Direct, enantioselective α-alkylation of aldehydes using simple olefins

Article abstract of DOI:10.1038/NCHEM.2797

Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes—photoredox, enamine and hydrogen-atom transfer (HAT) catalysis—enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra-and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons.

Full text of DOI:10.1038/NCHEM.2797

ARTICLES
PUBLISHED ONLINE: 26 JUNE 2017 | DOI: 10.1038/NCHEM.2797
Direct, enantioselective α-alkylation of aldehydes
using simple olefins
Andrew G. Capacci, Justin T. Malinowski, Neil J. McAlpine, Jerome Kuhne
and David W. C. MacMillan
*
Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has
proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and
unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here,
we show that the synergistic merger of three catalytic processes—photoredox, enamine and hydrogen-atom transfer
(HAT) catalysis—enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling
partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible
light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and
electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene
coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy
ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step
while consuming only photons.
he stereoselective α-alkylation of carbonyl compounds has olefin partners (for example, silyl ketene acetals, allyl silanes) that
long been a fundamental transformation within the field of can engage the electrophilic 3πe– enaminyl radical.
T
organic chemistry. In the 1980s, the seminal research of
Recently, we questioned whether photoredox catalysis and
Evans, Meyers, Oppolzer, Seebach and Myers1 demonstrated that organocatalysis might be successfully merged to enable the enantio-
chiral auxiliaries can offer a general approach to the enantioselective selective α-alkylation of carbonyl compounds using simple,
construction of α-carbonyl stereocentres2,3, which today remains the unactivated olefin coupling partners and without the requirement
method of choice for enolate-based fragment coupling. In recent of stoichiometric oxidants (Fig. 1). We recognized that the
years a variety of novel catalytic methods have been developed for
asymmetric α-carbonyl alkylation, including (1) phase transfer
additions of glycine-derived imines, (2) chiral triamine ligation of
Established
asymmetric
transformations
Challenging
reactivity
ketone-derived lithium enolates, and (3) the use of Jacobsen’s Cr
(salen) complex with pre-formed stannous enolates4–6. Given
these important advances, the direct, enantioselective formation of
α-alkyl carbonyls from simple, abundant organic building blocks
remains an elusive yet important goal.
O
O
H
Aldol, Mannich
α-Halogenation
α-Allylation
Me
H
R
Me
Asymmetric
α-alkylation
Aldehyde
Over the last two decades, secondary amine-mediated organo-
catalysis has enabled the development of mild methods for the cataly-
α-Arylation
tic generation of reactive HOMO-raised enamine nucleophiles7–10
.
This activation platform has found broad utility in a variety of
α-functionalization reactions, most notably the enantioselective
formation of C–O, C–N, C–X and C–C bonds11. Despite these
efforts, the α-alkylation of carbonyl compounds using alkyl
halides remains an elusive transformation, mainly due to limitations
involving competitive self-aldol reactions and/or catalyst alkylation12.
In 2007 we first demonstrated that open-shell, radical pathways
can enable the enantioselective α-functionalization of carbonyl
compounds via a SOMO activation pathway13. This process
occurs via stoichiometric oxidation of a transiently formed
O
H
O
S
*IrIII
H
Me
R
Me
H
N
H
H•
e
En
R
Simple, abundant
precursors
High-value
products
Triple catalytic activation
enamine to generate a 3πe– enaminyl radical intermediate. This Figure 1 | Direct enantioselective α-alkylation of aldehydes with olefins via
electrophilic SOMO species can then be intercepted by a variety triple catalytic activation. Aldehydes are known to be efficient substrates
of prefunctionalized olefins and, following an additional oxidation for a number of fundamental carbonyl α-functionalization transformations for
event, can lead to a number of α-functionalized adducts14,15. While selective C−O, C−N, C−X and C−C bond formation. Despite this, the
the generality of this 3πe– enaminyl radical activation mode has catalytic, asymmetric α-alkylation of aldehydes has remained a challenge.
been demonstrated, widescale adoption has been restricted due to This transformation has now been accomplished through the merger of
(1) the requirement of two equivalents of a stoichiometric oxidant secondary amine organocatalysis, photoredox catalysis and HAT catalysis to
per bond formation and (2) the need for pre-generated π-nucleophilic produce α-alkyl carbonyl products from simple olefin and aldehyde substrates.
