screen Yield
Isoquinolines and pyridines are six membered heterocycles. Just like isoxazoles, these six
membered heterocycles are important for their unique structure and reactivity
[6]
. Yeom, Kim, et al.
reported the synthesis of isoquinoline by using an alkynyl oxime
[6]
. Their metal catalyst screen
revealed AgOTf to be the best catalyst forming 85% yield
[6]
. While Yeom, Kim, et al. used silver as
the metal catalyst, Depature and Hatem used (C4H9)3SnH as the catalyst. Depature and Hatem's study
included the observation of oxime ethers and allenes
[1][6]
. Their study, however, did not include any
catalyst screens and only conducted the study with (C4H9)3SnH with a constant ratio
[1]
. These initial
reagent screens are ultimately optimized to further study the reactivity of the oximes.
Oxime Reactivity
Yeom, Kim, et al.'s study tested the oxime's reactivity by reacting various
alkynyl derivatives
[6]
. The R group C6H4 produced the best results with 96%
product formation (figure 3)
[6]
. As for the study by Depature and Hatem it was
revealed that the R group N(Me)2 produced 89% product yield which was the best
out of 12 other alkynyl derivatives
[1]
.
Conclusion
The development of heterocyclic synthesis has vastly improved greatly, especially with the
use of oximes as precursors. Reactions that involve oximes with alkynes has been studied in great
depth with metal catalysts, as well as chemical reagents. There have been a few studies with oximes
and other groups such as allenes and alkenes, but they were nowhere near as extensive as the alkyne
group. The alkene and phenyl groups are important to study because they provide a link to form
bonds due to their reactivity. Some future studies should involve alkene and phenyls as the reacting
group because understanding these groups behavior will contribute to understanding heterocycle
synthesis in greater detail.
[6]
[1]
References
[1] Depature, Michal, and Jacques Hatem. "Tributyltin Hydride-mediated Free Radical Cyclization
of Allene-tethered Oxime Ethers, Oxime Esters and Hydrazones. Influence of the
Substituents Borne by the C=N Double Bond on the Course of the Reaction." Comptes
Rendus De L'Acadmie Des Sciences - Series IIC - Chemistry 4.6 (2001): 523-29. Print.
[2] Faulkner, Adele, Nicholas J. Race, James S. Scott, and John F. Bower. "Copper Catalyzed Heck-
like Cyclizations of Oxime Esters." Royal Society of Chemistry (2014): n. pag. Web. 20 Apr.
2014.
[3] Jawalekar, Anup M., Erik Reubsaet, Floris P. J. T. Rutjes, and Floris L. Van Delft. "Synthesis of
Isoxazoles by Hypervalent Iodine-induced Cycloaddition of Nitrile Oxides to
Alkynes." Chemical Communications 47.11 (2011): 3198. Print.
[4] Ueda, Masafumi, Aoi Sato, Yuki Ikeda, Tetsuya Miyoshi, Takeaki Naito, and Okiko Miyata.
"Direct Synthesis of Trisubstituted Isoxazoles through Gold-Catalyzed Domino Reaction of
Alkynyl Oxime Ethers." Organic Letters12.11 (2010): 2594-597. Print.
[5] Ueda, Masafumi, Yuki Ikeda, Aoi Sato, Yuta Ito, Maiko Kakiuchi, Hiroko Shono, Tetsuya
Miyoshi, Takeaki Naito, and Okiko Miyata. "Silver-catalyzed Synthesis of Disubstituted
Isoxazoles by Cyclization of Alkynyl Oxime Ethers." Tetrahedron 67.25 (2011): 4612-615.
Print.
[6] Yeom, Hyun-Suk, Sunghwan Kim, and Seunghoon Shin. "ChemInform Abstract: Silver(I)-
Catalyzed Direct Route to Isoquinoline-N-Oxides." ChemInform39.32 (2008): n. pag. Print.


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