Reductive Coupling of Acrylates with Ketones and Ketimines by a Nickel-Catalyzed Transfer-Hydrogenative Strategy

Article abstract of DOI:10.1002/anie.201707531

Nickel-catalyzed coupling of benzyl acrylates with activated ketones and imines provides γ-butyrolactones and lactams, respectively. The benzyl alcohol byproduct released during the lactonization/lactamization event is relayed to the next cycle where it serves as the reductant for C?C bond formation. This strategy represents a conceptually unique approach to transfer-hydrogenative C?C bond formation, thus providing examples of reductive heterocyclizations where hydrogen embedded within an alcohol leaving group facilitates turnover.

Full text of DOI:10.1002/anie.201707531

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Accepted Article
Title: Reductive Coupling of Acrylates with Ketones and Ketimines
via a Nickel-Catalyzed Transfer Hydrogenative Reductant Relay
Strategy
Authors: Craig Buxton, David Blakemore, and John Bower
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Reductive Coupling of Acrylates with Ketones and Ketimines via
a Nickel-Catalyzed Transfer Hydrogenative Reductant Relay
Strategy
Craig S. Buxton, David C. Blakemore, and John F. Bower*
Abstract: Ni-catalyzed coupling of benzyl acrylates with activated
ketones or imines provides γ-butyrolactones and lactams. The benzyl
alcohol byproduct released during the lactonization/lactamization
event is relayed to the next cycle where it serves as the reductant for
C-C bond formation. This strategy represents a conceptually unique
approach to transfer hydrogenative C-C bond formation, providing
examples of reductive heterocyclizations where hydrogen embedded
within an alcohol leaving group facilitates turnover.
reduction of the starting materials. We reasoned that these criteria
might be fulfilled by coupling the release of the reductant to the
formation of the lactone or lactam, thereby minimizing non-
productive background reduction events. Such a proposition
appears practically challenging, however, a simple solution is
availed by harnessing the native reducing power of the alcohol
released upon cyclization to drive turnover. In this way, the
alcohol byproduct from one cycle is relayed to the next, where it
then serves as the reductant for C-C bond formation. Herein, as
proof-of-concept, we show that lactones or lactams can be
generated by Ni-catalyzed union of activated ketones or ketimines
with O-benzyl acrylates. This provides unique examples of
reductive heterocyclizations where hydrogen embedded within an
alcohol leaving group facilitates catalytic turnover,[8] adding a new
vista to the wider area of transfer hydrogenative C-C bond
formation.[1-3]
The identification of catalytic paradigms for the direct and
atom economical assembly of C-C bonds is a key goal of organic
chemistry. Within this context, transfer hydrogenative C-C bond
formation has emerged as a powerful platform for reaction design.
For example, “hydrogen borrowing” allows the direct α-alkylation
of carbonyl compounds with alcohols, via
a
catalytic
dehydrogenation-condensation-reduction sequence (Scheme 1,
Eqn. 1).[1] The related Guerbet reaction effects the dehydrative
union of two alcohols, providing an efficient method to upgrade
bioethanol to butanol (Eqn. 2).[2] Krische and co-workers have
pioneered transfer hydrogenative alcohol C-H functionalizations,
as exemplified by processes where alcohol dehydrogenation
drives the reductive generation of nucleophilic metal-allyls in
advance of carbonyl addition (Eqn. 3).[3] Each of these reaction
classes merges redox events with C-C bond formation, thus
avoiding stepwise generation of reactive functionality and
enhancing substantially atom economy. As such, new transfer
hydrogenative C-C bond forming strategies are likely to find wide
utility in reaction design.
Our studies in this area were initiated by considering synthetic
entries to γ-butyrolactones and lactams,[4-7] which are versatile
intermediates as well as core motifs in an array of natural products.
An appealing, yet unrealized approach to these compounds
resides in metal-catalyzed reductive coupling of a carbonyl or
imine with an acrylate to afford a γ-amino or -hydroxy ester, which
upon cyclization would provide the target (Scheme 1, Eqn. 4).