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA. e-mail: dmacmill@princeton.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2797
ARTICLES
O
O
Enantioenriched
α-alkyl aldehyde
R
R
+
H
H
Ir
En
H
Me
Aldehyde
Me
Olefin
Me
O
Me
Me
O
O
N
2
9
N
N
e–
10
Ar
Bn
t-Bu
N
+
S
*IrIII (4)
oxidant
H
Bn
t-Bu
Bn
t-Bu
N
N
Organocatalyst 1
R
Me
Me
Photoredox
catalytic
cycle
HAT
catalytic
cycle
–
IrIII (3)
S
SET
HAT
Ar
11
Me
O
Me
O
e–
N
N
IrII (5)
reductant
SH
+
Ar
+
Bn
t-Bu
N
8
Bn
t-Bu
N
Me
6
7
Si-face
approach
R
Me
R
Electrophilic radical
Nucleophilic radical
Figure 2 | Proposed mechanism for aldehyde α-alkylation via photoredox, HAT and organocatalysis. Condensation of organocatalyst 1 with an aldehyde
substrate initiates the catalytic cycle. Concurrently, irradiation of iridium photocatalyst 3 generates an excited state species (4). This intermediate can then
oxidize enamine 2 through single electron transfer (SET) and generate the 3πe− enaminyl radical 6. Reversible radical addition across an olefin substrate then
produces the carbon radical 7, which is trapped through HAT with thiol HAT catalyst 8. Hydrolysis of iminium 9 provides the enantioenriched α-alkyl
aldehyde and regenerates amine catalyst 1. Finally, reduction of thiyl radical 10 by the Ir(II) species (5) subsequently regenerates thiol catalyst 8 as well as
the Ir(III) catalyst 3 to complete the remaining redox cycles.
combination of both the SOMO and photoredox activation modes (Fmppy = 2-(4-fluorophenyl)-4-(methylpyridine), dtbbpy = 4,4′-di-
might enable hydrogen atom and electron borrowing to achieve tert-butyl-2,2′-bipyridine) with visible light would produce the
enaminyl radical formation before coupling with an olefin long-lived (τ = 1.2 µs) excited-state complex 4 (ref. 20). This highly
substrate16. The generation of simple olefin adducts was deemed oxidizing charge transfer species (E [*IrIII/IrII] = +0.77 V versus
red
1/2
feasible, provided the initial enaminyl radical–olefin addition saturated calomel electrode, SCE) would be capable of mediating
event could be rendered non-reversible. To this end, we rationalized a single-electron transfer (SET) from the electron-rich enamine 2
that the use of a third catalytic cycle, involving a reductive hydrogen- to generate reduced IrII complex 5 and the critical 3πe– enaminyl
atom transfer, would capture the radical intermediate arising from radical species 6. This electrophilic radical should then rapidly
the olefin addition step17–19, thereby ensuring that the overall undergo addition to an olefin coupling partner to generate a new
mechanism is redox-neutral (that is, non-oxidative, with only C–C bond, a stereogenic centre and a secondary alkyl radical. At
photons being consumed in the process).
this stage we hypothesized that this nucleophilic radical 7 would
From a conceptual standpoint, we hypothesized that three cata- participate in a HAT event with a sufficiently acidic and weak
lytic cycles could be used in concert to enable this unique alkylation: S–H bond (HAT catalyst 8, thiophenol S–H BDE = 78 kcal mol–1)21.
(1) amine catalysis (= enamine formation), (2) photoredox catalysis This HAT process is governed both by the polarity match and relative
(= enamine oxidation to generate an activated 3πe– enaminyl radical bond strengths of the donor and acceptor species, and is expected
and reduction of a thiyl radical), and (3) HAT catalysis (= hydrogen- to rapidly trap the alkyl radical species at near diffusion control22.
atom transfer to the alkyl radical species after olefin addition) Following HAT, hydrolysis of iminium ion 9 would liberate the
(Fig. 2). As such, a critical feature of this transformation would be organocatalyst while also providing an enantioenriched aldehyde
the identification of three highly selective yet independent catalysts product. Finally, thiyl radical 10 (Er1e/d2[PhS•/PhS–] = +0.02 V versus
and their controlled interface. For example, a selective HAT catalyst SCE in dimethylsulfoxide)23 engages in a SET event with the
red
would be required to successfully discriminate between trapping of highly reducing IrII complex 5 (E [IrIII/IrII] = –1.50 V versus
1/2
the initial electrophilic 3πe– enaminyl radical intermediate and the SCE) to regenerate both the ground state IrIII complex 3 as well as
alkyl radical species generated following olefin coupling. Second, the HAT thiol catalyst after protonation of thiolate 11.
