Vinyl Triflate–Aldehyde Reductive Coupling–Redox Isomerization Mediated by Formate: Rhodium-Catalyzed Ketone Synthesis in the Absence of Stoichiometric Metals

Article abstract of DOI:10.1002/chem.201903668

Direct conversion of aldehydes to ketones is achieved via rhodium-catalyzed vinyl triflate-aldehyde reductive coupling-redox isomerization mediated by potassium formate. This method circumvents premetalated C-nucleophiles and discrete redox manipulations typically required to form ketones from aldehydes.

Full text of DOI:10.1002/chem.201903668

A Journal of
Accepted Article
Title: Vinyl Triflate-Aldehyde Reductive Coupling-Redox Isomerization
Mediated by Formate: Rhodium-Catalyzed Ketone Synthesis in
the Absence of Stoichiometric Metals
Authors: Michael Joseph Krische, William G. Shuler, Robert A. Swyka,
Tabitha T. Schempp, and Brian J. Spinello
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To be cited as: Chem. Eur. J. 10.1002/chem.201903668
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Chemistry - A European Journal
10.1002/chem.201903668
Vinyl Triflate-Aldehyde Reductive Coupling-Redox Isomerization Mediated by Formate:
Rhodium-Catalyzed Ketone Synthesis in the Absence of Stoichiometric Metals
William G. Shuler, Robert A. Swyka, Tabitha T. Schempp, Brian J. Spinello,
and Michael J. Krische*
University of Texas at Austin, Department of Chemistry
1
05 E 24th St. (A5300), Austin, TX 78712-1167 (USA)
<Graphical Abstract>
Beyond Stoichiometric Metals. Direct conversion of aldehydes to ketones is achieved via
rhodium-catalyzed vinyl triflate-aldehyde reductive coupling-redox isomerization mediated by
potassium formate. This method circumvents premetalated C-nucleophiles and discrete redox
manipulations typically required to form ketones from aldehydes.
Keywords: Rhodium, Redox-Isomerization, Transfer Hydrogenation, Formate, C-C Bond
Formation.
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Vinyl Triflate-Aldehyde Reductive Coupling-Redox Isomerization Mediated by Formate:
Rhodium-Catalyzed Ketone Synthesis in the Absence of Stoichiometric Metals**
William G. Shuler, Robert A. Swyka, Tabitha T. Schempp, Brian J. Spinello, and Michael J.
Krische*
[
*]
Dr. William G. Shuler, Dr. Robert A. Swyka, Ms. Tabitha T. Schempp, Mr. Brian J. Spinello and Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry
1
05 E 24th St. (A5300), Austin, TX 78712-1167 (USA)
Email: mkrische@mail.utexas.edu
[
**]
The Welch Foundation (F-0038) and the NIH (RO1-GM069445) are acknowledged for partial support of this research.
Eli Lilly and Company is acknowledged for LIFA postdoctoral fellowship funding (R.A.S.).
Metal-catalyzed carbonyl reductive coupling offers an alternative to the use of
stoichiometric organometallic reagents in an ever-increasing range of C-C bond forming
processes.[1] Despite significant advances in this field, many catalytic reactions of this type
exploit reductants that are metallic (Mn, Zn), pyrophoric (Et
3
B, Et Zn) or expensive/mass-
2
intensive (R SiH, TDAE), which pose issues of safety and waste generation, impacting the
3
ultimate metric of cost.[2] Inspired by the enormous impact of hydroformylation, our laboratory
has advanced methods for catalytic carbonyl reductive coupling via hydrogenation, transfer
hydrogenation and hydrogen auto-transfer.[3] In the course of these studies, ketone syntheses
[
4]
were developed based on hydrogen-mediated styrene-anhydride reductive coupling, hydrogen-
[5]
mediated aryl halide-ketone reductive cyclizations, and the transfer hydrogenative coupling of
alcohols (or aldehydes) with dienes or alkynes.[6] In a recent step forward, a regiodivergent
rhodium-catalyzed ketone synthesis was developed wherein aldehydes are directly converted to
branched or linear alkyl ketones through formate-mediated vinyl bromide-aldehyde reductive
coupling-redox isomerization.[7,8,9,10] The ability to transfer aliphatic fragments complements the
scope of related redox-neutral ketone formations involving aryl halide-aldehyde C-C
coupling.[11,12,13] Further, unlike ketone formation through metal-catalyzed reductive couplings to
carboxylic acid derivatives[14,15] (including redox-active esters[16]), stoichiometric metallic
reductants are not required.
