Iodine-mediated hydration of alkynes on keto-functionalized scaffolds: Mechanistic insight and the regiospecific hydration of internal alkynes

Article abstract of DOI:10.3762/bjoc.15.265

An iodine-mediated hydration reaction of alkynes serves as a green alternative to metal-catalyzed procedures. Previous work has shown that this method works well with terminal alkynes on keto-functionalized scaffolds, including 1,3-dicarbonyls and their heteroatom analogues. It was hypothesized that the reaction proceeds through a 5-exo-dig neighboring group participation (NGP) cyclization and an α-iodo intermediate. The work described herein probes the existence of the intermediate through NMR investigations and explores the scope of the hydration process with internal alkynes. The NMR experiments confirm the existence of the α-iodo intermediate, and methodology studies demonstrate that alkyl-capped, asymmetric, internal alkynes undergo a regiospecific hydration, also via the 5-exo-dig NGP pathway.

Full text of DOI:10.3762/bjoc.15.265

Iodine-mediated hydration of alkynes on keto-functionalized
scaffolds: mechanistic insight and the regiospecific hydration
of internal alkynes
Zachary Lee, Brandon R. Jones, Nyochembeng Nkengbeza, Michael Phillips,
Kayla Valentine, Alexis Stewart, Brandon Sellers, Nicholas Shuber and Karelle S. Aiken*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2747–2752.
Chemistry & Biochemistry, Georgia Southern University, PO Box
8064, Statesboro, GA 30460, USA
doi:10.3762/bjoc.15.265
Received: 26 July 2019
Email:
Accepted: 04 November 2019
Published: 14 November 2019
Karelle S. Aiken* - kaiken@georgiasouthern.edu
* Corresponding author
Associate Editor: L. Vaccaro
Keywords:
© 2019 Lee et al.; licensee Beilstein-Institut.
License and terms: see end of document.
α-iodo intermediate; internal alkyne; iodine-mediated hydration;
neighboring group participation; regiospecific hydration
Abstract
An iodine-mediated hydration reaction of alkynes serves as a green alternative to metal-catalyzed procedures. Previous work has
shown that this method works well with terminal alkynes on keto-functionalized scaffolds, including 1,3-dicarbonyls and their
heteroatom analogues. It was hypothesized that the reaction proceeds through a 5-exo-dig neighboring group participation (NGP)
cyclization and an α-iodo intermediate. The work described herein probes the existence of the intermediate through NMR investiga-
tions and explores the scope of the hydration process with internal alkynes. The NMR experiments confirm the existence of the
α-iodo intermediate, and methodology studies demonstrate that alkyl-capped, asymmetric, internal alkynes undergo a regiospecific
hydration, also via the 5-exo-dig NGP pathway.
Findings
The Kucherov reaction is one of the most well-known ap- of less harmful reagents. Success has been obtained with many
proaches for the hydration of alkynes. This reaction, originally other transition metal salts, for example, palladium(II) [4,5],
published in 1881, requires the use of mercury(II) salts in cata- rhodium(III) [6], copper(II) [7], silver(I) [8], and gold(I)/(III)
lytic quantities [1,2]. Countless studies have shown that [9-12]. While less toxic than mercury, such catalysts are still
mercury-based compounds are extremely harmful to environ- environmental hazards and tend to be costlier [13,14]. The
mental and biological systems [3]. In light of mercury’s toxici- iodine-mediated hydration described herein is a viable solution
ty, the synthetic community has given much attention to the use to these issues [15,16]. This metal-free method produces
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innocuous, water-soluble byproducts, such as iodide and sulfate were much slower as compared to what has been reported for
salts, and uses inexpensive molecular iodine to facilitate the the larger-scale processes.
hydration. Moreover, unlike other metal-free alkyne hydration
procedures, heat and strong acids are not required [17-20]. The Initial attempts to observe the intermediate 9 involved the treat-
reaction proceeds under mild conditions at room temperature.
