Decarboxylative Hydroalkylation of Alkynes

Article abstract of DOI:10.1021/jacs.8b02834

The merger of open- and closed-shell elementary organometallic steps has enabled the selective intermolecular addition of nucleophilic radicals to unactivated alkynes. A range of carboxylic acids can be subjected to a CO₂ extrusion, nickel capture, migratory insertion sequence with terminal and internal alkynes to generate stereodefined functionalized olefins. This platform has been further extended, via hydrogen atom transfer, to the direct vinylation of unactivated C-H bonds. Preliminary studies indicate that a Ni-alkyl migratory insertion is operative.

Full text of DOI:10.1021/jacs.8b02834

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Decarboxylative Hydroalkylation of Alkynes
Nicholas A Till, Russell T Smith, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02834 • Publication Date (Web): 17 Apr 2018
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Decarboxylative Hydroalkylation of Alkynes
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Nicholas A. Till, Russell T. Smith, and David W. C. MacMillan*
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Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
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Supporting Information Placeholder
ABSTRACT: The merger of open- and closed-shell
elusive reaction: selective radical addition to unactivated alkynes
elementary organometallic steps has enabled the selective
intermolecular addition of nucleophilic radicals to unactivated
alkynes. A range of carboxylic acids can be subjected to a CO2
extrusion, nickel capture, migratory insertion sequence with
terminal and internal alkynes to generate stereodefined
functionalized olefins. This platform has been further extended,
via hydrogen atom transfer, to the direct vinylation of
unactivated C–H bonds. Preliminary studies indicate that a Ni-
alkyl migratory insertion is operative.
slow kinetics
R
R
R
N
N
R
Boc
Boc
this work: stereoselective radical addition to unactivated alkynes
radical capture
migratory insertion
Ni
Ni
The direct addition of alkyl radicals to carbon-carbon π-
bonds represents one of the most widely exploited
transformations within the realm of open-shell chemistry.
Indeed, this mechanism is central to a variety of bond-forming
cascades in natural product total synthesis,1 the large-scale
preparation of high-value polymers,2,3 and the synthesis of
pharmaceutical agents.4 In the case of olefin SOMOphiles,
radical additions often proceed rapidly and with predictable
regioselectivity, a feature that has been broadly leveraged to
effect carbon-carbon bond formations with simple alkenes,
styrenes, and enones.5 In contrast, the direct addition of radicals
to unactivated alkynes is often problematic due to i) the
diminished rate of C–C bond formation1,6 and ii) the generation
of high-energy vinyl radical intermediates that can readily
participate in various undesirable open-shell pathways.
R
R
R
R
R
NiLn
X
X
NiLn
NiLn
LnNi
R
t-Bu
open-shell
closed-shell
X
N
N
Ni
R
R
radical generation
1e– oxidation
1e– reduction
π-bond activation
migratory insertion
protodemetallation
t-Bu
X
Can we merge open- and closed-shell pathways?
In recent years, metallaphotoredox has become a useful
multi-catalysis strategy, wherein traditionally inert functional
groups are readily converted to carbon-centered radicals that
subsequently engage in organometallic cross-couplings via a
two-stage radical capture and reductive elimination cycle.
Recently we questioned if it might be possible to merge
photoredox activation with an alternative elementary coupling
step, namely migratory insertion. We recognized that such a
merger of open-shell radical chemistry with a closed-shell
migratory insertion pathway might provide a new strategy for
the union of alkyl radicals and alkynes, an often-elusive
coupling step. In this context, we hypothesized that a nickel
catalyst might mediate the requisite coupling given that it
readily participates in both 1 e– and 2 e– oxidation state changes,
X
H
X
Ir Ni
OH
R
R
R
R
O
carboxylic acid
alkyne
stereodefined olefin
Figure 1. Dual-catalytic alkyne hydroalkylation.
