Aminium cation-radical catalysed selective hydration of (E)-aryl enynes

Article abstract of DOI:10.1039/d1cc02257a

The hydration of carbon-carbon triple bonds is an important and atom economic synthetic transformation. Herein, we report a mild and selective method for the catalytic Markovnikov hydration of (E)-aryl enynes to the corresponding enones, mediated through the bench-stable aminium salt, tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA). The chemoselective and diastereoselective method proceeds under neutral metal-free conditions, delivering excellent product yields from terminal and internal alkyne units. The synthesis of biologically important (E)-3-styrylisocoumarins, including a formal synthesis of the natural product achlisocoumarin III, demonstrates the utility of this novel transformation.

Full text of DOI:10.1039/d1cc02257a

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Aminium cation-radical catalysed selective
hydration of (E)-aryl enynes†
Cite this: Chem. Commun., 2021,
57, 6991
a
a
Marie-Claire Giel,a Andrew S. Barrow,
Christopher J. Smedley,
b
cd
Received 17th May 2021,
Accepted 14th June 2021
William Lewis
and John E. Moses
*
DOI: 10.1039/d1cc02257a
rsc.li/chemcomm
The hydration of carbon–carbon triple bonds is an important and atom catalysis. The (E)-enyne selective method delivers the Markovnikov
economic synthetic transformation. Herein, we report a mild and hydration products with (E)-configuration in excellent yield.
selective method for the catalytic Markovnikov hydration of (E)-aryl
The selective hydration of enynes to enones presents a signifi-
enynes to the corresponding enones, mediated through the bench- cant challenge due to competing alkene hydration potential.15 The
stable aminium salt, tris(4-bromophenyl)ammoniumyl hexachloroanti- few examples that have been reported require either strong Brønsted
monate (TBPA). The chemoselective and diastereoselective method acids15a or mercury(II) salt catalysts.17 During our work on single-
proceeds under neutral metal-free conditions, delivering excellent electron transfer reactions,18 we made an observation that led us to
product yields from terminal and internal alkyne units. The synthesis envisage a new approach for enyne hydration mediated through a
of biologically important (E)-3-styrylisocoumarins, including a formal cation-radical initiated pathway. In the presence of the aminium
synthesis of the natural product achlisocoumarin III, demonstrates the cation-radical salt tris(4-bromophenyl)ammoniumyl hexachloroanti-
utility of this novel transformation.
monate (TBPA; Ledwith–Weitz salt),19 (E)-1-(but-1-en-3-yn-1-yl)-4-
methoxybenzene (1) underwent hydration to the aryl enone 2 in
Alkyne hydration1 is an important, atom economical2 reaction trace quantities (Table 1). The following optimised protocol was
with enormous significance in organic synthesis. First reported subsequently developed: [0.1 eq. of TBPA, stirring for 2 h at 40 1C in
over 150 years ago, classical hydration reactions require strong reagent grade acetone that had been purged with nitrogen gas] that
protic acids such as H2SO4 to overcome the activation barriers increased the overall yield of the enone 2 to 74% (Table 1, entry 5).
of the otherwise exergonic process.3
A trace quantity of product 3, thought to arise through an aldol
Mechanistically, the hydration of a terminal alkyne follows either condensation process between 2 and acetone was also observed.
a Markovnikov addition pathway to give the ketone or the anti-
Markovnikov route to an aldehyde; non-symmetrical internal
alkynes, on the other hand, can lead to mixtures of both possible
ketone regioisomers (Fig. 1). The discovery by Kucherov in 18814 of
the rate acceleration of alkyne hydration by mercury(II) salts had a
significant impact in synthetic1 and industrial applications.5
However, the use of toxic mercury salts is undesirable, particularly
for large-scale applications, and several environmentally friendlier
protocols have emerged.1,6–16
Herein, we report a mild, atom economical, and metal-free
protocol for the hydration of aryl enynes using aminium ion
a La Trobe Institute for Molecular Science, Melbourne, VIC, 3086, Australia
b School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia
c Cancer Center, Cold Spring Harbor Laboratory, 1 Bungtown Road,
Cold Spring Harbor, NY, 11724, USA. E-mail: moses@cshl.edu
d Department of Chemistry, Stony Brook University, NY, 11794, USA
Fig. 1 (A) Classical Brønsted acid and Kucherov-type alkyne hydration
protocols; (B) this work: TBPA aminium cation-radical mediated hydration
of (E)-aryl enynes.
