Metallaphotoredox-catalysed sp3-sp3 cross-coupling of carboxylic acids with alkyl halides

Article abstract of DOI:10.1038/nature19056

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp³-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp²-hybridized species, the development of methods for sp³-sp³ bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp³-sp³ bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step-and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp³-sp³ coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp³-sp³ bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Full text of DOI:10.1038/nature19056

LETTER
doi:10.1038/nature19056
Metallaphotoredox-catalysed sp3–sp3 cross-
coupling of carboxylic acids with alkyl halides
Craig P. Johnston1*, Russell T. smith1*, simon Allmendinger1 & David W. C. MacMillan1
In the past 50 years, cross-coupling reactions mediated by transition Indeed, the electronic duality of photocatalyst excited states (which
metals have changed the way in which complex organic molecules are simultaneously strong oxidants and reductants) has prompted
are synthesized. The predictable and chemoselective nature of these the exploitation of these polypyridyl transition metal complexes in
transformations has led to their widespread adoption across many unconventional bond disconnections15 and facilitated the manipu-
areas of chemical research1. However, the construction of a bond lation of oxidation states in organometallic complexes to enable pre-
between two sp3-hybridized carbon atoms, a fundamental unit of viously elusive reactions16–19. For example, the synergistic merger of
organic chemistry, remains an important yet elusive objective for single-electron transfer (SET) based decarboxylation with nickel-
engineering cross-coupling reactions2. In comparison to related activated electrophiles has promoted the formation of valuable sp2–sp3
procedures with sp2-hybridized species, the development of bonds while broadening the field of cross-coupling chemistry via the
methods for sp3–sp3 bond formation via transition metal catalysis use of non-conventional reaction substrates20,21. This work has further
has been hampered historically by deleterious side-reactions, such served as a foundation for several extensions of our decarboxylative
as β-hydride elimination with palladium catalysis or the reluctance nickel cross-coupling concept using preactivated phthalimido-
of alkyl halides to undergo oxidative addition3,4. To address this derivatized acids7,22. Recently, we hypothesized that a straightforward and
issue, nickel-catalysed cross-coupling processes can be used to generic procedure might be developed to enable sp3–sp3 bond forma-
form sp3–sp3 bonds that utilize organometallic nucleophiles and tion via the application of ubiquitous carboxylic acids in a decarboxy-
alkyl electrophiles5–7. In particular, the coupling of alkyl halides lative cross-coupling with alkyl halides using photoredox catalysis. In
with pre-generated organozinc8,9, Grignard10 and organoborane11 developing a method for direct coupling of carboxylic acids with alkyl
species has been used to furnish diverse molecular structures. halides, we hoped to introduce a paradigm for carbon–carbon bond
However, the manipulations required to produce these activated construction that would (i) provide rapid access to complex fragments
structures is inefficient, leading to poor step- and atom-economies. via sp3–sp3 coupling, (ii) systematically streamline synthetic routes
Moreover, the operational difficulties associated with making and towards drug candidates, and (iii) enable alkyl–alkyl coupling using
using these reactive coupling partners, and preserving them through native functional groups and without substrate preactivation.
a synthetic sequence, has hindered their widespread adoption. A
generically useful sp3–sp3 coupling technology that uses bench-
stable, native organic functional groups, without the need for
pre-functionalization or substrate derivatization, would therefore
be valuable. Here we demonstrate that the synergistic merger of
photoredox and nickel catalysis enables the direct formation of
sp3–sp3 bonds using only simple carboxylic acids and alkyl halides
as the nucleophilic and electrophilic coupling partners, respectively.
This metallaphotoredox protocol is suitable for many primary and
secondary carboxylic acids. The merit of this coupling strategy is
illustrated by the synthesis of the pharmaceutical tirofiban in four
steps from commercially available starting materials.
Within the field of drug discovery, there is a demonstrated statistical
correlation between clinical success and the molecular complexity of
medicinal candidates with respect to the inherent ratio of sp2–sp3 to
sp3–sp3 bond content12. Not surprisingly, these findings have created
an emerging demand within medicinal chemistry for new reaction
technologies that enable rapid access to drug-like molecules via the
coupling of fragments that incorporate or build novel sp3–sp3 bonds.
