Decarboxylative sp 3 C-N coupling via dual copper and photoredox catalysis

Article abstract of DOI:10.1038/s41586-018-0234-8

Over the past three decades, considerable progress has been made in the development of methods to construct sp ² carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis ^1,2 . However, the incorporation of alkyl substrates to form sp ³ C-N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.

Full text of DOI:10.1038/s41586-018-0234-8

Letter
https://doi.org/10.1038/s41586-018-0234-8
Decarboxylative sp3 C–N coupling via dual copper
and photoredox catalysis
Yufan Liang1,2, Xiaheng Zhang1,2 & David W. C. MacMillan1*
Over the past three decades, considerable progress has been made nature of alkyl carboxylic acids and nitrogen nucleophiles such as
in the development of methods to construct sp2 carbon–nitrogen heteroaromatics, sulfonamides, amides and anilines, we hoped to devise
(C–N) bonds using palladium, copper or nickel catalysis1,2. However, a new fragment coupling reaction that would be broadly useful yet
the incorporation of alkyl substrates to form sp3 C–N bonds remains mechanistically orthogonal to established alkylation reactions (Fig. 1).
one of the major challenges in the field of cross-coupling chemistry. Recently, two methods have been reported with this aim in mind19,20
,
Here we demonstrate that the synergistic combination of copper and these illustrate the capacity of copper to function in decarboxylative
catalysis and photoredox catalysis can provide a general platform mechanisms.
from which to address this challenge. This cross-coupling system
A detailed mechanism for the proposed decarboxylative coupling of
uses naturally abundant alkyl carboxylic acids and commercially sp3 carbon with nitrogen nucleophiles is outlined in Fig. 2a. Excitation
available nitrogen nucleophiles as coupling partners. It is applicable of photocatalyst Ir(F-Meppy)2(dtbbpy)PF6 (1) (F-Meppy=2-(4-fluoro-
to a wide variety of primary, secondary and tertiary alkyl carboxylic phenyl)-5-(methyl)pyridine, dtbbpy = 4,4ʹ-di-tert-butyl-2,2ʹ-bi-
acids (through iodonium activation), as well as a vast array of pyridine) is known to generate the long-lived triplet-excited-state
nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides *Iriii complex 2 (with a lifetime, τ, of 1.1μs)21. At the same time, we
and anilines can undergo C–N coupling to provide N-alkyl products proposed that coordination of the nitrogen nucleophile 11 with a
in good to excellent efficiency, at room temperature and on short copper(i) precatalyst followed by deprotonation would readily form
timescales (five minutes to one hour). We demonstrate that this the copper(i)-amido species 3. The excited state *Iriii complex 2
C–N coupling protocol proceeds with high regioselectivity using (E1/2red [*Iriii/Irii] =0.94 V versus the standard calomel electrode
substrates that contain several amine groups, and can also be (SCE) in CH3CN)21 should rapidly oxidize this copper(i) complex
applied to complex drug molecules, enabling the rapid construction 3 (E1/2red [Cuii(BPhen)2/Cui(BPhen)2]=0.08V versus SCE in DMF,
of molecular complexity and the late-stage functionalization of BPhen=4,7-diphenyl-1,10-phenanthroline)22 to generate the corre-
bioactive pharmaceuticals.
sponding copper(ii)-amido system 4 and the corresponding iridium(ii)
Within the field of organic chemistry, the efficient construction complex 5. At this stage we considered that iodomesitylene dicarbo-
of C–N bonds is important owing to the prevalence of nitrogen- xylate 8 (which is preformed via the mixing of carboxylic acid 6 and
containing motifs in a wide array of natural products, pharmaceuticals iodomesitylene diacetate 7, see Supplementary Information) would
red
and functional materials3–5. There are several notable routes to the be readily reduced by the newly formed iridium(ii) species 5 (E1/2
formation of sp2 C–N bonds, including the Buchwald–Hartwig reac- [Iriii/Irii]=−1.50V versus SCE in CH3CN21, Ep [8/8•−]=−1.14V
tion1, Ullmann coupling6 and Chan–Lam amination7. However, sp3 versus SCE in CH3CN) to generate a carboxyl radical, which upon
C–N bond formation typically relies on classical methods, such as CO2 extrusion23,24 would produce the desired alkyl radical 9, while
nucleophilic substitution reactions between nitrogen nucleophiles reconstituting the ground-state photocatalyst 1. At this stage, we antic-
and alkyl halides8, Mitsunobu alkylations of alcohols using nitro- ipated that copper(ii)-amido complex 4 would capture alkyl radical 9
gen nucleophiles9, reductive amination with carbonyls10 or olefin to form copper(iii) complex 10, which upon reductive elimination25
hydroamination11. Recently, several research groups have reported would yield the desired fragment-coupled sp3 C–N bearing adduct 12
transition-metal-catalysed variants of the alkylation reaction of nitro- and regenerate copper(i) catalyst 3.