given the reversible nature of the olefin addition event, the kinetic
We first tested the proposed aldehyde alkylation on an intra-
efficiency of the HAT catalyst would dictate the retention or loss molecular variant to determine if enantioselective ring formation
of enantiocontrol gained in the SOMO-addition step. Finally, was feasible using this mechanism. As shown in Table 1, hetero-
the redox activity of the three catalysts would be interdependent, cyclic or carbocyclic rings were readily generated with high
and efficient regeneration of the ground-state photocatalyst and efficiency and enantiocontrol using this tricatalytic method. For
HAT catalyst would require a multicatalytic process that is example, N-tethered aldehydic olefins with either sulfonamide or
temporally synchronized.
carbamate protecting groups are tolerated, giving rise to piperidine
adducts in high yield (13 and 14, 85% yield, 93% e.e. and 88% yield,
95% e.e., respectively). Moreover, an ether-linked system provided
Merging photoredox, organocatalysis and HAT catalysis
A detailed description of our proposed mechanism for the enantiose- the desired trans-disubstituted tetrahydropyran with useful
lective α-alkylation of aldehydes is outlined in Fig. 2. We presumed efficiency (15, 65% yield, 94% e.e.). Carbocycles were also prepared
that the process would begin with condensation of amine catalyst 1 in good yield via this protocol, as exemplified by the gem-diester-
and an aldehyde substrate to provide enamine 2. Concurrently, containing substrate 18 (76% yield, 91% e.e.). Notably, the reaction
irradiation of the iridium photocatalyst 3 Ir(Fmppy)2(dtbbpy)PF6 proceeded well using an unsubstituted alkyl tether to generate the
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2797
ARTICLES
Table 1 | Tether and olefin scope of enantioselective intramolecular α-alkylation of aldehydes.
Catalyst combination
–
Me
PF6
2
2
20 mol% organocatalyst 12
3 mol% photocatalyst 3
Me
O
SH
CHO
X
R
CHO
X
R
t-Bu
t-Bu
i-Pr
i-Pr
N
N
Ir
N
F
F
R1
R1
N
N
t-Bu
N
20 mol% thiophenol 8
H
DMSO:NMA
1-naph
12
i-Pr
Me
Cyclic aldehyde
3
Aldehyde
8
6-exo cyclization
13
14
15
16
17
CHO
CHO
CHO
CHO
CHO
Me
Me
Me
Me
Me
Me
Me
NPh
N
N
N
O
N
N
Ph
Ts
Boc
Ts
Ts
77% yield
90% e.e., 3:1 d.r.
Me
Me
85% yield
93% e.e., 10:1 d.r.
88% yield
95% e.e., >20:1 d.r.
65% yield
94% e.e., 10:1 d.r.
62% yield
88% e.e., 3:1 d.r.
18
19
20
21
22
TMS
CHO
CHO
CHO
CHO
CHO
Me
Me
Me
Me
Me
N
N
N
Ts
Ts
Ts
t-BuO2C CO2t-Bu
64% yield
95% e.e., >20:1 d.r.
86% yield
92% e.e., 6:1 d.r.
82% yield
90% e.e., 5:1 d.r.
81% yield
94% e.e., 11:11:1:1 d.r.
76% yield
91% e.e., >20:1 d.r.
6-exo formation of quaternary centre
7-endo cyclization
CHO
Me
Me
Me
OHC
OHC
CHOMe
23
25
Me
Me
Me
Me
60% yield*
50% e.e., >20:1 d.r.
89% yield
88% e.e., 7:1 d.r.
N
N
N
N
Ts
Ts
Ts
Ts
5-exo cyclization
OHC
OHC
Me
Me
24
26
OHC
OHC
Me
Me
Me
Me
91% yield
71% yield
N
N
84% e.e., >20:1 d.r.
84% e.e., 9:1 d.r.
t-BuO2C CO2t-Bu
t-BuO2C CO2t-Bu
Ts
Ts
For each product number (in bold), data are reported as percent isolated yield, and diastereometric ratio (d.r.) was determined by 1H NMR. *(R)-2-tert-butyl-3-methylimidazolidin-4-one (20 mol%) was used.