Given the well-established ability of rhodium(I) complexes to engage vinyl and aryl
sulfonates in oxidative addition,[17] along with their ability to catalyze redox isomerization[9,10]
and reductive C-C coupling,[1,3] it was posited that vinyl triflates might be competent partners for
rhodium-catalyzed aldehyde reductive coupling-redox isomerization mediated by formate. The
availability of vinyl triflates from structurally diverse ketones provided further impetus to
explore their use in this capacity.[18] Here, we report that vinyl triflates derived from ketones
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Chemistry - A European Journal
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engage in efficient reductive coupling-redox isomerization to form cycloalkyl ketones. Like the
parent vinyl bromide-aldehyde reductive coupling-redox isomerizations, this protocol may be
viewed as an alternative to the addition of stoichiometric organometallic reagents to Weinreb or
morpholine amides,[19,20] however, complementing the scope of the corresponding vinyl bromide
couplings, cycloalkyl fragments are amenable to transfer.
In an initial series of experiments, conditions optimized for the rhodium-catalyzed
reductive coupling-redox isomerization of vinyl bromides mediated by formate were applied to
[
7]
the coupling of piperonal 1a with vinyl triflate 2a (Table 1). Remarkably, although cyclic vinyl
bromides were not competent pronucleophiles for rhodium-catalyzed reductive coupling-redox
isomerization (<40% yield despite extensive optimization), the desired product 3a could be
formed from equimolar quantities of 1a and 2a in 79% yield after chromatographic isolation.
Notwithstanding the aforesaid change in stoichiometry, deviation from these conditions did not
avail further improvement. As corroborated by GC-MS, application of these conditions to acyclic
vinyl triflates (e.g. hex-1-en-2-yl trifluoromethanesulfonate) provides <10% yield of the desired
coupling products due to competing elimination to form alkyne byproducts.[21]
Table 1. Selected optimization experiments in the rhodium-catalyzed reductive coupling-redox
a
isomerization of piperonal 1a with vinyl triflate 2a.
aYields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.
To assess the scope of this process, optimal conditions for the rhodium-catalyzed
reductive coupling-redox isomerization of piperonal 1a with vinyl triflate 2a were applied to
structurally diverse aldehydes 1a-1n. Aromatic aldehydes 1a-1h, heteroaromatic aldehydes 1i-
1
k, and aliphatic aldehydes 1l-1n were converted to the corresponding cyclohexyl ketones 3a-3n
in moderate to good yield. As illustrated by the formation of products 3d-3f and 3j, aryl fluoride
and aryl chloride functional groups are tolerated. Additionally, the formation of product 3m
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Table 2. Rhodium-catalyzed reductive coupling-redox isomerization of diverse aldehydes 1a-1n
with vinyl triflate 2a to form cyclohexyl ketones 3a-3n.a
aYields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.
demonstrates compatibility with olefinic functional groups under the reducing conditions of the
reaction. The formation of adducts 3l-3n, which are derived from aliphatic aldehydes, was
accompanied by trace (<5% yield) quantities of aldol dimerization product (Table 2).