This disconnection requires the identification of a strategy that
enables reductive C-C bond formation, but avoids non-productive
Dr C. S. Buxton, Prof. J. F. Bower
School of Chemistry,
University of Bristol,
Scheme 1. Transfer hydrogenative C-C bond forming strategies.
Bristol, BS8 1TS, United Kingdom
E-mail: john.bower@bris.ac.uk
Dr D. C. Blakemore
Medicine Design, Pfizer Inc.,
Eastern Point Road,
In early studies, we assayed a wide range of late transition
metal systems for the reductive coupling of isatin 1a and ethyl
o
Groton, CT 06340, USA
acrylate 2a (R = Et) (Table 1). At 150 C in PhMe, and with 10
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10.1002/anie.201707531
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mol% benzyl alcohol as the initiator (see Scheme 1, Eqn 4.), the
combination of 7.5 mol% Ni(cod)2 and 15 mol% P(o-OMeC6H4)3
provided target lactone 3a in 19% yield, with unreacted starting
material accounting for the mass balance (Entry 1). Here,
according to our reaction design, ethanol released during the first
turnover must then function as the reductant for subsequent
cycles. Based on this we considered whether more easily oxidized
alcohol-based leaving groups might provide increased
efficiencies.[9] Ultimately, this led to the conditions outlined in
Entry 3, which use 300 mol% benzyl acrylate 2b (R = Bn) as the
reaction partner, and generate 3a in 84% yield. Some turnover
was observed in the absence of the initiating alcohol (Entry 4),
likely facilitated by hydrolytic release of BnOH from benzyl
acrylate under the reaction conditions. This generates acrylic acid
as a byproduct, a component that control experiments found to be
inhibitory to the reductive lactonization process.[10] Lower loadings
of either the benzyl alcohol initiator or the Ni-pre-catalyst resulted
in diminished efficiencies (Entry 5), and use of stoichiometric
BnOH also resulted in a lower yield (Entry 6); this latter result
highlights the benefits of coupling reductant release to turnover.
3a was generated in 58% yield when the reaction was run with
only 100 mol% 2b (Entry 7). A Ni(0)-pre-catalyst is essential for
efficient reactivity; Ni(II)-systems (e.g. Entry 8) or commonly
employed transfer hydrogenation catalysts, such as [IrCp*Cl2]2
(Entry 9), were completely ineffective.[11]
and 3l were assigned by X-ray diffraction;[14] interestingly, these
products possess opposite relative configurations. β-Substituted
acrylates also participate, such that targets 3m and 3n were
formed in 77% and 73% yield, respectively. In the latter case, the
Lewis acid co-catalyst was not required, likely due to the high
electrophilicity of the acrylate partner, trans-dibenzylfumarate 2f
(vide infra).
Table 1. Preliminary results and optimization studies.
The scope of the process with respect to the isatin component
is outlined in Table 2. A variety of electronically distinct systems
1a-j participated to provide the target spirocyclic systems 3a-j in
moderate to excellent yield. The protocol shows useful functional
group tolerance, with both esters (3h) and methoxy (3d)
substituents surviving despite the established lability of these
functionalities under Ni(0)-catalyzed conditions.[12] Processes
involving disubstituted acrylates required the addition of Mg(OTf)2
as a Lewis acidic co-catalyst;[13] using this modification, reductive
coupling of 1a with α-methyl (2c) and α-phenyl (2d) benzyl
acrylate provided targets 3k and 3l in high yield and as single
diastereomers (>20:1 d.r.). The relative stereochemistries of 3k
Table 2. Reductive coupling of benzyl acrylate with isatins.