route to the requisite alkyl-nickel species using simple yet
abundant alkyl carboxylic acids. While decarboxylative
vinylation with nickel has been demonstrated by our lab, 11 and
thereafter by Reisman12 and Baran,13 we recognized that such
strategies require vinyl bromides or vinyl zinc systems,
substrates that are typically prepared in one or two steps,
respectively. As such, direct use of the parent alkyne14 in a
cross-coupling vinylation would clearly be advantageous – a
strategy recently employed by Wu in the Ni–H catalyzed
hydroalkylation of phenylacetylenes and enynes.15
From a design perspective, we envisioned that this radical
capture/migratory insertion mechanism would proceed as
shown in Scheme 1. Upon irradiation with visible light, the
photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1) is known to
access the highly oxidizing excited state (ES) species *Ir(III)
(ES-2) (E1/2red [*IrIII/IrII] = +1.21 V vs. the saturated calomel
7
(i.e. it can readily function in both open- and closed-shell
mechanisms). With respect to olefin geometry control, it is
important to note that vinyl radicals undergo rapid inversion
(kinv = 109 s-1, –133 °C)9 between (E)- and (Z)-isomers, whereas
vinyl carbon-Ni bonds are configurationally stable and can be
stereospecifically protonated.8 As such, the regio- and
stereoselectivity of the alkyne addition process would be strictly
enforced by the migratory insertion step.8
Based upon recent studies in photocatalytic decarboxylative
radical generation,10 we were optimistic that a photo-
redox/nickel dual-catalysis platform would provide a mild
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Scheme 1. Proposed metallaphotoredox dual-catalytic cycle.
excellent regioselectivity and yield are maintained across a
1
2
3
4
5
6
7
8
range of alkynes of varying steric demand at the propargylic
position (12 and 13, 77 and 58% yield, respectively).
Importantly, a large range of functional groups are readily
tolerated, including alkyl chlorides, esters, nitriles,
phthalimides, and perhaps most notable, unprotected alcohols
(14–20, 72–85% yield). It should be noted that nearly all of the
alkynes employed in Table 2 are commercially available,
whereas only two of the vinyl halide or boronate analogs can be
purchased, further demonstrating the advantages of directly
employing alkynes in this new C(sp3)–vinylation reaction.
We next turned our attention to the capacity of internal
alkynes to participate in this decarboxylative hydroalkylation
protocol. We first examined the symmetrical 4-octyne system,
and were delighted to find that our optimized reaction
conditions achieved useful yield and excellent selectively for
production of the (E)-isomer (21, 60% yield, E:Z >20:1),
consistent with the proposed migratory insertion pathway. Next
we faced the challenge of unsymmetrical internal alkynes, a
notoriously difficult substrate class with respect to
regioselective hydrofunctionalization.19 Remarkably, we
observed excellent regiocontrol in the hydroalkylation of a
variety of non-symmetrical acetylide systems (22-25, 64-74%
yield, >20:1 r.r.), wherein the observed selectivity apparently
arises from preferential alkyl-migratory insertion to position the
nickel center at the C(sp) position of greatest electron density,
and the incoming alkyl group at the site of highest
electrophilicity based on the latent polarity of the alkyne.