The feasibility of utilizing alternate vinyl triflates 2b-g was examined in reductive
couplings with piperonal 1a (Table 3). The carbocyclic vinyl triflates 2b-2d, which include the
ketal-containing vinyl triflate 2b, the sterically hindered vinyl triflate 2c derived from (+)-
nopinone, and the vinyl triflate 2d derived from cyclooctanone, were competent partners for
reductive coupling-redox isomerization. Additionally, the heterocyclic vinyl triflates derived
from tetrahydro-4-pyranone (2e) and 4-piperidinone (2f) were converted to the corresponding
ketones 3r and 3s in good yields. Notably, these processes complement the scope of
corresponding vinyl bromide couplings, which are restricted to acyclic proelectrophiles.[7]
Conversely, with the exception of vinyl triflate 2g derived from cyclohexane carboxaldehyde,
attempted reactions of acyclic vinyl triflates are inefficient (<10% yield) due to competing
elimination to form alkynes (vide supra).[21]
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Table 3. Rhodium-catalyzed reductive coupling-redox isomerization of piperonal 1a with vinyl
a
triflates 2b-2g to form ketones 3o-3t.
a
b
Yields are of material isolated by silica gel chromatography. Vinyl triflate (200 mol%). See Supporting Information for further
experimental details.
The catalytic mechanism was corroborated through a series of deuterium labeling
experiments (Scheme 1). Exposure of aldehyde deuterio-1a and vinyl triflate 2a to standard
2
reaction conditions provides deuterio-3a, which incorporates deuterium (>95% H) at the β-
carbon. Exposure of deuterio-iso-3a to
Scheme 1. Proposed catalytic mechanism as
corroborated by isotopic labelling studies.
standard reaction conditions provides
deuterio-3a, with an identical pattern of
deuterium incorporation (>95% 2H).
These results are consistent with vinyl
triflate-aldehyde reductive coupling to
form a transient allylic alcohol that is
a
subject
isomerization.[7,9,10] Finally, aldehyde 1a
was exposed to NaO D under standard
conditions. Deuterium was not
to
internal
redox-
2
incorporated, which is again consistent
with internal redox-isomerization of a
transient allylic alcohol.
In summary, we report a method
for the direct conversion of aldehydes to
ketones via rhodium-catalyzed vinyl
triflate-aldehyde reductive coupling-
a
The pattern and extent of deuterium incorporation was assessed
1
2
through H, H NMR and HRMS analyses. See Supporting
Information for further experimental details.
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redox isomerization mediated by potassium formate. Unlike classical protocols for the
preparation of ketones from aldehydes, the present method circumvents the use of stoichiometric
metals, premetalated C-nucleophiles and discrete redox manipulations. More broadly, this work
adds to a growing body of metal-catalyzed reductive couplings that signify a departure from the
use of stoichiometric organometallic reagents in C-C bond formation.[3]
References
[
1] For general reviews on metal-catalyzed reductive coupling, see: a) M. J. Krische, H.-Y. Jang,
Metal-Catalyzed Reductive Cyclization (C=C, C≡C, C=O Bonds), Comprehensive
Organometallic Chemistry III, Vol. 10 (Eds.: M. Mingos, R. Crabtree), Elsevier, Amsterdam,
2
006, pp 493−536; b) Metal-Catalyzed Reductive C−C Bond Formation, Topics in Current
Chemistry, Vol. 279 (Ed.: M. J. Krische) Springer, Berlin, Heidelberg, 2007; c) T. Moragas, A.
Correa, R. Martin, Chem. Eur. J. 2014, 20, 8242-8258; d) C. E. I. Knappke, S. Grupe, D.
Gärtner, M. Corpet, C. Gosmini, A. J. von Wangelin, Chem. Eur. J. 2014, 20, 6826-6842; e) K.
D. Nguyen, B. Y. Park, T. Luong, H. Sato, V. J. Garza, M. J. Krische, Science 2016, 354,
aah5133; f) M. Holmes, L. A. Schwartz, M. J. Krische, Chem. Rev. 2018, 118, 6026-6052; g) E.
Richmond, J. Moran, Synthesis 2018, 50, 499-513.
[
2
2] For a discussion on the characteristics of a scalable reaction, see: K. Rossen, J. Org. Chem.