NMA, N-methyl acetamide; Me, methyl; Ts, tosyl; Boc, tert-butyl carbamoyl; TMS, trimethylsilyl; Ph, phenyl. See Supplementary Information for experimental details.
disubstituted cyclohexane product (19, 64% yield, 95% e.e., >20:1 observed in the cases where radical-stabilization was possible after
d.r.). We also explored the formation of a substituted pyrrolidine the cyclization event (17, 21 versus 16). Perhaps most notably,
product through a 5-exo cyclization and were pleased to obtain quaternary carbon stereocentres could also be formed via a tethered
the product in excellent yield and moderate stereoselectivity (24, tetrasubstituted olefin using (R)-2-tert-butyl-3-methylimidazolidin-
91% yield, 84% e.e.). The diminished enantioinduction observed 4-one, albeit with lower enantiocontrol (23, 60% yield, 50% e.e.,
in this case is probably due to the enhanced reversibility of the >20:1 d.r.). Moreover, we also found that seven-membered rings
alkylation step as the Baeyer ring strain in five-membered rings could be formed through a 7-endo cyclization to provide the
exceeds that of six-membered analogues24.
corresponding azepanes or cycloheptanes in excellent yields (25
Next, we turned our attention to the alkene component in this and 26, 89% yield, 88% e.e. and 71% yield, 84% e.e., respectively).
intramolecular variant. Trisubstituted olefins proved to be highly This process is believed to occur through reversible 6-exo and
efficient (20 and 22, 86% yield, 92% e.e. and 81% yield, 94% e.e., 7-endo radical cyclizations that ultimately favour the formation of
respectively). As might be expected, trisubstituted olefins that the more thermodynamically stable tertiary radical intermediate
incorporate two prochiral carbons achieve high diastereocontrol at before intermolecular HAT.
the stereocentres involved in ring formation, yet effectively no
Having successfully demonstrated this enantioselective α-formyl
selectivity in the HAT step (22, 11:11:1:1 d.r.). It should be noted alkylation in a unimolecular sense, we next turned our attention
that, in the case of the geraniol-derived example 22, where multiple to an intermolecular variant. Initially we focused on widely
olefins are present in the tethered aldehyde substrate, only the prox- available styrene coupling partners, given their established
imal alkene undergoes radical addition. Notably, 1,2-disubstituted propensity as radicalphiles25. Indeed, we observed excellent
olefins were also effective in the transformation (16, 17 and 21, efficiency and selectivity in this case using a less oxidizing hetero-
62–82% yield, 88–90% e.e.). However, superior efficiency was leptic iridium(III) photocatalyst, Ir(dmppy)2(dtbbpy)PF6 (ref. 26)
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2797
ARTICLES
Table 2 | Aldehyde and styrene scope of enantioselective intermolecular α-alkylation.
Catalyst combination
Ar
1 mol% 27
20 mol% 28
10 mol% 29
–
Me
PF6
SH
O
O
R2
t-Bu
t-Bu
t-Bu
t-Bu
N
Ir
N
Me
Me
Ar
N
R2
+
N
N
H
H
H
OTMS
R1
R1
α-Alkyl aldehyde
DME
10 °C
Ar =
3,5-(CF3)2C6H3
t-Bu
Me
Styrene
Aldehyde
27
28
29
Aldehyde scope
Styrene scope
OMe
F
30
31
36
37
O
O
O
O
H
H
H
H
H
n-Hex
Me
n-Hex
n-Hex
81% yield, 90% e.e.
72% yield, 83% e.e.
94% yield, 93% e.e.
83% yield, 89% e.e.
CF3
N
NBn
O
O
O
O
32
34
33
35
38
40
39
41
H
H
H
n-Hex
n-Hex
4
Me
Me
Cl
72% yield, 90% e.e.
92% yield, 90% e.e.
50% yield, 92% e.e.
86% yield, 92% e.e.
O
O
O
O
N
H
H
H
H
n-Hex
n-Hex
3
CO2Et
73% yield, 90% e.e.
NHCbz
60% yield, 90% e.e.
56% yield, 87% e.e.
68% yield, 90% e.e.
For each product number (in bold), data are reported as percent isolated yield. Cbz, benzyl carbamoyl; Bn, benzyl. See Supplementary Information for experimental details.