† Electronic supplementary information (ESI) available. CCDC 2059518. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1cc02257a
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TBPA catalyst, the 18O labelled hydration product was detected by
electrospray ionization (ESI) mass spectrometry, suggesting water
is the source of the incorporated oxygen (see ESI†).
Table
1
Optimisation of aminium cation radical-mediated enyne
hydrationa
The method performs well with both terminal and internal
(E)-aryl enynes and is tolerant of several functional groups, includ-
ing Cl (4l), I (4m), OAc (4n), OTs (4o); each giving consistently high
yields of the aryl enone products (5l–5o) (Scheme 1A). The speci-
ficity for enynes over alkynes is particularly noteworthy—in the
case of 4c, the propynyloxy group was unaffected by the hydration
conditions, giving the enone product 5c in 78% yield. The TBPA
mediated reaction of the enynol substrates 4p and 4q resulted in
the 2,2-dimethyltetrahydrofuran-3-yl products 5p (43%) and 5q
(29%), respectively. The tetrahydrofuran ring structure of 5q was
corroborated through single-crystal X-ray crystallography of the
4-nitrobenzoate derivative 5r (Scheme 1B). Both 5p and 5q
presumably incorporate acetone through an aldol-type process,
followed by intramolecular cyclisation. Interestingly, when the
(Z)-enynes 4s and 4t were exposed to the optimised reaction
conditions, no hydration products were detected, suggesting a
high level of selectivity (Scheme 1C).
W
Temperature
Time
(X)/h
Yield (%) Yield (%)
Entry Solvent (mol%) (T)/1C
of 2
of 3
1
2
3
4
5
CH2Cl2 10
CH2Cl2 10
0
1
1
2
2
2
Trace
Trace
0
0
0
0
0
40
40
40
40
THF
10
MeCN 10
Acetone 10
14
74
Trace
a
The reactions were performed on a 0.20 mmol scale of enyne 1;
isolated yields.
Interestingly, when high purity acetone20 was used as the solvent,
the yield of 2 was significantly reduced (28%). However, the
addition of 1.0 equivalent of water to the high purity acetone
resulted in 78% yield of the product (cf. 74% yield using reagent
grade ‘‘wet’’ acetone). Gradually increasing the concentration of
water to 5.0 equivalents led to a steady reduction in the yield (7%)
(see ESI,† T1). TBPA is known to be degraded by water to tris
(4-bromophenyl)amine, which itself, when used in place of TBPA,
was inactive (see ESI†).21,22 When the enyne 1 was taken into high
purity acetone followed by the addition of 1.0 eq. of H218O and
Mechanistically, TBPA mediated reactions generally follow: (i) a
cation-radical mediated pathway,23 and/or (ii) a classic Brønsted
acid directed process.24 To investigate, we first performed the
TBPA mediated hydration of enyne 1 in the presence of 2,6-di-
tert-butyl-4-methylpyridine (20 mol%) according to Gassman’s
test.23c,24 The outcome remained unchanged—the hydration
Scheme 1 Substrate scope for the aminium cation radical-mediated hydration protocol. a The reactions were performed on a 0.20 mmol scale of enyne
4; isolated yields. b Reaction performed at 50 1C. c Reaction proceeded for 3 h. d Reaction performed on 0.40 mmol scale of enyne 4l. e Reaction
performed on 0.29 mmol scale of enyne 4m. f Reaction performed on 0.41 mmol scale of enyne 4n. g Reaction performed on 0.62 mmol scale of enyne
4p. h Reaction performed at 45 1C. i Reaction performed on 0.94 mmol scale of enyne 4q. j No product observed. Compound 5r was synthesised from 5q
in two steps; i: TBAF (1.0 M in THF) (1.40 eq.), THF, r.t., 5 min, 94%, ii: 4-nitrobenzoyl chloride (1.00 eq.), Et3N (2.05 eq.), CH2Cl2, 0 1C – r.t., 0.5 h, 70% (see
ESI† for experimental procedures).