019, 84, 4580-4582 and references cited therein.
[
3] For selected reviews on metal-catalyzed carbonyl reductive coupling via hydrogenation,
transfer hydrogenation and hydrogen auto-transfer see: a) M.-Y. Ngai, J.-R. Kong, M. J. Krische,
J. Org. Chem. 2007, 72, 1063-1072; b) H. Iida, M. J. Krische, Top. Curr. Chem. 2007, 279, 77-
1
04; c) J. F. Bower, M. J. Krische, Top. Organomet. Chem. 2011, 43, 107-138; d) A. Hassan, M.
J. Krische, Org. Proc. Res. Devel. 2011, 15, 1236-1242; e) J. M. Ketcham, I. Shin, T. P.
Montgomery, M. J. Krische, Angew. Chem. 2014, 126, 9294-9302; Angew. Chem. Int. Ed. 2014,
5
3, 9142-9150; f) S. W. Kim, W. Zhang, M. J. Krische, Acc. Chem. Res. 2017, 50, 2371-2380; g)
B. R. Ambler, S. K. Woo, Krische, M. J. ChemCatChem 2019, 11, 324-332; h) R. S. Doerksen,
C. C. Meyer, M. J. Krische, Angew. Chem. 2019, 131, DOI: 10.1002/ange.201905532; Angew.
Chem. Int. Ed. 2019, 58, DOI: 10.1002/anie.201905532.
[
4] a) Y.-T. Hong, A. Barchuk, M. J. Krische, Angew. Chem. 2006, 118, 7039-7042; Angew.
Chem. Int. Ed. 2006, 45, 6885-6888; b) J. S. Bandar, E. Ascic, S. L. Buchwald, J. Am. Chem.
Soc. 2016, 138, 5821-5824.
[
5] Shin, I.; Ramgren, S. D.; Krische, M. J. Tetrahedron 2015, 71, 5776-5780.
[
6] For ruthenium-catalyzed couplings of dienes and alkynes to α,β-unsaturated ketones, see: a)
F. Shibahara, J. F. Bower, M. J. Krische, J. Am. Chem. Soc. 2008, 130, 14120-14122; b) V. M.
Williams, J. C. Leung, R. L. Patman, M. J. Krische, Tetrahedron 2009, 65, 5024-5029.
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Chemistry - A European Journal
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[
1
7] R. A. Swyka, W. G. Shuler, B. J. Spinello, C. Lan, M. J. Krische, J. Am. Chem. Soc. 2019,
41, 6864-6868.
[
8] For a related rhodium-catalyzed aryl halide-aldehyde reductive coupling mediated by
formate, see: R. A. Swyka, W. Zhang, J. Richardson, J. C. Ruble, M. J. Krische, J. Am. Chem.
Soc. 2019, 141, 1828-1832.
[
9] For selected reviews on metal-catalyzed redox isomerization of unsaturated alcohols to form
ketones, see: a) R. Uma, C. Crevisy, R. Gree, Chem. Rev. 2003, 103, 27-51; b) L. Mantilli, C.
Mazet, Chem. Lett. 2011, 40, 341-344; c) D. Cahard, S. Gaillard, J.-L. Renaud, Tetrahedron Lett.
2
015, 56, 6159-6169.
[
10] For a recent example of enantioselective rhodium-catalyzed internal redox isomerization of
homoallylic and bishomoallylic secondary alcohols, see: R.-Z. Huang, K. K. Lau, Z. Li, T.-L.
Liu, Y. Zhao, J. Am. Chem. Soc. 2018, 140, 14647-14654.
[
11] For redox-neutral metal-catalyzed aryl halide-aldehyde C-C coupling to form ketone
products, see: a) Palladium: T. Satoh, T. Itaya, M. Miura, M. Nomura, Chem. Lett. 1996, 25,
23-824; b) S. Ko, B. Kang, S. Chang, Angew. Chem., Int. Ed., 2005, 44, 455−457; Angew.