ment of 8 with two equivalents of molecular iodine in deuter-
ated acetonitrile (Figure 1a and Figure 1b). Significant changes
Previous work by our group has shown that terminal alkynes on in the 1H NMR spectrum of 8 were observed after 21 h, where
keto scaffolds undergo iodine-mediated hydration to form 1,4- new signals emerged and the substrate’s resonances disap-
diketo products 2 (Scheme 1) [15]. At that time, our studies peared. However, signals for 10 were also observed, suggesting
revealed that a keto group must be present in the substrate, as that as soon as the intermediate 9 was formed, it was converted
the hydration requires neighboring group participation for to the final hydration product 10. Quenching of this reaction
5-exo-dig cyclization from 3 to 4. It was further hypothesized mixture cleanly resulted in the generation of 10 (Figure 1d).
that the reaction continues through an α-iodo intermediate 6, a Changes in the resonances for the phenyl protons, H-8, H-9, and
tautomer of 5, from which deiodination followed by tautomer- H-10, if any, were indiscernible.
ization of 7 produces the final product 2.
To increase the lifetime of the intermediate 9 so that more
In the studies described herein, NMR experiments were used to detailed analyses could be performed, the iodonium source was
probe the existence of an α-iodo intermediate 9, and methodolo- changed from I2 to ICl (Figure 1c). The chloride anion pro-
gy work was used to investigate the outcome of the reaction duced using ICl is less nucleophilic than iodide released from
using alkyl-capped, asymmetric, internal alkynes 11.
molecular iodine. As such, it was thought that the deiodination
of intermediate 9 would proceed at a slower rate with Cl− and
The NMR investigations utilized different electrophilic iodine hence, the intermediate would be longer lasting. This proved
sources and the β-keto sulfone 8, which allowed for detailed true: after five hours in the presence of two equivalents of ICl,
analysis of the reaction pathway. Compound 8, having a rela- signals at 2.85–2.93 ppm, 3.96 ppm, and 4.36 ppm, in addition
tively long reaction time of 6.5 h, was chosen for this study to the phenyl protons, were observed, without any evidence of
because its rate of reaction fitted the NMR timescale [15]. It 10 being present. Based on literature reports for α-iodo ketones
should also be noted that the NMR experiments were per- [21,22], it was clear that the signal at 3.96 ppm corresponded to
formed in NMR tubes without stirring. As such, the reactions H-1 in 9. This was substantiated by a 1H,13C-HSQC experi-
Scheme 1: Proposed mechanism for the iodine-mediated hydration of terminal alkynes 1 [15].
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Figure 1: 1H NMR investigations on the iodine-mediated hydration of 8 (the range of 1.75–5.25 ppm is displayed). a) Spectrum of starting material 8.
b) Spectrum of 8 upon treatment with two equivalents of I2. c) Spectrum of 8 upon treatment with two equivalents of ICl. d) Spectrum of the hydration
product 10. Figure 1a inset shows the phenyl region in the range of 7.55–8.00 ppm.
ment, which showed the signal corresponding to C-1 at is an excellent leaving group and therefore, the generation of
6.92 ppm in the 13C NMR spectrum, upfield from those for C-3 α-substituted hydration products through the addition of suit-
and C-4 (Figure 2). This relatively low 13C chemical shift was able nucleophiles to the reaction mixture is a strong possibility.
evidenced to be a result of the shielding effect of the iodo sub-
stituent on C-1. Similarities in the signals observed in Figure 1b Having proven the existence of the α-iodo intermediate 9, we
and Figure 1c confirmed that the I2- and ICl-mediated hydra- turned our attention to investigating the reaction of internal
tions occurred via the same intermediate. Furthermore, alkynes 11 to examine the regioselectivity of the hydration
quenching of the ICl-facilitated reaction also resulted in the for- process. Ester, sulfone, and phosphonate substrates were em-
mation of compound 10.