Indeed, examination of the products from reactions with three
sterically similar alkynes, namely Me–C≡C–R, where R =
CH2OH, (25), R = CH2CH2OH (26), and R = CH2CH2CH3 (27),
reveals a consistent trend (>20:1 r.r., 4.5:1 r.r., 2.0:1 r.r.,
respectively), demonstrating that alkyne polarization plays a
determining role in the selectivity of the migratory insertion
step. Furthermore, comparing the products from reactions with
sterically unsymmetrical alkynes, the incoming alkyl group is
preferentially placed farthest from the bulky alkyne substituent
(27 and 28 2.0:1 and 6.8:1 r.r., respectively), consistent with
studies on the stoichiometric insertion of alkyl-nickel species
into alkynes.8 We next focused on the scope of the carboxylic
acid component. A number of cyclic and acyclic α-amino acids
undergo efficient coupling with 1-heptyne (11, 29–34, 41–80%
yield). Moreover, α-oxy carboxylic acids—in both cyclic and
acyclic formats—undergo proficient alkyne coupling to access
light-mediated
radical generation
CO2H
N
N
– H+
Boc
Boc
– CO2
carboxylic acid
5
SET
3
n-pentyl
N
*IrIII (2)
IrII (4)
11
Boc
Photoredox
(±)-coupled product
9
Catalytic Cycle
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X
X
nNiII
10
L
IrIII (1)
H+
SET
Alk
n-pent
visible
light
I
NiII
Ln
6
L
nNi
Nickel
X
X
Catalytic Cycle
9
5
N
Boc
X
nNiII
L
Alk
nickel-mediated
radical addition
n-pentyl
7
alkyne
8
electrode (SCE) in MeCN).16 Deprotonation of the carboxylic
acid substrate (e.g., N-Boc-proline (3)) and subsequent single-
electron oxidation of the resulting carboxylate functionality by
ES-2 should generate alkyl radical 5 (upon CO2 extrusion)17 and
reduced Ir(II) species 4. Open-shell alkyl species 5 is expected
to rapidly engage in an oxidative radical capture with low-
valent nickel species 6, generating alkyl-Ni(II) complex 7. At
this stage, we hoped that this nucleophilic Ni(II) species would
undergo the critical migratory insertion coupling step with
alkyne 8 to generate vinyl-nickel complex 9 with a high degree
of stereo- and regioselectivity based on the established
mechanistic bias for cis-carbometallation and the studies by
Bergman using stoichiometric nickel complexes.8 Subsequent
protodemetallation by either protonated base or carboxylic acid
would then provide C(sp3)–C(sp2) coupled product 11. A single
electron transfer event from Ir(II) species 4 (E1/2red [IrIII/IrII] = –
1.37 V vs. SCE in MeCN)16 to Ni(II) species 10 would
regenerate both the Ir(III) species and low-valent nickel 6
(E1/2red[NiII/Ni0] = –1.2 V vs. SCE in DMF), simultaneously
completing both the nickel and photocatalyst cycles.18
Table 1. Control experiments for the alkyne hydroalkylation.a
This new decarboxylation/metal capture/migratory insertion
coupling protocol was first examined by exposure of N-Boc-
proline and 1-heptyne to visible light irradiation (40 W blue
2 mol% photocatalyst 1
10 mol% NiCl2•dtbbpy
OH
n-pentyl
10 mol% TMG
n-pentyl
LEDs) and
catalytic quantities of
NiCl2•dtbbpy,
N
N
H2O
O
Boc
Boc
Ir[dF(CF3)ppy]2(dtbbpy)PF6, and 1,1,3,3-tetramethylguanidine
(TMG). To our delight, this dual-catalytic combination
provided the desired hydroalkylation product 11 in modest yield,
yet with excellent selectivity for the branched regioisomer
(Table 1, entry 1). By lowering the base loading, the yield of the
branched product could be increased to 80% (entry 2) with no
erosion in regioselectivity. Given that direct radical-alkyne
addition furnishes the linear olefin product, the marked
selectivity for the branched isomer indicates that the nickel-
mediated pathway is exclusively operative. Indeed, control
experiments revealed that Ni, photocatalyst, and light are all
critical for C–C bond formation (entries 3-5).
DMF
carboxylic acid
alkyne
sp3-sp2 adduct
30 °C, 24 h
entry
yield
r.r.
conditions
1
2
3
4
5
6
>20:1
1.0 equiv TMG
0.1 equiv TMG
no light
17%
80% (80%)b
0%
>20:1
-
-
-
no photocatalyst
no Ni catalyst
4-CzIPN catalystc
0%
<5%
>20:1
70%
aPerformed with H2O (20 equiv), carboxylic acid (1.0 equiv), and 1-
With optimized conditions in hand, we next evaluated the
scope of the alkyne component, utilizing N-Boc-proline as the
common carboxylic acid coupling partner. As shown in Table 2,
1
b
heptyne (1.3 equiv). Yields by H NMR. Yields in parentheses are
isolated. c4-CzIPN (2 mol%) used in place of Ir catalyst.
