Azido-Enolonium Species in C-C and C-N Bond-Forming Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.9b03824

Vinyl azides react with boron trifluoride activated Koser's hypervalent iodine reagent to afford azido-enolonium species. These previously unknown azido-enolonium species react efficiently with aromatic compounds, allyltrimethylsilane, and azoles under mi

Full text of DOI:10.1021/acs.orglett.9b03824

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Letter
Azido-Enolonium Species in C−C and C−N Bond-Forming Coupling
Reactions
Atul A. More, Sourav K. Santra, and Alex M. Szpilman*
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ABSTRACT: Vinyl azides react with boron trifluoride activated
Koser’s hypervalent iodine reagent to afford azido-enolonium
species. These previously unknown azido-enolonium species react
efficiently with aromatic compounds, allyltrimethylsilane, and
azoles under mild conditions, with no need for a transition-metal
catalyst, forming C−C and C−N bonds to give a variety of α-
functionalized ketones. The intermediacy of the proposed azido-
enolonium species is supported by spectroscopic studies.
iscrete enolonium species1 (4) are umpoled2 ketone
enolate equivalents, i.e., electrophiles, and are typically
While the scope of nucleophiles available for reaction with
enolonium species (4) keeps expanding, the source of
enolonium species (4), whether discrete or transient, remains
largely limited to TMS-enol ethers8,15 and dicarbonyl
compounds.10,13 Thus, it would be attractive to develop
alternative readily accessible enolonium species. We were
particularly interested in studying the effect of an azido-
nitrogen in place of the enol oxygen (i.e., as in 8, Scheme 1b)
hoping to find increased reactivity.16 Importantly, vinyl azides
(7) are readily available from alkenes17 or alkynes18 in a single
step. In comparison to TMS-enol ethers, vinyl azides are
available in one less step than most aromatic ketones that are
produced from alkenes by the Wacker reaction,19 from
oxygenation of alkanes, or oxidation of alcohols. An additional
goal was to compare the reactivity of these novel species with
that of other enamines. Enamines,20 enamine-ones,21 and
enamides22 have mainly been reported to undergo attack at the
α-position by carboxylates rather than C−C bond-forming
reactions. However, Du and Zhao have reported a cyclization
of enamines of anilines to give indoles using PIDA23 as well as
arylation of the enamine nitrogen with concomitant iodina-
tion.24 Waser has reported stable N-tosyl-N-p-methoxypheny-
lenamide hypervalent iodine reagents and has shown their
value in transition-metal-catalyzed Stille and Sonogashira
cross-coupling reactions.25
D
formed by the reaction of TMS-enol ethers (1) with Lewis acid
activated hypervalent iodine reagents (Scheme 1a).3 Numer-
Scheme 1. This Work in Context
ous reactions including fluorination,4 chlorination,5 acetox-
ylation,6 tosylation,7 amination,8 arylations,9 and alkylations10
have been proposed to involve formation of similar, but
transient, enolonium species. Recently, we have shown that
discrete enolonium species (4) are able to undergo α-
arylation,11 and allylation,1 as well as cross coupling with
TMS-enol ethers to form unsymmetrical 1,4-dicarbonyl
compounds (Scheme 1a).12 Maulide has shown that the α-
arylation is also possible intramolecularly using similar
conditions.13 In addition, we have shown that discrete
enolonium species (4) may react with nitrogen nucleophiles
such as azides and azoles in C−N bond-forming reactions.14
Vinyl azides (7) are chameleonic species with a rich
chemistry26 that enables them to react as enamine equivalents
with electrophiles as well as with strong nucleophiles like
organolithium reagents depending on conditions and reaction
Received: October 26, 2019
https://dx.doi.org/10.1021/acs.orglett.9b03824
© XXXX American Chemical Society
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Scheme 2. Scope of the Reaction of Azido-Enolonium Species 10 Generated from Vinyl Azides 9
a
b
At 0.5 mmol scale. At 1 mmol scale using 1.5 equiv of Koser’s reagent (2).
partners.27 Notably, vinyl azides do not themselves undergo
reaction with simple aromatic compounds.
phenyl)-vinyl azide reacts with 2-methylindole under the
standard conditions to give 13k in 59% yield. With a tert-butyl
substituent, the analogous product 13l is formed in 69% yield.