Our observations are that isatins are privileged substrates for
this reductant relay process. Nevertheless, we have established
that, in certain cases, other classes of 1,2-dicarbonyl also
participate, suggesting potentially wider applications of the
strategy. For example, benzil systems 4a-c generated the
corresponding mono-cyclic lactones 5a-c in modest to very good
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yield (Scheme 3). Cyclic system 6 was also a competent reaction
partner, generating lactone 7 in 52% yield when Mg(OTf)2 was
used as co-catalyst. As far as we are aware, the examples in
of Ni-catalyst was feasible, but resulted in low conversion to 3a
(15% yield). Thus, if path a is operative, the Ni-catalyst must play
an intimate role in enhancing the C-C bond forming event. One
possibility is that oxidative addition of Ni(0) into the C3-H bond of
8 generates a Ni-enolate; this kind of process has been suggested
in other contexts.[21] Exposure of 8 to benzaldehyde (100 mol%)
under standard catalytic conditions (in the absence of acrylate)
resulted in a 35% yield of 1a, showing that reduction of 1a is
reversible. Because of this, initial oxidation of 8 to 1a in advance
of spirolactonization via path b cannot be ruled out. As already
discussed, Ni(II)-systems or commonly employed Ru- and Ir-
based transfer hydrogenation catalysts do not promote the
reaction, supporting a role for the Ni(0)-system beyond simply
effecting transfer hydrogenation of 1a.
Table
2 and Scheme 2 are the first catalytic reductive
lactonizations that harness carbonyls and unfunctionalized
acrylate esters. Existing non-catalytic protocols use exogenous
stoichiometric reductants,[5] whereas catalytic approaches require
alcohols as the starting material, which, in turn, mandates prior
reduction of the carbonyl partner.[4]
Scheme 2. Reductive coupling of benzyl acrylate with activated ketones.
To probe the mechanism of the process a series of
experiments was undertaken. When deuterio-2b, which
incorporates deuterium at the benzylic positions, was exposed to
optimized conditions, 40% deuterium transfer to C2 of deuterio-
3a was observed (Scheme 3A). Significant deuterium
incorporation was also found at C2’, indicating that the Ni(0)-
system can also activate the N-benzylic position.[15] For 1a to 3a
(84 % Yield), GCMS analysis of the crude reaction mixture
revealed the concomitant formation of benzaldehyde in 78% yield.
These observations show that the benzyloxy unit of the acrylate
partner (2b) acts as the reductant for C-C bond formation. Under
optimized conditions we have confirmed that benzyl acrylates are
most effective (Scheme 3B). Other systems with primary or
secondary alcohol based leaving groups, such as methyl, ethyl
and cyclohexyl acrylate also enabled turnover, but provided 3a in
significantly diminished yields. Conversely, phenyl and tert-butyl
acrylate, which release “non-oxidizable” phenol or t-BuOH, did not
allow turnover, with the yield of 3a limited to the loading of the
benzyl alcohol initiator (10 mol%). Overall, these observations are
consistent with the reductive formation of γ-hydroxy ester 9, in
advance of lactonization to product 3a (Scheme 3C). Intermediate
9 might arise via either a carbonyl reduction-conjugate addition
pathway (path a)[16] or an oxidative coupling-reduction sequence
(path b).[17,18] Two key observations provide circumstantial
support for path a: (1) an adjacent acidifying group is required on
the carbonyl partner[19] and (2) products of oxidative coupling with
the benzaldehyde byproduct are not formed.[20] The beneficial
effects of Mg(OTf)2 in certain cases would be consistent with
Lewis acid activation of the acrylate for conjugate addition.
Exposure of 8 (the reduced form of 1a) to optimized conditions,
with either benzyl (2b) or phenyl acrylate (2c), generated 3a in
high yield (Scheme 3D). Lactone formation from 8 in the absence
Scheme 3. Preliminary mechanistic studies.