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Scheme 3 Investigation into substrate scope of 1,4-diarylenynes 11. a The
reactions were performed on a 0.20 mmol scale; isolated yields. b Reaction
performed on 0.66 mmol of 1,4-diarylenyne 11j for 7 h.
in 82% yield. A selection of methyl (E)-2-(4-phenylbut-3-en-1-yn-
1-yl)benzoate derivatives (12) were subsequently converted to
the corresponding (E)-3-styrylisocoumarins (13) in good yield
(30–82%) under the mild reaction conditions. Notably, the
synthesis of (E)-3-styrylisocoumarin 13j constitutes a formal
synthesis of the natural product, achlisocoumarin III (13k).28b
In summary, we have developed a novel and selective
method for the hydration of conjugated (E)-aryl enynes cata-
lysed by the cation-radical salt TBPA. The new protocol abets
the hydration of both terminal and internal conjugated enynes
in good to excellent yield. The aryl enone hydration products
are prized synthetic intermediates with the ability to undergo a
range of valuable chemistries including intramolecular cyclisa-
tion to yield isocoumarin-type cores. The application of the
methodology was showcased in the formal synthesis of the
3-styrylisocoumarin natural product, achlisocoumarin III. We
believe the novel aminium radical mediated hydration method
is a valuable addition to the toolbox of alkyne reactivity,
offering a new mild and selective pathway to useful synthetic
intermediates.
Scheme 2 A plausible working mechanism for the TBPA catalysed hydra-
tion of the (E)-aryl enynes.
product was obtained in a comparable 68% yield—suggesting
Brønsted acid catalysis was unlikely. In the presence of the radical
scavenger TEMPO (20 mol%), no hydration of 1 was observed.
Similarly, introducing oxygen to the solvent resulted in lower
product yields (see ESI†). Collectively, these control experiments
lend support for a cation-radical pathway.
We tentatively propose the catalytic cycle illustrated in
Scheme 2 to rationalise the selective hydration of (E)-aryl enynes
and the formation of related products. Initiation of the cation-
radical mediated process is presumed to proceed by oxidation of
the (E)-enyne 4 by TBPA to give the cation-radical [SbCl6]À inter-
mediate 6. Nucleophilic attack by water on intermediate 6 gives the
cation-radical enol intermediate 7, that upon tautomerisation
delivers the ketone intermediate 8. Reduction of 8 through
single-electron transfer from the triarylamine (or an equivalent
species) yields the (E)-aryl enone 5 along with regeneration of
TBPA.23,25 Alternatively, and consistent with the work of Mares and
co-workers,26 it is feasible that the cation-radical intermediates 7
and/or 8 (or related, e.g., 6) could be chain propagating species
with TBPA functioning as the initiator.
We thank Cold Spring Harbor Laboratory for Developmental
Funds from the NCI Cancer Center Support Grant 5P30CA045508
(J. E. M.) and the Australian Research Council (J. E. M.) (Future
Fellowship; FT170100156) for financial support.
The formation of the 2,2-dimethyltetrahydrofuran-3-yl pro-
ducts (e.g., 5p, where R = –CH2CH2OH) can be rationalised by
the reversible aldol-type condensation of 7 with acetone to give
intermediate 9, followed by dehydrative cyclisation. When
R = H, aldol condensation of 7 with acetone explains the origin
of the side product 10.
To showcase the potential utility of the new methodology,
we selected the important 3-styryliscoumarin core, which is a
prevalent motif in several natural products.27–30 We envisaged a
pathway where enyne hydration of 11 is followed by cyclisation
of the enol tautomer 12 to deliver the 3-styryliscoumarin core 13
(Scheme 3). Using methyl (E)-2-(4-(2,4-dimethoxyphenyl)but-3-
en-1-yn-1-yl)benzoate (11a) as a model substrate with 10 mol%
TBPA at 50 1C for 1 h, the styrylisocoumarin (13a) was isolated
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 For a comprehensive review of the catalytic hydration of alkynes to
the year 2007, see: L. Hintermann and A. Labonne, Synthesis, 2007,
1121–1150.