gen nucleophiles with aliphatic halides12,13. In 1894, Curtius reported
We first examined the proposed sp3 C–N coupling using three elec-
the rearrangement of acyl azides to form C–N-containing aliphatic tronically disparate nitrogen nucleophiles (indole 11a, azaindole 11b
substrates14. We questioned whether it might be possible to expand this and indazole 11c, Fig. 2b), along with cyclohexyl carboxylic acid 6 as
concept to complex, medicinally relevant nitrogen-bearing fragments, the alkylating reagent, and a wide range of copper(i) and photore-
thereby accelerating access to drug-like complexity in one step.
dox catalysts. The desired decarboxylative sp3 C–N coupling can be
The synergistic merger of photoredox15 and transition metal catalysis achieved in good to excellent efficiency for all three substrates (60%,
(termed metallaphotoredox catalysis) has resulted in the development 76% and 90% yield, respectively) using Ir(F-Meppy)2(dtbbpy)PF6
of many cross-coupling reactions that are now being widely adopted as the photocatalyst, CuTC (TC=thiophene-2-carboxylate) as the
within the pharmaceutical sector16. The combination of nickel and pho- copper catalyst, BPhen or dOMe-Phen (dOMe-Phen=4,7-dimethoxy-
toredox catalysis has enabled the efficient construction of C(sp3)–C(sp2) 1,10-phenanthroline) as the ligand, BTMG (BTMG=2-tert-butyl-
and C(sp3)–C(sp3) bonds using abundant alkyl carboxylic acids17 and 1,1,3,3-tetramethylguanidine) as the base, with exposure to 34-W
alcohols18. Here we show that metallaphotoredox catalysis involving blue light-emitting diodes (LEDs). Notably, a series of control experi-
copper in place of nickel enables alkyl sp3 C–N bond formation in a ments revealed that although the copper(i) catalyst is essential for the
generic sense without the use of alkyl halides or other prototypical desired C–N bond formation in all cases, the absence of light and/or
electrophiles. More specifically, we hoped to merge the capacity of photocatalyst has a profound effect on reaction efficiency depending
photoredox reactions to form alkyl radicals from iodonium carboxy- on the nitrogen nucleophile used. More specifically, the alkylation of
lates (derived in situ from carboxylic acids) with the long-established indazole 11c is successful with or without photocatalysis (90% com-
propensity of copper to participate in reductive elimination to form pared with 86% yield, respectively), whereas indole 11a and azaindole
carbon–heteroatom bonds2. By taking advantage of the widely abundant 11b achieve markedly improved yields and reaction times when light
1Merck Center for Catalysis at Princeton University, Princeton, NJ, USA. 2These authors contributed equally: Yufan Liang, Xiaheng Zhang. *e-mail: dmacmill@princeton.edu
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reSeArCH Letter
O
a
H
N
O
P
a
O
Heat
Boc Curtius
1894
PhO
N3
OH
OCOCy
I
–MesI
t-BuOH
OH
OPh
–CO2
–CyCO2
Mes
OCOCy
MesI(OAc)2
–
Carboxylic
acid
Nitrogen-atom
installation
Azide source
6
7
8
9
Carboxylic acid
No puriꢀcation
Alkyl radical
b
Ir
Y
X
MeO2C
CO2H
N
Y
SET
MeO2C
N
H
N
N
X
Cu
IrII
IrIII
Carboxylic
acid
Nitrogen
nucleophile
N-alkyl product
photocatalyst
reductant
9
Alkyl radical
5
1
XLnCuII Nu
>140 examples with 15 classes of nitrogen nucleophiles
4
Fig. 1 | Decarboxylative nitrogen-nucleophile fragment coupling.
a, An example of the Curtius14 rearrangement of acyl azides to form C–N-
containing aliphatic substrates. b, A general platform for decarboxylative
sp3 C–N coupling can be realized by the combination of copper catalysis
and photoredox catalysis. A broad range of readily available carboxylic
acids and nitrogen nucleophiles are used to generate various N-alkyl
products. Boc, tert-butoxycarbonyl; Ph, phenyl; X and Y, carbon or
nitrogen atom.