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Table 2. Alkyne and carboxylic acid scope in the Ni/photoredox-mediated decarboxylative hydroalkylation of unactivated alkynes.a
1
2
3
4
5
6
7
F3C
–
PF6
F
2 mol% photocatalyst 1
10 mol% NiCl2•dtbbpy
10 mol% TMG
tBu
tBu
N
Ir
N
N
OH
F
F
R
R
1
R
Ir
40 W blue LED, 30 °C
O
R
N
20 equiv H2O, DMF
F
carboxylic acid
alkyne
stereodefined olefin
F3C
8
9
alkyne scope
carboxylic acid scope
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
n-pentyl
N
N
N
n-pentyl
n-pentyl
n-pentyl
N
N
N
Boc
Boc
Boc
Boc
Boc
Boc
(±)-11, 80% yield
(±)-12, 77% yield
(±)-13, 58% yield
(±)-29, 80% yield
(±)-30, 80% yield
(±)-31, 74% yield
CN
Cl
CO2Me
i-Pr
N
N
N
2
2
Boc
Boc
Boc
Me
n-pentyl
Me
n-pentyl
H
n-pentyl
N
N
N
(±)-16, 75% yield
(±)-14, 85% yield
(±)-15, 83% yield
Boc
Boc
Boc
(±)-32, 74% yield
33, 78% yield
34, 41% yield
NPhth
OH
N
NHBoc
N
N
2
2
Me Me
Boc
Boc
Boc
CO2Me
O
O
O
(±)-17, 72% yield
(±)-18, 76% yield
(±)-19, 84% yield
n-pentyl
O
Me
Me
n-pentyl
n-pentyl
O
MeO
O
O
OH
N
n-Pr
N
N
Boc
(±)-37, 71% yieldb
35, 56% yield
36, 72% yield
n-Pr
Me
O
Boc
Boc
>20:1 d.r.
>20:1 d.r.
(±)-20, 66% yield
(±)-21, 60% yield
(±)-22, 71% yield
Me
>20:1 E:Z
>20:1 r.r.
n-pentyl
n-pentyl
n-pentyl
BnO
BnO
Ph
OH
NHBoc
N
TMS
N
N
38, 65% yield
40, 64% yieldb
(±)-39, 70% yield
Me
Me
Boc
Me
Boc
Boc
(±)-23, 74% yield
(±)-24, 64% yield
(±)-25, 64% yield
aliphatic carboxylic acids c, d
>20:1 r.r.
>20:1 r.r.
>20:1 r.r.
F
Boc
O
F
N
Me
n-pentyl
n-pentyl
n-pentyl
Me
N
OH
N
N
Me
Me
Me
Boc
Me
Boc
Boc
41, 60% yield
13:1 r.r.
42, 57% yield
43, 56% yield
(±)-26, 70% yield
(±)-27, 63% yield
(±)-28, 43% yield
4.5:1 r.r.
2.0:1 r.r.
6.8:1 r.r.
13:1 r.r.
13:1 r.r.
C–H vinylation via HAT
O
3-hexyne
Me
NiCl2•dtbbpy, 1
O
n-Pr
N
N
n-Pr
n-Pr
N
N
3-OAc quinuclidine
X
n-Pr
n-Pr
Me
Me
n-Pr
n-Pr
Boc
Me
X
H
H2O
n-Pr
vinylation product
(±)-21
44
72% yield
(±)-45
58% yield, 5:1 r.r.
EtOAc
C–H nucleophile
77% yield
aAll yields are isolated. Performed with photocatalyst 1 (2 mol%), NiCl2•dtbbpy (10 mol%), TMG (10 mol%), carboxylic acid (1.0 equiv), alkyne (1.3
b
1
c
equiv). All products obtained in >20:1 r.r. and >20:1 E:Z, unless otherwise noted. Yield determined by H NMR. Reactions performed in the
integrated photoreactor in DMSO, utilizing CsF (0.5 equiv) as the base. dRegioisomeric ratio refers to the branched and linear olefins.
allylic ethers in an analogous fashion (35–39, 56–72% yield).