2 B. M. Trost, Science, 1991, 254, 1471–1477.
3 (a) M. Berthelot, Ann. Chim. Phys., 1863, 67, 52; (b) H. Lagermarck
and A. Eltekoff, Chem. Ber., 1877, 10, 637; (c) R. Fittig and
A. Schrohe, Chem. Ber., 1875, 8, 367.
4 (a) M. Kucherov, J. Russ. Chem. Soc., 1881, 13, 533–542;
(b) M. Kutscheroff, Berichte der Dtsch. Chem. Gesellschaft, 1881, 14,
1540–1542; (c) M. Kutscheroff, Chem. Ber., 1884, 17, 13–29.
5 A. S. Hester and K. Himmler, Ind. Eng. Chem., 1959, 51, 1424–1430.
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6 (a) W.-L. Wong, K.-P. Ho, L. Y. S. Lee, K.-M. Lam, Z.-Y. Zhou, 17 (a) M. E. Jung and N. Nishimura, Org. Lett., 2001, 3, 2113–2115;
T. H. Chan and K.-Y. Wong, ACS Catal., 2011, 1, 116–119; (b) G. La
Sorella, L. Sperni, P. Ballester, G. Strukul and A. Scarso, Catal. Sci.
Technol., 2016, 6, 6031–6036.
7 For examples of [Au] catalysed alkyne hydration see: (a) E. Mizushima,
K. Sato, T. Hayashi and M. Tanaka, Angew. Chem., Int. Ed., 2002, 41,
4563–4565; (b) W. Wang, B. Xu and G. B. Hammond, J. Org. Chem.,
2009, 74, 1640–1643; (c) L. Xie, Y. Wu, W. Yi, L. Zhu, J. Xiang and W. He,
J. Org. Chem., 2013, 78, 9190–9195; (d) S. Liang, J. Jasinski,
G. B. Hammond and B. Xu, Org. Lett., 2015, 17, 162–165.
(b) N. Ohyabu, T. Nishikawa and M. Isobe, J. Am. Chem. Soc., 2003,
125, 8798.
18 (a) P. Sharma, D. J. Ritson, J. Burnley and J. E. Moses, Chem.
Commun., 2011, 47, 10605–10607; (b) J. C. Moore, E. S. Davies,
D. A. Walsh, P. Sharma and J. E. Moses, Chem. Commun., 2014,
50, 12523–12525; (c) J. Burnley, G. Carbone and J. E. Moses, Synlett,
2013, 652–656; (d) G. Carbone, J. Burnley and J. E. Moses, Chem.
Commun., 2013, 49, 2759–2761.
19 F. A. Bell, A. Ledwith and D. C. Sherrington, J. Chem. Soc. C, 1969,
2719–2720.
8 For examples of [Ag] catalysed alkyne hydration see: (a) R. Das and
D. Chakraborty, Appl. Organomet. Chem., 2012, 26, 722–726; 20 The high purify acetone was sourced from a commercial supplier
(b) K. T. Venkateswara Rao, P. S. Sai Prasad and N. Lingaiah, Green with a maximum water content of 0.01%.
Chem., 2012, 14, 1507–1514; (c) Q. Dong, N. Li, R. Qiu, J. Wang, 21 Reagent-grade acetone was subsequently used for investigating the
C. Guo and X. Xu, J. Organomet. Chem., 2015, 799, 122–127. substrate scope.
9 For examples of [Ru] catalysed alkyne hydration, see: 22 M. R. Talipov and R. Rathore, in Organic Redox Systems: Synthesis
(a) D. B. Grotjahn and D. A. Lev, J. Am. Chem. Soc., 2004, 126,
12232–12233; (b) L. Li, M. Zeng and S. B. Herzon, Angew. Chem., Int.
Ed., 2014, 53, 7892–7895.
Properties, and Applications, ed. T. Nishinaga, John Wiley & Sons,
Hoboken New Jersey, 2015, ch. 5, pp. 133–134.