Importantly, azido-enolonium species 10, like those of its
analogue 4, is not limited to terminal enolonium species
although the yield is reduced. Thus, (9, R1 = H, R2 = Me,
Scheme 2) affords product 13j in 44% yield.
Rapidly, it was found that vinyl azides (9) react with Koser’s
reagent (2)7a preactivated by boron trifluoride etherate (3)
and aromatic compounds to give arylated ketones after
hydrolysis during water workup (Scheme 1b and Scheme 2).
Only 1.5 equiv of the aromatic compounds is necessary to
achieve the yields shown in Scheme 2.
The scope of the aromatic coupling partner was also
investigated mainly using 1-(4-tert-butyl-phenyl)vinyl azide (9,
R1 = t-Bu, R2 = H, Scheme 2) as the starting material. This
vinyl azide reacts with simple indole to afford 13m in 57%
yield compared to 2-methylindole product 13l, which was
formed in 60% yield. The lower yield of 13m may have to do
with substituted indole products being less prone to react twice
under the reaction conditions. 5-Methyl-1H-indole reacts with
1-(4-tert-butyl-phenyl)-vinyl azide to give 13n in 65% yield.
However, 2-phenylindole reacts with 1-(4-tert-butyl-phenyl)-
vinyl azide to give 13s in 55% yield. In contrast, the reaction
with 3-methylindole leads to formation of a complicated
reaction mixture. 5-Fluoro-1H-indole reacts with 1-(4-tert-
butyl-phenyl)-vinyl azide to give 13o in 64% yield, while the
corresponding 5-bromo-1H-indole and 5-iodo-1H-indole react
with 1-(4-tert-butyl-phenyl)-vinyl azide to give 13p and 13q in
68% and 71% yield, respectively. This again shows the
compatibility of bromo and iodo functionalities with the
reaction conditions. An important result in view of these
functions may be used subsequently as handles for, e.g.,
palladium-catalyzed cross-coupling reactions. Another notable
The scope with respect to vinyl azide and aromatic coupling
partner is quite wide. Simple 1-phenyl-vinyl azide (9, R1 = H,
R2 = H) reacts with 2-methylindole to give 13a in 67% yield.
The vinyl azide coupling partner may contain a number of
different functionalities (Scheme 2). For example, 1-(4-fluoro-
phenyl)-vinyl azide, 1-(4-chloro-phenyl)-vinyl azide, 1-(4-
bromo-phenyl)-vinyl azide, and 1-(4-iodophenyl)-vinyl azide
react with 2-methylindole to give products 13b, 13c, 13e, and
13g in comparable yields in the 56−68% range (Scheme 2). In
particular, the formation of 13e and 13g is notable, as these
halogens could in principle be oxidized by the hypervalent
iodine reagents. Electron-withdrawing functionalities such as
nitro and methylester are also compatible with the reaction
conditions. Thus, 1-(4-nitrophenyl)-vinyl azide provides
product 13h in 76% yield. The corresponding methyl 4-(1-
azidovinyl)benzoate (9i, R1 = CO2Me, R2 = H, Scheme 2)
provides product 13i in 69% yield. This is quite comparable to
yields achieved via the analogous enolonium species 4
(Scheme 1a).11 Simple alkyl groups are compatible with the
reaction conditions as well. Methyl-substituted 1-(4-methyl-
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compatibility is that the electron-rich group of 5-methoxy-2-
methyl-1H-indole is left unscathed under the reaction
conditions when coupled with 1-(4-tert-butyl-phenyl)-vinyl
azide to give 13r in72% yield. 1-(4-Chloro-phenyl)-vinyl azide
also reacts with 5-methoxy-2methyl-1H-indole to give 13d in
79% yield.
imine carbon allowing other reactions to take place including
the displacement of nitrogen (N2) by water on the imine
nitrogen leading to14. This result opens up for future work
aimed at favoring formation of the oxime.
We have shown that enolonium species 4 are capable of
undergoing other C−C forming reactions, such as allylation,1
cross coupling with TMS-enol ethers,12 and C−N bond
forming reaction with azoles.14 Thus, in order to demarcate the
capabilities of azido-enolonium species 10 we also tested their
reaction with allyltrimethylsilane (15) as well as triazole (17)
and two tetrazoles (18, Scheme 4).