However, a major hurdle associated with achieving sp3–sp3 bond for-
mation via transition metal catalysis is the limited availability of a
Figure 1 | Carboxylic acids as coupling partners in a metallaphotoredox-
diverse suite of nucleophilic coupling partners that are bench-stable,
mediated process to form sp3–sp3 bonds. a, The majority of transition-
inexpensive, and easily procured. An attractive option would be to use
metal-catalysed cross-couplings commonly use at least one sp2-hydridized
simple carboxylic acids, an abundant native functional group that is
coupling partner (top). At present, sp3–sp3 cross-coupling is underexploited
chemically robust yet can be readily exploited as a latent leaving group
(bottom). b, The direct utilization of abundant, bench-stable, native
after multistep synthetic sequences (Fig. 1).
functional groups such as carboxylic acids in combination with Ni and Ir
The emergence of visible-light-mediated photoredox catalysis within
the field of synthetic organic chemistry has enabled the discovery and
synergistic catalysis under mild conditions (top) should encourage greater
adoption of sp3–sp3 bond forming methods, leading to products such as
those shown at the bottom. M, metal; R, organic functional group.
invention of numerous unique and valuable transformations13,14
.
1Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.
*These authors contributed equally to this work.
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Letter reSeArCH
was observed. Therefore, we recognized that judicious selection of sol-
vent and base would be necessary to suppress this unwanted by-product
formation without obstructing the desired photocatalytic oxidation
reaction pathway. To accomplish this goal, a survey of solvents and
inorganic bases was conducted in the presence of Ir[dF(CF3)ppy]2
(dtbbpy)PF6, NiCl2⋅glyme and dtbbpy with visible-light irradiation
from blue-light-emitting diodes (LEDs). This revealed that the com-
bination of acetonitrile and K2CO3 greatly reduced the rate of carboxy-
late alkylation and furnished the desired product in 68% yield. Further
optimization improved conversion to product through switching to
the more electron-rich ligand 4,4′-dOMe-bpy (4,4′-dimethoxy-2,2′-
bipyridine). Finally, the addition of water, which decelerated ester
formation, provided an additional enhancement and an isolated yield of
85%. A series of control experiments omitting each individual reaction
component highlighted the importance of photocatalyst, nickel and
light for promoting this decarboxylative sp3–sp3 bond-forming reaction
(see Supplementary Information).
With optimal metallaphotoredox conditions in hand, we probed the
generality of this process with respect to the aliphatic halide electro-
phile. As representative nucleophilic coupling partners, N-Boc- and
N-Cbz proline (Cbz, carboxybenzyl) were used interchangeably for this
purpose (Fig. 3). Simple unfunctionalized primary alkyl halides such
as 1-bromo-3-phenylpropane were examined, and these underwent
efficient cross-coupling (12, 85% yield). Functionality vicinal to the
bromide was also tolerated, with benzyl 2-bromoethyl ether coupling
in good yield (13, 65% yield). A substrate bearing a terminal olefin
performed favourably under the reaction conditions to deliver the
desired product (14, 84% yield). As this protocol is conducted at near
ambient temperature, hydrolysis of an ethyl ester does not occur under
the optimized basic reaction conditions, and the corresponding car-
bamate-protected amine was isolated in good yield (15, 64% yield). In
addition, perfect chemoselective functionalization of an alkyl bromide
in the presence of a primary chloroalkane was observed (16, 96% yield).
A deprotection-cyclization sequence with this material would provide
rapid access to the bicyclic tertiary amine core of the naturally occur-
ring pyrrolizidine alkaloids. The presence of free hydroxyl groups is
fully compatible with the iridium photocatalyst and the nickel complex
(17, 86% yield). Moreover, reactive Lewis basic functionalities, such as
epoxides and aldehydes, are well tolerated in this cross-coupling pro-
cedure and provide numerous opportunities for further derivatization
(18 and 19, 83% and 62% yield, respectively).
Figure 2 | Proposed mechanism for the metallaphotoredox-mediated
cross-coupling of carboxylic acids to generate sp3–sp3 bonds. The
photoredox catalytic cycle commences with excitation of IrIII 1 to give the
excited state 2. Single electron oxidation of the carboxylate anion derived
from acid 3 by oxidant 2 produces the alkyl radical 4 after CO2-extrusion
along with IrII 5. The nickel catalytic cycle starts with Ni0 catalyst 6 capturing
the alkyl radical 4 (boxed at top) to form the NiI species 7. Ensuing oxidative
addition with alkyl halide 8 leads to nickel(iii) intermediate 9. Reductive
elimination would then liberate the desired product 10 (boxed at bottom)
and NiI 11. Both catalytic cycles converge to complete a single turnover via a
SET event that regenerates the photoredox and nickel catalysts.