SET
Y
Z
III
*
N
Ir
LnCuI Nu
oxidant
XLnCuIII
10
2
3
Y
Y
–H+
12
N
Z
N
Z
N-alkyl product
H
11
and the iridium photocatalyst are combined with copper (indole 11a,
60% compared with 7% yield; azaindole 11b, 76% compared with 47%
yield). We speculate that a non-photonic mechanism is possible when
copper(i)-amido species 3 is sufficiently electron-rich to undergo direct
electron-transfer with the iodomesitylene dicarboxylate 8, thereby
removing the requirement for a redox catalyst to act as an electron
shuttle. However, when copper(i)-amido species 3 is not sufficiently
reducing, or is formed slowly, the presence of a photoexcited electron-
shuttle catalyst becomes essential to achieve useful efficiencies. Indeed,
this latter case was found to be the most common, with non-photonic
conditions leading to useful yields with only a small subset of sub-
strates (yields for non-photonic conditions are reported in parentheses
in Figs. 3 and 4). As such, the combination of copper and photoredox
catalysts with light was identified as the superior protocol with which
to evaluate a broad range of sp3 C–N cross-coupling reactions.
Nitrogen
nucleophile
b
Cl
Cl
Cl
N
CO2H
N
H
N
H
N
N
H
6
11a
Indole
11b
Azaindole
11c
Carboxylic acid
Indazole
Conditions
No Cu(I)
Yield
<1%
7%
Yield
<1%
47%
Yield
<1%
86%
With Cu(I), no light
Having established the preferred reaction conditions, we next exam-
ined the generality of this new C–N fragment coupling by exploring
the scope of the carboxylic-acid alkylation partner (Fig. 3). Notably, a
diverse range of alkyl carboxylic acids can be used in this new protocol
to deliver the N-alkyl heteroaryl derivatives in good to excellent
efficiency. It is important to highlight that in all cases the reactions
were complete at room temperature within 1h. Another feature of this
protocol is that only one regioisomer of the product is produced for
all cases shown in Fig. 3, which offers a notable advantage when com-
pared to traditional N-alkylation reactions. Indeed, a broad series of
differentially substituted primary alkyl acids can readily participate in
this new C–N coupling (13–21, 50–82% yield). Moreover, these mild
reaction conditions are compatible with a range of common functional
groups, such as terminal olefins (17, 64% yield), terminal alkynes (18,
80% yield), nitro groups (19, 50% yield), esters (21, 80% yield) and
protected amines (16 and 20, 63% and 82% yield, respectively). In
contrast to many established alkylation reactions, steric encumbrance
proximal to the acid group is also well tolerated, as exemplified by
the successful incorporation of a neopentyl system (15, 54% yield).
Moreover, direct N-methylation (13, 65% yield) can also be realized by
carrying out the C–N coupling protocol using commercial MesI(OAc)2
7. Finally, we successfully applied this coupling technology to three
complex natural products that contain alcohols, ketones and internal
alkenes. All were found to participate in decarboxylative N-alkylation
with high efficiency (22–24, 54%–76% yield).
With Cu(I), with light
11%
50%
86%
With Cu(I), with light,
with photocatalyst
60%
76%
90%
Fig. 2 | Catalytic cycles and control experiments. a, A proposed
mechanism is outlined. Photocatalyst 1 is excited by visible light to
produce a long-lived triplet excited state (2), which can readily oxidize
copper(i) catalyst 3 to yield copper(ii) species 4. The reduced iridium(ii)
complex 5 can then be oxidized by iodomesitylene dicarboxylate 8, which
is derived from the reaction of carboxylic acid 6 and iodomesitylene
diacetate 7, to release alkyl radical 9 and photocatalyst 1. Concurrently in
the copper catalytic cycle, copper(ii)-amido complex 4 can capture alkyl
radical 9 to form the highly unstable copper(iii) complex 10. Reductive
elimination from complex 10 provides the desired sp3 C–N coupled
product and regenerates the copper(i) catalyst 3 after coordination with
the nitrogen nucleophile 11. b, Control experiments were performed with
three different nitrogen nucleophiles. In all cases, the presence of both
the copper(i) catalyst and the photoredox catalyst under light irradiation
conditions is crucial to achieve the best efficiency for the C–N coupling
reactions. Cy, cyclohexyl; L, ligand; Mes, mesityl; Nu, nucleophile; SET,
single-electron transfer; X, anionic ligand, such as a carboxylate; Y and Z,
carbon or nitrogen atoms.