23 (a) D. J. Bellville, D. D. Wirth and N. L. Bauld, J. Am. Chem. Soc.,
1981, 3, 718–720; (b) N. L. Bauld, D. J. Bellville, B. Harirchian,
K. T. Lorenz, R. A. Pabon, Jr., D. W. Reynolds, D. D. Wirth,
H.-S. Chiou and B. K. Marsh, Acc. Chem. Res., 1987, 20, 371–378;
(c) D. W. Reynolds, K. T. Lorenz, H. S. Chiou, D. J. Bellville,
R. A. Pabon and N. L. Bauld, J. Am. Chem. Soc., 1987, 109,
4960–4968; (d) N. L. Bauld, Tetrahedron, 1989, 45, 5307–5363.
10 For examples of [Pd] catalysed alkyne hydration, see: (a) Z. Zhang, L. Wu,
J. Liao, W. Wu, H. Jiang, J. Li and J. Li, J. Org. Chem., 2015, 80, 7594–7603;
(b) T. Kusakabe, Y. Ito, M. Kamimura, T. Shirai, K. Takahashi,
T. Mochida and K. Kato, Asian J. Org. Chem., 2017, 6, 1086.
11 For examples of [Fe] catalysed alkyne hydration, see: (a) J. Park,
J. Yeon, P. H. Lee and K. Lee, Tetrahedron Lett., 2013, 54, 4414–4417;
(b) M. Bassetti, S. Ciceri, F. Lancia and C. Pasquini, Tetrahedron 24 P. G. Gassman and D. A. Singleton, J. Am. Chem. Soc., 1984, 106,
Lett., 2014, 55, 1608–1612. 7994–7995.
12 For examples of [Cu] catalysed alkyne hydration, see: (a) Q. Mei, H. Liu, 25 D. H. R. Barton, G. Leclerc, P. D. Magnus and I. D. Menzies, J. Chem.
M. Hou, H. Liu and B. Han, New J. Chem., 2017, 41, 6290–6295; Soc., Chem. Commun., 1972, 447–449.
(b) T.-F. Niu, D.-Y. Jiang, S.-Y. Li, X.-G. Shu, H. Li, A.-L. Zhang, 26 R. Tang, H. J. Yue, J. F. Wolf and F. Mares, J. Am. Chem. Soc., 1978,
J.-Y. Xu and B.-Q. Ni, Tetrahedron Lett., 2017, 58, 1156–1159. 100, 5248–5249.
13 For examples of [Co] catalysed alkyne hydration, see: (a) T. Tachinami, 27 A. Saeed, Eur. J. Med. Chem., 2016, 116, 290–317.
T. Nishimura, R. Ushimaru, R. Noyori and H. Naka, J. Am. Chem. Soc., 28 (a) A. Saeed and P. A. Mahesar, Tetrahedron, 2014, 70, 1401–1407;
2013, 135, 50–53; (b) Z. Lin, Z.-M. Zhang, Y.-S. Chen and W. Lin, Angew.
Chem., Int. Ed., 2016, 55, 13739–13743.
14 D. Chen, D. Wang, W. Wu and L. Xiao, Appl. Sci., 2015, 5, 114–121.
(b) A. Saeed and N. H. Rama, Arabian J. Sci. Eng., 1996, 21, 403–406;
(c) A. Saeed, N. H. Rama and M. Arfan, J. Heterocycl. Chem., 2003, 40,
519–522.
15 (a) T. Tsuchimoto, T. Joya, E. Shirakawa and Y. Kawakami, Synlett, 29 E. M. K. Wijeratne, P. A. Paranangama and A. A. L. Gunatilaka,
2000, 1777–1778; (b) N. Olivi, E. Thomas, J.-F. Peyrat, M. Alami and Tetrahedron, 2006, 62, 8439–8446.
J.-D. Brion, Synlett, 2004, 2175–2179; (c) W. Liu, H. Wang and 30 (a) P. Saikia and S. Gogoi, Adv. Synth. Catal., 2018, 360, 2063–2075;
C.-J. Li, Org. Lett., 2016, 18, 2184–2187.
16 G. Oss, J. Ho and T. V. Nguyen, Eur. J. Org. Chem., 2018, 3974–3981.
(b) A. Saeed, H. Rafique and Z. Ashraf, J. Asian Nat. Prod. Res., 2013,
15, 37–41.
6994 | Chem. Commun., 2021, 57, 6991–6994
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