A detailed mechanism for the proposed decarboxylative sp3–sp3
coupling is delineated in Fig. 2. Initial visible-light excitation of the
iridium(iii) photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1) would gen-
erate the long-lived (lifetime τ=2.3μs)23 excited-state *IrIII complex
2 (dF(CF3)ppy=2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine,
dtbbpy=4,4′-di-tert-butyl- 2,2′-bipyridine). Complex 2 is a strong
single-electron oxidant (half-wave redox potential E1/2red [*IrIII/IrII]=
+1.21V versus the standard calomel electrode, SCE, in CH3CN)23
and should undergo reduction by a carboxylate anion derived from
deprotonation of the acid 3. The resultant carboxyl radical is expected
to rapidly extrude CO2 to produce alkyl radical 4 and the reduced IrII
catalyst 5. Concurrently, the ligated nickel(0) complex 6 is generated
in situ via two discrete SET reductions of (dtbbpy)Ni(ii)Cl2 by the
iridium(ii) state of the photocatalyst through sacrificial carboxylic
acid consumption (E1/2red [IrIII/IrII]=−1.37V versus SCE in CH3CN,
The influence of substitution on the alkyl halide was also investi-
gated to probe the steric limits of the electrophilic coupling partner. No
detrimental effects to the efficiency of this process were observed when
a β,β-disubstituted bromoalkane was used, and neopentyl bromide
coupled in modest yield (20 and 21, 75% and 52% yield, respectively).
The higher propensity for activated electrophiles to promote esterifi-
cation led to the utilization of benzyl chloride, as opposed to benzyl
bromide, which generated a homobenzylic amine in good yield (22,
84% yield). Notably, bromomethane was a competent coupling partner
in this protocol which formally affords the product of a fully reduced
carboxylic acid moiety in a single step (23, 62% yield).
red
E1/2 [NiII/Ni0] = −1.2 V versus SCE in dimethylformamide,
DMF)23,24. The Ni0 complex 6 can intercept radical 4 to produce alkyl-NiI
intermediate 725. Subsequent oxidative addition with alkyl halide 8
forms the putative organometallic NiIII species 9, which after reductive
elimination forges the desired sp3–sp3 bond to furnish the coupled
product 10 and NiI adduct 1126–28. At this stage the two catalytic
cycles would converge by reduction of nickel(i) intermediate 11 by
the reduced form of the iridium photocatalyst to re-establish both the
IrIII complex 1 and the Ni0 catalyst 623. At present, we cannot rule out
the possibility of an alternative mechanism that involves Ni0-mediated
Expanding the substrate scope to encompass secondary alkyl
halides permitted us to forge sp3–sp3 bonds with adjacent tertiary
carbon centres. For example, five- and six-membered cyclic bromoal-
kanes smoothly reacted to form the desired alkylated products in good
to excellent yields (24–26, 57−91% yield). Smaller ring systems, includ-
ing cyclopropane and oxetane, were also introduced via this metalla-
photoredox procedure (27 and 28, 50% and 79% yield, respectively).
These motifs have found application in drug discovery programmes
as chemically and metabolically stable bioisosteres29. Lastly, an acyclic
secondary alkyl bromide was also successfully cross-coupled to gener-
ate the desired Cbz-protected amine (29, 69% yield).
oxidative addition and trapping of the alkyl radical 4 by a NiII species20,25
.
Based on this approach, we began our primary investigations with
consideration of the metallaphotoredox conditions previously devel-
oped within our group20. In these studies we used N-Boc proline
(Boc, t-butyloxycarbonyl) and 1-bromo-3-phenylpropane as coupling
partners. Unfortunately, owing to the basic reaction conditions in com-
bination with the polar aprotic solvent DMF, exclusive ester formation
We subsequently examined the scope of the nucleophilic com-
ponent and found that an assortment of readily available car-
boxylic acids were viable for this transformation. For instance,
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reSeArCH Letter
F3C
Catalyst combination
MeO
a
2 mol% Ir photocatalyst
10 mol% NiCl2 glyme
1
F
F
–
PF6
•
t-Bu
t-Bu
N
F
F
CO2H
R
10 mol% 4,4′-dOMe-bpy
N
N
Cl
N
R
Ir
Ni
Br
N
Cl
N
K2CO3, H2O, MeCN, RT,
blue LEDs, 48 h
MeO
F3C
Carboxylic acid
Alkyl halide
sp3
–
sp3 coupled product
b
Alkyl halides
CO2Et
Cl
OH
Ph
OBn
N
N
N
N
N
N
Boc
Boc
Cbz
Boc
Boc
Boc
( )-12 85% yield
( )-13 65% yield
( )-14 84% yield
( )-15 64% yield
( )-16 96% yield
( )-17 86% yield
Me
Me
Me
O
O
Me
N
N
N
N
N
N
7
Boc
Boc
Boc
Boc
Boc
Boc
( )-18 83% yield
( )-19 62% yield
( )-20 75% yield
( )-21 52% yield
( )-22 84% yield
( )-23 62% yield
Me
N
N
N
N
N
N
Cbz
O
O
Me
Cbz
Cbz
Boc
Boc
Cbz
( )-24 72% yield
( )-25 57% yield
( )-26 91% yield
( )-27 50% yield
d α-alkyl acids
( )-28 79% yield
( )-29 69% yield
c
α-heteroatom acids
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
N
N
HN
Boc
CbzN
Boc
Boc
O
( )-30 61% yield
( )-31 70% yield
( )-32 72% yield
36 62% yield
( )-37 66% yield
38 52% yield
Me
Ph
Ph
Ph
Ph
BocHN
Ph
Ph
HN
MeO
O
CO2Me
Me
Boc
34 61% yield
40 43% yield
41 40% yield
( )-33 71% yield
( )-35 74% yield
( )-39 58% yield
Figure 3 | Carboxylic acid and alkyl halide scope in the dual nickel-
photoredox catalysed sp3–sp3 coupling reaction. A broad array of
alkyl halides and carboxylic acids are amenable coupling partners in this
substituted carboxylic acids could also be used to form functionalized amines
and ethers. Challenging substrates lacking apparent radical stabilization
could also be used successfully. Isolated yields are reported below each entry.