to excellent efficiency (26–31, 40%–85% yield). Moreover, this new
transformation is not limited to cyclic systems, as exemplified by the
rapid incorporation of acyclic secondary alkyl groups (25, 61% yield), a
transformation that is not readily achieved using established alkylation
protocols. An additional six examples using other secondary alkyl acids
for this sp3 C–N coupling are detailed in Supplementary Information
and Extended Data Fig. 1.
We next sought to examine the scope of secondary alkyl carboxylic
acids as alkylating agents. Importantly, a large array of ring-bearing
carboxylates can be used to access N-cycloalkylation adducts in good
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Letter reSeArCH
Cl
−
Me
PF6
Cl
O
N
a) MesI(OAc)2 without puriꢀcation
t-Bu
t-Bu
Ph
N
+
F
F
OH
N
N
N
N
N
b) 1 mol%1, 20 mol% CuTC,
30 mol% BPhen, BTMG
blue LED, dioxane, r.t., 1 h
Ir
N
Cu
TC
N
H
N
Ph
Carboxylic acid
(2 equiv.)
Nitrogen
nucleophile
C–N coupled product
Me
1
Primary alkyl acids
O
O
p-NO2Ph
n-Pentyl
t-Bu
14, 84% yield
19, 50% yield
20, 82% yield
21, 80% yield
(70% yield)
HO
Me
HO
Cl
R
NPhth
15, 54% yield
16, 63% yield
17, 64% yield
18, 80% yield
NHCbz
Cl
CO2Et
N
N
22, 76% yield
N
5
Oleic acid
Me
N
R
n-octyl
13, 65% yield
(42% yield)
H
H
H
H
O
O
O
H
O
OH
OH
Dehydrocholic
Lithocholic
acid
acid
75% yield
54% yield
H
H
H
H
H
H
H
H
O
Me
H
O
Me
H
O
Me
H
O
Me
O
O
Indazole
Indazole
23
24
Me
Me
Me
Me
HO
HO
Me
Me
Me
Me
Secondary alkyl acids
Tertiary alkyl acids
Cl
Cl
Cl
Cl
N
N
N
N
N
N
N
N
N
Et
N
N
n-Pentyl
N
N
N
Cl
Cl
Cl
Et
25, 61% yield
(48% yield)
26, 40% yield
(34% yield)
27, 85% yield
(80% yield)
28, 71% yield
(56% yield)
32, 74% yield
(62% yield)
33, 53% yield
(38% yield)
34, 72% yield
(26% yield)
Cl
Cl
Cl
N
N
N
N
N
N
N
CO2Me
N
CO2Me
N
N
NBoc
Cl
Cl
29, 84% yield
(86% yield)
30, 67% yield
31, 60% yield
(44% yield)
35, 60% yield
(32% yield)
36, 80% yield
(20% yield)
Fig. 3 | Decarboxylative C–N couplings of 3-chloroindazole with a range
of alkyl carboxylic acids. A wide variety of alkyl carboxylic acids can
be cross-coupled with 3-chloroindazole. The carboxylic acid is added as
part of step a, and the nitrogen nucleophile as part of step b. The protocol
provides the product as a single regioisomer in all cases. The yields shown
first are isolated yields of reactions conducted according to our standard
protocol; yields shown in parentheses are for reactions that were conducted
in the absence of light and a photocatalyst and were determined by 1H
nuclear magnetic resonance (1H NMR) spectroscopy with an internal
standard. See Supplementary Information for full experimental details, and
Extended Data Fig. 1 for additional examples. All reactions were replicated
at least twice for consistency. Ac, acetyl; BTMG, 2-tert-butyl-1,1,3,3-
tetramethylguanidine; Cbz, carboxybenzyl; Et, ethyl; Me, methyl; NPhth,
phthalimide; TC, thiophene-2-carboxylate; r.t., room temperature.