ployed and, in all cases, the internal alkyne unit was capped by
an ethyl group (Scheme 2). In general, asymmetric, internal
Importantly, the existence of the α-iodo intermediate 9 holds alkynes capped by alkyl groups typically yield two ketone prod-
promise for further development of the reaction. The iodo group ucts, as the incorporation of the new oxo group can occur at
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Figure 2: 1H—13C HSQC spectrum for α-iodo intermediate 9 in CD3CN in the range of 0.90–5.00 ppm (for 1H NMR signals) and −1.0–77.0 ppm (for
13C NMR signals), respectively.
either carbon atom of the triple bond. In fact, unless the sub- with different variations, including adjustments in the reaction
strate contains a carbocation-stabilizing group, such as a phe- time, variations in the equivalents of iodine used, and the addi-
nyl unit, hydration of asymmetric, internal alkynes results in a tion of water to facilitate the process. However, neither the
mixture of regioisomers [20,23,24]. Moreover, per Baldwin’s starting material 11c nor 15c were ever recovered. In contrast,
rules, with neighboring group participation, a 5-exo-dig (via 13 the phosphonate 11d and the sulfone 11e smoothly converted to
and 14) or 6-endo-dig pathway (via 16 and 17), or both, are 15d and 15e in yields of 68% and 71%, respectively. The
possible outcomes for such alkynes [25]. The 5-exo-dig route hydration of the phosphonate required 22 h, while the reaction
would provide 15, while the 6-endo-dig cyclization would result of the sulfone was complete in 3.5 h. Overall, successful
in diketone 18.
outcomes were obtained for the phosphonate, sulfone, and
methyl/ethyl ester substrates at room temperature under the
Significantly, the iodine-mediated hydration of all substrates 11 mild reaction conditions employed.
that were studied gave rise to one type of product, 15
(Scheme 3). This indicated that the reaction with alkyl-capped, Conclusion
internal alkynes occurred exclusively through the 5-exo-dig The studies described herein confirm the existence of an α-iodo
route, a regiospecific outcome. Accordingly, derivatives of 18 intermediate in the iodine-mediated hydration of alkynes on a
were never observed.
keto scaffold and also demonstrate that the reaction is regiospe-
cific for alkyl-capped, asymmetric, internal alkynes 11. The
The methyl and ethyl esters 11a and 11b were subjected to the α-iodo intermediate 9 was observed using NMR spectroscopic
standard conditions, two equivalents of iodine in acetonitrile at investigations to monitor the conversion from alkyne to ketone
room temperature [15]. Substrates 11a and 11b provided the in situ. Moreover, the use of ICl in the NMR studies, as
hydration products in good yield, 80% for 15a and 85% for opposed to I2, allowed for clear and unambiguous characteriza-
15b. For the tert-butyl ester 11c, multiple attempts were made tion of the intermediate 9. With respect to the internal alkynes
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Scheme 2: Possible outcomes of the iodine-mediated hydration of asymmetric, internal alkynes with neighboring group participation via the 5-exo-dig
and 6-endo-dig pathway, respectively.
Scheme 3: Iodine-mediated hydration of asymmetric, internal alkynes 11a–e.
11, the reaction was regiospecific, occurring exclusively via a well as phosphonate and sulfone analogues of the keto scaffold.
5-exo-dig NGP pathway. Yields between 68% and 85% were Notably, the existence of the iodo intermediate points at the
obtained for 15 using the representative substrates 11. This potential to synthesize α-substituted targets upon further devel-
hydration process is amenable to methyl and ethyl esters, as opment of the method.
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Acknowledgements
All authors would like to acknowledge the support of the
Georgia Southern (GS) University Chemistry and Biochemistry
Department. NS acknowledges the GS Honors Program. ZL
acknowledges the GS College of Science and Mathematics’
(COSM) College Office of Undergraduate Research (COUR)
and NN acknowledges the GS McNair Scholars Program.
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