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According to the mechanistic blueprint outlined in Scheme 1,
Eqn. 4, other classes of process might be achievable using a
reductant relay approach. Although further expansion of the
strategy will require the identification of new catalysts and/or
fragment coupling steps, we were keen to uncover additional
processes that might be achieved using the Ni(0)-system
presented here. Specifically, we envisaged that α-oxo imines
might couple with acrylates to provide lactams. This proposition
was appealing because only sparse reports document the use of
stoichiometric metallic reductants to achieve this seemingly
simple process, and no catalytic approaches are available.[7]
Pleasingly, when N-p-methoxyphenyl imine 10a was exposed to
conditions optimized for lactonization, spirocyclic lactam 11a was
generated in 68% yield (Table 3). Further evaluation revealed that
this lactamization process has similar scope to the lactonization
methodology. Indeed, electronically diverse isatin-based imines
10b-e all engaged in smooth reductive coupling to provide lactam
targets 11b-e in good to excellent yield. Extension of the protocol
to the imine derived from benzil 4b provided monocyclic system
12 in 68% yield; the alternate lactone product was not observed.
In summary, we demonstrate a unique approach to transfer
hydrogenative C-C bond formation, wherein the native reducing
power of an alcohol released upon lactonization or lactamization
is used to drive catalytic turnover. This provides an interesting
example of atom economical methodology, highlighting how an
otherwise wasted byproduct can be used productively. The
studies described here encompass the first catalytic methods for
accessing lactones or lactams by the direct reductive coupling of
carbonyls/imines with unfunctionalized acrylates. Future studies
will seek to identify other catalyst systems that can promote the
stereocontrolled coupling of a wider range of reaction partners.
Acknowledgements
The Bristol Chemical Synthesis CDT, funded by EPSRC
(EP/G036764/1) and Pfizer, for a studentship (to C.S.B.). The
European Research Council (ERC Grant 639594 CatHet) and the
Royal Society for a University Research Fellowship (to J.F.B).
We have also investigated
a one-pot imine formation-
Keywords: transfer hydrogenation, C-C bond, lactone, lactam
lactamization sequence (Scheme 4). Exposure of isatin 1a to p-
methoxyaniline under acidic conditions generated imine 10a.
Removal of the volatile components was followed by direct
addition of the reagents required for reductive lactamization,
allowing a telescoped synthesis of 11a in 50% yield over the one-
pot, three component process.
[1]
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110, 681. (b) J. Leonard, A. J. Blacker, S. P. Marsden, M. F. Jones, K. R.
Mulholland, R. Newton, Org. Process Res. Dev. 2015, 19, 1400.
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K. E. Christensen, N. G. Stevenson, T. J. Donohoe, J. Am. Chem. Soc.
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enones/acrylates: (a) J. L. Jeffrey, J. A. Terrett, D. W. C. MacMillan,
Nature 2015, 349, 1532; (b) E. L. McIntruff, J. Mowat, A. R. Waldeck, M.
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Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 971; (d) J. Dugal-Tessier,
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Chem. Int. Ed. 2012, 51, 4963; (e) B. M. Trost, K. Hirano, Org. Lett. 2012,
14, 2446.
[2]
[3]
[4]
[5]
Non-catalytic methodologies to access γ-butyrolactones from carbonyls
and acrylates: (a) T. Shono, H. Ohmizu, S. Kawakami, H. Sugiyama,
Tetrahedron Lett. 1980, 21, 5029; (b) S.-i. Fukuzawa, A. Nakanishi, T.
Fujinami, S. Sakai, J. Chem. Soc. Perkin Trans 1 1988, 1669; (c) K.
Otsubo, J. Inanaga, M. Yamaguchi, Tetrahedron Lett. 1986, 27, 5763.
γ-Butyrolactones by (2+2+1) cycloaddition of ketones, ethylene and CO:
M. Tobisu, N. Chatani, T. Asaumi, K. Amako, Y. Ie, Y. Fukumoto, S.
Murai, J. Am. Chem. Soc. 2000, 122, 12663.
Table 3. Reductive coupling of benzyl acrylate with ketimines.
[6]
[7]
Non-catalytic methodologies to access γ-butyrolactams from imines and
acrylates: (a) N. Akane, T. Hatano, H. Kusui, Y. Nishiyama, Y. Ishii, J.
Org. Chem. 1994, 59, 7902. For a similar approach to lactams, see: (b)
Y. Hoshimoto, K. Ashida, Y. Sasaoka, R. Kumar, K. Kamikawa, X.
Verdaguer, A. Riera, M. Ohashi, S. Ogoshi, Angew. Chem. Int. Ed. 2017,
56, 8206.