(dmppy = 2-(4-methylphenyl)-4-(methylpyridine)) (27) and the vinyl arenes can be employed while retaining excellent enantio-
diarylsilylprolinol organocatalyst, α,α-bis[3,5-bis(trifluoromethyl) selectivity (36–38, 50–94% yield, 89–93% e.e.). Additionally,
phenyl]-2-pyrrolidine-methanol trimethylsilyl ether (28). Moreover, heteroaromatics in the form of 3-vinyl pyridine and a 4-vinyl
the use of a more sterically congested thiophenol catalyst 29 was pyrazole were shown to be viable substrates (39 and 40, 86%
required in this case to overcome side reactions arising from yield, 92% e.e. and 56% yield, 87% e.e., respectively). Furthermore,
thiol-ene type processes.
1,2-disubstituted styrenes could also be employed, as exemplified
With these conditions in hand, we found that a variety of sub- by indene, to generate the corresponding alkylation adduct in excel-
stituted aldehydes provided the desired alkylated products in good lent yield and enantiocontrol (41, 68% yield, 90% e.e.).
yield and selectivity (Table 2). Interestingly, 6-chlorohexanal
Finally, we examined this α-alkylation manifold with simple
provided the desired product (33) in high efficiency rather than olefin coupling partners. Although terminal olefins were found to
the alternative 6-exo-tet intramolecular enamine alkylation be less reactive (see Supplementary Information), π-nucleophilic
adduct. Moreover, β,β-disubstituted and β-amino aldehydes were 1,1-disubstituted olefins were found to be suitable, with moderate
well-tolerated in the transformation (32 and 35, 72% yield, 90% to useful levels of efficiency. As shown in Fig. 3, we were pleased
e.e. and 60% yield, 90% e.e., respectively). Next, we examined the to find that this triple catalytic activation mode allows methylene-
effect of the aromatic group of the styrene component. Notably, cyclopentane and methylenecyclohexane to participate in the desired
we found that a variety of electron-rich and electron-deficient alkylation event with high levels of enantiocontrol. We attribute
the viability of these substrates to be due, in part, to the reversible
photocatalytic generation of the key 3πe– enaminyl radical inter-
mediate and subsequent interaction with the HAT catalyst only
after addition across the olefin substrate.
O
O
O
n-Hex
n-Hex
H
In summary, we have developed a novel reaction platform where
simple aldehyde substrates undergo coupling with a wide variety of
olefin reaction partners to enantioselectively produce α-alkyl
carbonyl adducts. This visible light-mediated transformation is
accomplished via a hydrogen atom and electron borrowing
mechanism that involves three discrete catalytic cycles that are
temporally matched to function in concert. This multicatalytic
process enables both intra- and intermolecular coupling of
H
H
n-Hex
Aldehyde
α-Alkyl aldehyde
74% yield, 90% e.e.
α-Alkyl aldehyde
47% yield, 88% e.e.
H•
Ir
En
Figure 3 | Intermolecular α-alkylation of aldehydes with non-functionalized aldehydes to construct both cyclic and acyclic products, respectively.
olefins. Intermolecular coupling between 1,1-disubstituted olefins and
octanal. Data are reported as percent isolated yield. Reaction conditions:
1 mol% 27, 20 mol% 28, 10 mol% 29, DME, blue LED light, −65 °C.
We expect the capacity of employing feedstock chemicals in a new
enantioselective coupling reaction that employs visible light will
find utility across a number of research and industrial applications.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2797
ARTICLES
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Received 6 February 2017; accepted 8 May 2017;
published online 26 June 2017
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Research reported in this publication was supported by the National Institute of
General Medical Sciences (NIGMS), the NIH (under award no. R01 GM078201-05) to
D.W.C.M., A.G.C., J.T.M., N.J.M. and J.K. and by gifts from Merck, Abbvie, BMS and
Janssen. J.T.M. acknowledges the NIH for a postdoctoral fellowship (F32 GM108217-02).
The content is solely the responsibility of the authors and does not necessarily represent
the official views of NIGMS.
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Author contributions
A.G.C., J.T.M., N.J.M. and J.K. performed and analysed experiments. A.G.C., J.T.M.,
N.J.M., J.K. and D.W.C.M. designed experiments to develop the intramolecular variant of
this reaction and probe its utility. A.G.C., N.J.M., and D.W.C.M. designed experiments to
develop the intermolecular variant of this reaction and probe its utility. A.G.C. and
D.W.C.M. prepared this manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. Correspondence and
requests for materials should be addressed to D.W.C.M.
16. Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic Competing financial interests
chemistry. J. Org. Chem. 81, 6896–6926 (2016).
The authors declare no competing financial interests.
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