transformation. a, Generalized reaction; b–d, substrate scope. Optimal catalysts See Supplementary Information for full experimental details. For product
shown in the top right box (some substrates require minor modification;
see Supplementary Information). Primary and secondary electrophiles
were coupled efficiently with proline derivatives. Alternative α-heteroatom
( )-23 shown in shaded box at right in b, a yield of 55% was obtained when
the reaction was run in flow (GC yield); see Supplementary Information. For
product 40 at bottom right in d, cyclopropylacetic acid was used.
Boc-protected pipecolic acid and an azetidine derivative both tetrahydro-2H-pyran derivative were cleanly converted to the cor-
underwent decarboxylative coupling to furnish alkylated prod- responding coupled products in an effective fashion (36 and 37,
ucts in good yields (30 and 31, 61% and 70% yield, respectively). 62% and 66% yield, respectively). Simple alkyl precursors lacking
Naturally occurring amino acids, which are inexpensive and obtain- heteroatoms can also be used, with cyclohexanecarboxylic acid
able from ample biomass feedstocks, can also be exploited to form reacting in reasonable yield (38, 52% yield). An acyclic β-amino
α-functionalized amines with excellent efficiency (32 and 33, acid that would generate a secondary radical upon decarboxyla-
72% and 71% yield, respectively). Similarly, O-methylated tion exhibited respectable efficiency and offers the opportunity to
glycolic acid functions well to provide access to linear ethers in a synthesize β-functionalized amines with ease (39, 58% yield).
straightforward manner (34, 61% yield). The cyclic substrate tet-
Finally, two primary substrates were evaluated in this system to fully
rahydrofuran-2-carboxylic acid was also coupled with 1-bromo-3- exemplify the power of this new sp3–sp3 coupling paradigm. The rear-
phenylpropane under these dual nickel-photoredox conditions rangement of a cyclopropyl system under the reaction conditions pre-
to afford the ethereal product in very good yield (35, 74% yield). sents the opportunity to produce alkylated homoallylic products in a
Although beneficial, the inclusion of an α-heteroatom on the single step (40, 43% yield). Moreover, the monomethyl ester of glutaric
acid fragment is not a prerequisite for this sp3–sp3 bond form- acid was subjected to the optimized metallaphotoredox procedure and
ing process. For example, Cbz-protected isonipecotic acid and a provided an encouraging quantity of the desired product (41, 40% yield).
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Letter reSeArCH
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synthesis of tirofiban. The cross-coupling of acid 42 and alkyl halide 43
(top left) using Ni and Ir catalysis generates a new sp3–sp3 bond, and
subsequent tetrabutylammonium fluoride (TBAF) deprotection provides
alcohol 44 (top right). Tirofiban 45 (bottom left) is then synthesized in two
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We have established a robust strategy for the direct formation of
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Supplementary Information is available in the online version of the paper.
Acknowledgements Financial support was provided by NIHGMS (R01
GM093213-01); we acknowledge gifts from Merck, AbbVie, and Bristol-Myers
Squibb. C.P.J. thanks Marie Curie Actions for an international outgoing
fellowship (PIOF-GA-2013-627695). S.A. thanks the Deutsche
Forschungsgemeinschaft (DFG) for a postdoctoral fellowship
(AL 1860/2-1).
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Author Contributions C.P.J., R.T.S. and S.A. performed and analysed
experiments. C.P.J., R.T.S., S.A. and D.W.C.M. designed experiments to develop
this reaction and probe its utility, and wrote the paper.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial
interests. Readers are welcome to comment on the online version of the paper.
Correspondence and requests for materials should be addressed to
D.W.C.M. (dmacmill@princeton.edu).
8. Giovannini, R., Stüdemann, T., Dussin, G. & Knochel, P. An efficient nickel-
catalyzed cross-coupling between sp3 carbon centers. Angew. Chem. Int. Ed.
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reviewer Information Nature thanks E. Peterson and the other anonymous
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