Scheme 4. One-pot imine formation-lactamization.
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[8]
For a process where dehydrogenation of an alcohol leaving group
provides the substrate for the next cycle, see: B. Gnanprakasam, D.
Milstein, J. Am. Chem. Soc. 2011, 133, 1682.
[9]
H. Adkins, R. M. Elofson, A. G. Rossow, C. C. Robinson, J. Am. Chem.
Soc. 1949, 71, 3622.
[10] Addition of 20 mol% acrylic acid to optimized conditions completely
suppressed the formation of 3a, and 1a was recovered in 82% yield. This
is likely due to competitive formation of an oxanickelacyclopentanone: T.
Yamamoto, K. Igarashi, S. Komiya, A. Yamamoto, J. Am. Chem. Soc.
1980, 102, 7448.
[11] A wide range of other Ni(II) or Ir sources, such as NiBr2, Ni(acac)2,
Ni(OAc)2, [Ir(cod)Cl]2, [IrCp2Cl]2, and IrCl3 did not lead to appreciable
yields of 3a. At this stage, we have been unable to confirm whether or
not the active catalytic species is a Ni(0)-complex.
[12] For a review on Ni-catalyzed cross-couplings of C-O bonds, see: B. M.
Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K.
Garg, V. Percec, Chem. Rev. 2011, 111, 1346.
[13] Other Lewis acids, such as ZnCl2 and In(OTf)3, were less effective.
[14] CCDC 1564245-1564249 contain crystallographic data for this paper.
[15] Selected processes involving Ni-catalyzed C(sp3)-H activation: (a) Y.
Aihara, N. Chatani, J. Am. Chem. Soc. 2014, 136, 898; (b) D. Liu, C. Liu,
H. Li, A. Lei, Angew. Chem. Int. Ed. 2013, 52, 4453.
[16] Examples of Ni-catalyzed transfer hydrogenations: (a) N. Castellanos-
Blanco, A. Arévalo, J. J. García, Dalton Trans. 2016, 45, 13604; (b) S.
Kuhl, R. Schneider, Y. Fort, Organometallics 2003, 22, 4184.
[17] For a review on Ni-catalyzed reductive couplings, see: J. Montgomery,
Angew. Chem. Int. Ed. 2004, 43, 3890.
[18] For transfer hydrogenative cleavage of catalytically generated
oxanickelacyclopentenones by alcohols, see: K. Nakai, Y. Yoshida, T.
Kurahashi, S. Matsubara, J. Am. Chem. Soc. 2014, 136, 7797. In this
process, the aldehyde “byproduct” serves as the substrate for the next
cycle. For
a conceptually similar strategy that proceeds via an
oxaruthenacyclopentane, see reference 4b.
[19] The adjacent carbonyl may facilitate enolization in advance of conjugate
addition. For isatin-based systems (e.g. compound 8), enolization may
also be driven by aromatization.
[20] Benzaldehyde is an established substrate for accessing
oxanickelacyclopentane-like intermediates (see reference 17); however,
we note that oxidative coupling processes often have prescriptive
substrate requirements (see reference 6).
[21] (a) K. Y. T. Ho, C. Aïssa, Chem. Eur. J. 2012, 18, 3486; (b) A. Thakur,
M. E. Facer, J. Louie, Angew. Chem. Int. Ed. 2013, 52, 12161.
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COMMUNICATION
Craig S. Buxton, David C. Blakemore
and John F. Bower*
Page No. – Page No.
Reductive Coupling of Acrylates with
Ketones and Ketimines via a Nickel-
Catalyzed Transfer Hydrogenative
Reductant Relay Strategy
Ni-catalyzed coupling of benzyl acrylates with activated ketones or imines provides
a direct entry to γ-butyrolactones and lactams. The benzyl alcohol byproduct released
during the lactonization/lactamization event is relayed to the next cycle where it then
serves as the reductant for C-C bond formation.
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