Chem. 2005, 117, 459-461; c) A. Takemiya, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 14800-
4801; d) J. Ruan, O. Saidi, J. A. Iggo, J. Xiao, J. Am. Chem. Soc., 2008, 130, 10510-10511; e)
8
1
A. Zanardi, J. A. Mata, E. Peris, Organometallics 2009, 28, 1480-1483; f) L. Adak, S. Bhadra, B.
C. Ranu, Tetrahedron Lett. 2010, 51, 3811-3814; g) N. Nowrouzi, S. Motevalli, D. Tarokh, J.
Mol. Catal. A: Chem. 2015, 396, 224-230; h) N. Nowrouzi, D. Tarokh, J. Iran. Chem. Soc. 2016,
1
3, 1493-1497; i) B. Suchand, G. Satyanarayana, J. Org. Chem. 2016, 81, 6409-6423; j) T.
Wakaki, T. Togo, D. Yoshidome, Y. Kuninobu, M. Kanai, ACS Catal. 2018, 8, 3123-3128; k)
Rhodium: T. Ishiyama, J. F. Hartwig, J. Am. Chem. Soc. 2000, 122, 12043-12044; l) M. L. Rao,
B. S. Ramakrishna, Eur. J. Org. Chem. 2017, 2017, 5080-5093; m) Nickel: Y. -C. Huang, K. K.
Majumdar, C. -H. Cheng, J. Org. Chem. 2002, 67, 1682-1684; n) N. Now-rouzi, M. Zarei, F.
Roozbin, RSC Adv. 2015, 5, 102448-102453; o) J. K. Vandavasi, X. Hua, H. Ben Halima, S. G.
Newman, Angew. Chem., Int. Ed. 2017, 56, 15441-15445; Angew. Chem. 2017, 129, 15643-
1
5647; p) X. Zhang, D. W. C. MacMillan, J. Am. Chem. Soc. 2017, 139, 11353−11356; q)
Cobalt: Y. L. Hu, Y. P. Wu, M. Lu, Appl. Organomet. Chem. 2018, 32, No. e4096.
[
12] For oxidative metal-catalyzed aryl halide-alcohol C-C couplings to form ketone products,
see: a) T. Verheyen, L. v. Turnhout, J. K. Vandavasi, W. M. De Borggraeve, E. S. Isbrandt, S. G.
Newman, J. Am. Chem. Soc. 2019, 141, 6869-6874.
[
13] Rhodium-catalyzed alkene hydroacylation enables conversion of aldehydes to alkyl ketones;
however, intermolecular variants normally require use of aldehydes with β-chelating groups to
suppress catalyst deactivation via aldehyde decarbonylation. For a review, see: J. C. Leung, M. J.
Krische, Chem. Sci. 2012, 3, 2202-2209.
[
14] For metal-catalyzed reductive coupling of organic halides to carboxylic acid derivatives to
form ketone products, see: a) M. Onaka, Y. Matsuoka, T. Mukaiyama, Chem. Lett. 1981, 10,
5
2
7
31-534; b) I. Kazmierski, M. Bastienne, C. Gosmini, J. -M. Paris, J. Perichon, J. Org. Chem.
004, 69, 936-942; c) H. Yin, C. Zhao, H. You, K. Lin, G. Gong, Chem. Commun. 2012, 48,
034-7036; d) A. C. Wotal, D. J. Weix, Org. Lett. 2012, 14, 1476-1479; e) F. Wu, W. Lu, Q.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201903668
Qian, Q. Ren, H. Gong, Org. Lett. 2012, 14, 3044-3047; f) W. Lu, Z. Liang, Y. Zhang, F. Wu, Q.