Alkyl carboxylic acids also participate in this Ni-mediated
hydrofunctionalization pathway, albeit with a slight erosion in
regioselectivity (41–43, 13:1 r.r.), wherein the minor
regioisomer most likely forms via direct, non-metal mediated
radical addition to the alkyne substrate. Given the established
nucleophilicity of non-stabilized aliphatic radicals, it is
remarkable to consider that the traditional open-shell alkyne
addition pathway is effectively bypassed using this radical
capture/migratory insertion sequence.
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Scheme 2. Alkylation selectivity as a function of acid size. 6.8:1, and 16:1 r.r., respectively), in complete accord with
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Scheme 1.
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Supporting Information
Experimental details and characterization data. This
information is available free of charge on the ACS
Publications website at DOI: (link to DOI)
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AUTHOR INFORMATION
Corresponding Author
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*dmacmill@princeton.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support provided by the NIHGMS (RO1
GM103558-05) and kind gifts from Merck, BMS,
Firmenich, Pfizer, Janssen, and Eli Lilly.
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From the outset, we envisioned that this combined
nickel/photoredox catalysis reaction could be modified with
respect to mode of radical generation while retaining the
coupling efficiency of the nickel migratory insertion step. With
this in mind, we have recently shown that the combination of
photoredox and quinuclidine catalysts can selectively perform
H• abstraction with hydridic C–H bonds.20 As shown in Table 2,
the combination of light, 3-acetoxyquinuclidine, photocatalyst
1, and catalytic nickel allows for the efficient and site-selective
vinylation of C–H bonds adjacent to carbamate, amide, and urea
functionalities (21, 44, 45, 60-77% yield).15
(12) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Org.
Lett. 2017, 19, 2150.
To further probe our mechanistic design plan (Scheme 1), we
studied the dependence of regioselectivity on the size of the
carboxylic acid coupling partner with a sterically biased internal
alkyne, 4-methylpent-2-yne (Scheme 2). Given that the
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W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei,
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hydroalkylations, see: (a) Uehling, M. R.; Suess, A. M.; Lalic, G. J.
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possibility
exists
for
an
alternative
Ni-hydride
addition/oxidative radical capture pathway (Scheme 2B), we
sought to distinguish that hypothesis from the migratory
insertion sequence proposed herein. Under the nickel hydride
mechanism, the regioselectivity-determining Ni–H insertion
occurs prior to engaging the alkyl coupling partner.15 For this
reason, the Ni–H mechanism predicts that the regioselectivity
will be independent of the steric demand of carboxylic acid
component. In contrast, the Ni-alkyl insertion step will involve
non-bonding interactions between the alkyne substituents and
incoming Ni-alkyl group, a feature that would lead to
regioselectivity being a function of the steric demand of the
carboxylic acid substrate (Scheme 2A). As such, we examined
carboxylic acids of electronic natures similar to that of our
model substrate (Boc-Pro), but with sterically smaller (Boc-Me-
Gly) and sterically larger (Boc-Me-Leu) profiles. Consistent
with a regioselectivity-determining Ni-alkyl insertion event, a
positive correlation was observed between alkyl partner size
and regioselectivity of hydroalkylation (46, 28, and 47, 4.4:1,
(18) Durandetti, M.; Devaud, M.; Périchon, J. New J. Chem. 1996, 20,
659.
(19) Liu, Z.; Derosa, J.; Engle, K. M. J. Am. Chem. Soc. 2016, 138,
13076.
(20) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.;
MacMillan, D. W. C. Science 2016, 352, 1304.
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Journal of the American Chemical Society
TOC Graphic
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X
H
X
Ir Ni
OH
R
R
R
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R
O
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carboxylic acid
alkyne
stereodefined olefin
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◼ ◼nickel-catalyzed
◼ ◼regioselective
◼ ◼stereospecific
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ACS Paragon Plus Environment