A cyano group is tolerated as well, as shown in the
production of 13t in 69% yield. Even an ethyl ester in the
aromatic coupling partner is tolerated as shown by the
preparation of 13u in 63% yield. An acid-sensitive Boc
protecting group is also compatible with the reaction
conditions. Thus, (9, R1 = Br, R2 = H) reacts with tert-butyl
2-methyl-1H-indole-1-carboxylate to give 13f in 71% yield.
Finally, 1-methoxy-3-methylbenzene was used to test a
benzene derivative. This compound reacted with (9, R1 = H,
R2 = H) to give 13v in 58% yield. This is an important
advantage of azido-enolonium species 10 in comparison to
their analogues 4 that do not react at all with 1-methoxy-3-
methylbenzene.11 Indeed, two or three methoxy group are
necessary to activate a benzene derivative to couple with 4 (R1
= Ph, R2 = H, see the structure in Scheme 1a).11 The reactivity
with other benzene derivatives will be explored further in a
later full report.
Scheme 4. Preliminary Experiments on Coupling of Azido-
Enolonium Species 10 with Allyltrimethylsilane (15),
Triazole (17), and Tetrazoles (19)
The intermediacy of azido-enolonium species 10 is
supported by IR studies of the reaction mixture (see the
Supporting Information). Thus, when 1-(4-methyl)phenylvinyl
azide 9 (R1 = Me, R2 = H) is made to react with 2-
methylindole, compound 12 (R1 = Me, R2 = H) is observed as
indicated by a strong signals at 1623 and 2111 cm−1 (Figure
S1). The latter signal is diagnostic for N3 species. Further,
when water is added the product 13k is formed. The formation
is accompanied by disappearance of the signal at 1623 cm−1
and formation of a new signal at approximately 1683 cm−1
(Figure S2). Importantly an azide signal remains at 2103 cm−1
(Figure S2) indicating release of inorganic azide anion. The
isolated product of the reaction has a characteristic carbonyl
stretch at 1676 cm−1 in solution (Figure S3). Importantly, the
purified product 13k has no signals in the 2110 cm−1 region
(Figure S3). Further evidence for 10 and 12 was found in the
reaction of (Z)-(1-azidobut-1-en-1-yl)benzene (9x) with 2-
methylindole (Scheme 3). When water is added a complex
reaction mixture results. From this product oxime 14 was
isolated in 16% yield. Compound 14 is not a hydrolysis
intermediate as neither it nor trace oxime products found in
other reactions undergo further hydrolysis to the ketone even
in the presence of aqueous acid. Apparently, the relatively
sterically hindered 12x does not undergo attack by water at the
When azido-enolonium species 10 (R2 = H) is prepared in
situ as before and allyltrimethylsilane (15, 1.5 equiv) is added
to the reaction mixture, the products 16a and 16b form within
3 h and are isolated in 48% and 51% yield, respectively. The
same azido-enolonium species also reacts with triazole (17)
within 18 h to afford the α-triazolium acetophenone 18 in 51%
yield. Finally, 10 reacts with tetrazole and 5-methyl-1H-
tetrazole to give the coupling products 20a in 38% yield and
20b in 46% yield.
In summary, we have presented the first example of azido-
enolonium species and outlined their reactivity in arylation,
allylation, and N-heteroarylation reactions. These studies show
that azido-enolonium species 8 (Scheme 1b) are as reactive as
ketone-derived enolonium species 4 (Scheme 1a), show
increased reactivity toward a benzene derivative, and
compatibility with a wide range of common functional groups.
The mechanism is supported by IR studies. Further studies on
the structure and reactivity of this new species will follow.
ASSOCIATED CONTENT
* Supporting Information
■
sı
Scheme 3. Oxime Formation for a Hindered Product
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03824.
Experimental description, characterization data (NMR,
IR, HRMS), and reproduction of NMR spectra; IR
spectra of the reaction mixture before and after water
was added (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Alex M. Szpilman − Ariel University, Ariel, Israel;
orcid.org/0000-0001-7790-4129;
Email: amszpilman@gmail.com
C
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Other Authors
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Atul A. More − Ariel University, Ariel, Israel;
orcid.org/0000-0003-4604-5354
Sourav K. Santra − Ariel University, Ariel, Israel
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b03824
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by an Israel Science Foundation
Individual Research Grant (Grant No. 870/19) to AMS.
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