Qian, H. Gong, Synthesis 2013, 45, 2234-2240; g) A. H. Chemey, N. T. Kadunce, S. E. Reisman,
J. Am. Chem. Soc. 2013, 135, 7442-7445; h) Z. Liang, W. Xue, K. Lin, H. Gong, Org. Lett.
2
1
014, 16, 5620-5623; i) C. Zhao, X. Jia, X. Wang, H. Gong, J. Am. Chem. Soc. 2014, 136,
7645-17651; j) X. Jia, X. Zhang, Q. Qian, H. Gong, Chem. Commun. 2015, 51, 10302-10305;
k) F.-F. Pan, P. Guo, C.-L. Li, P. Su, X.-Z. Shu, Org Lett. 2019, 21, 3701-3705; l) J. He, P. Song,
X. Xu, S. Zhu, Y. Wang, ACS Catal. 2019, 9, 3253-3259.
[
15] For metal-catalyzed reductive coupling of organic halides to nitriles and amides to form
ketone products, see: a) J.-C. Hsieh, Y.-C. Chen, A.-Y. Cheng, H.-C. Tseng, Org. Lett., 2012, 14,
282-1285; b) S. Ni, W. Zhang, H. Mei, J. Han, Y. Pan, Org. Lett. 2017, 19, 2536-2539.
1
[
16] For metal-catalyzed reductive coupling of redox-active esters to form ketone products, see:
a) K. M. M. Huihui, J. A. Caputo, Z. Melchor, A. M. Olivares, A. M. Spiewak, K. A. Johnson, T.
A. DiBenedetto, S. Kim, L. K. G. Ackerman, D. J. Weix, J. Am. Chem. Soc. 2016, 138, 5016-
5
019. b) S. Ni, N. M. Padial, C. Kingston, J. C. Vantourount, D. C. Schmitt, J. T. Edwards, M.
M. Kruszyk, R. R. Merchant, P. K. Mykhailiuk, B. B. Sanchez, S. Yang, M. A. Perry, G. M.
Gallego, J. J. Mousseau, M. R. Collins, R. J. Cherney, P. S. Lebed, J. S. Chen, T. Qin, P. S.
Baran, J. Am. Chem. Soc. 2019, 141, 6726-6739. c) J. Wang, B. P. Cary, P. D. Beyer, S. H.
Gellman, D. J. Weix, Angew. Chem. Int. Ed. 10.1002/anie.201906000; Angew. Chem.
1
0.1002/ange.201906000.
[
17] For oxidative addition of rhodium(I) complexes to vinyl or aryl sulfonates, see: a) J. Wu, L.
Zhang, Y. Luo, Tetrahedron Lett. 2006, 47, 6747-6750; b) M. Murata, H. Yamasaki, T. Ueta, M.
Nagata, M. Ishikura, S. Watanabe, Y. Masuda, Tetrahedron 2007, 63, 4087-4094; c) L. Zhang, J.
Wu, Adv. Synth. Catal. 2008, 350, 2409-2413.
[
18] For the synthesis of vinyl triflates from ketone enolates, see: a) J. E. McMurry, W. J. Scott,
Tetrahedron Lett. 1983, 24, 979-982; b) D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33,
299-6302.
6
[
19] For selected reviews on the synthesis of ketones from Weinreb amides, see: (a) S.
Balasubramaniam, I. S. Aidhen, Synthesis 2008, 3707-3738; b) S. G. Davies, A. M. Fletcher, J.
E. Thomson, Chem. Commun. 2013, 49, 8586-8598; c) M. Nowak, Synlett 2015, 26, 561-562.
[
20] R. Martín, P. Romea, C. Tey, F. Urpí, J. Vilarrasa, Synlett 1997, 12, 1414-1416.
[
21] For selected examples of the elimination of vinyl triflates to form alkynes using weak bases,
see: a) R. J. Hargrove, P. J. Stang, J. Org. Chem. 1974, 39, 581-582; b) I. Fleming, J. M.
Mwaniki, J. Chem. Soc., Perkin Trans. 1 1998, 1237-1247; c) J. Ramharter, H. Weinstabl, J.
Mulzer, J. Am. Chem. Soc. 2010, 132, 14338-14339; d) M. Okutani, Y. Mori, Chem. Pharm.
Bull. 2015, 63, 393-396.
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