A notable feature of this decarboxylative C–N coupling method
Next, we turned our attention to the scope of the nitrogen-nucleophile
is the number of tertiary-carbon-bearing carboxylic acids that can component in this new catalytic alkylation protocol (Fig. 4). Almost
be readily used to prepare heteroaryl N-tertiary alkyl derivatives every class of medicinally relevant nitrogen heterocycle, including, but
with good to excellent efficiency (32–36, 53%–80% yield). This is not limited to, indazoles (37 and 38, 81% and 73% yield, respectively),
especially important given that the N-alkylation using tertiary alkyl azaindoles (39 and 40, 89% and 75% yield, respectively), indoles (41, 58%
halides can often be elusive, if not impossible, using traditional yield), pyrazoles (42 and 43, 98% and 68% yield, respectively), pyrroles
technologies. Given the recent interest in the incorporation of rigid (51, 75% yield), imidazoles (52, 68% yield), triazoles (53, 90% yield),
bicyclic structures into drug-like compounds, such as the bicy- benzimidazoles (54, 67% yield), benzotriazoles (55, 80% yield), purines
clo[1.1.1]pentane core (as shown in product 36)26, we expect this (56, 60% yield) and carbazoles (57, 46% yield), can be successfully used
light-mediated N-alkylation protocol to be immediately applicable to to deliver N-alkyl products in good to excellent efficiency. Moreover, an
a large range of medicinal chemistry programs. Indeed, the capacity additional 42 examples using other nitrogen heterocycles are detailed
to access these bridged bicyclic aryl isosteres in only one operation in Supplementary Information and Extended Data Figs. 2 and 3. For
using commercial carboxylic acids and iodomesitylene diacetate (at nucleophiles that are as acidic as or more acidic than pyrazoles (such as
room temperature in less than 1 h) should enable the rapid adoption indazoles, triazoles and imidazoles), the addition of an exogenous base
of this method.
is not generally necessary. The carboxylate anion, which is generated
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reSeArCH Letter
Indazoles
Azaindoles
Indoles
Pyrazoles
CO2Me
Cl
Ac
CF3
Br
Br
N
MeO
EtO2C
N
N
N
N
N
N
N
N
N
N
N
N
Br
37, 81% yielda
38, 73% yielda
39, 89% yield
40, 75% yield
41, 58% yield
42, 98% yielda
43, 68% yield
Anilines
Sulfonamides
Amides
O
I
F
O
H
N
O
H
N
O
O
O
O
N
S
N
H
S
N
N
Bn
N
O
H
H
Ac
O
F
Br
44, 55% yield
45, 70% yield
46, 59% yield
47, 51% yield
48, 79% yield
49, 61% yield
50, 71% yield
Other nitrogen heterocycles
CO2Me
Br
Ph
N
N
N
N
N
N
N
Cl
N
N
N
N
N
N
N
N
N
51, 75% yield
52, 68% yielda
53, 90% yielda
54, 67% yield
55, 80% yielda
56, 60% yielda
57, 46% yield
(39% yield)
(37% yield)
(22% yield)
(19% yield)
(31% yield)
(17% yield)
(7% yield)
Pharmaceutical compounds
Cl
Me
Me
OCF3
O
O
n-Pentyl
S
N
O
S
N
H
O
N
N
O
O
N
F3C
N
S
N
O
N
F
N
O
N
HN
S
H
N
N
n-Pr
N
O
Et
S
O
NHMe
Me
F
O
O
58, 55% yield
59, 73% yielda
60, 63% yielda
61, 67% yield
62, 44% yield
63, 90% yield
Fig. 4 | Decarboxylative C–N couplings of cyclohexyl carboxylic acid
with various nitrogen nucleophiles. This new C–N bond-forming
protocol shows a markedly broad scope with respect to the nitrogen
nucleophiles. Almost every class of important nitrogen heterocycle can
provide N-alkylated products in good yields and excellent regioselectivity.
Less nucleophilic substrates and complex drug molecules are all
viable coupling partners. The yields shown first are isolated yields for
the decarboxylative C–N coupling step; yields shown in parentheses
are for reactions that were conducted in the absence of light and a
photocatalyst and were determined by 1H NMR with an internal standard.
See Supplementary Information for full experimental details, and
Extended Data Figs. 2–4 for additional examples. aSingle regioisomer. Bn,
benzyl; Pr, propyl.
upon the reduction of iodomesitylene dicarboxylate 8 (Fig. 2a), can our optimized conditions, a large selection of electron-deficient (and
function as a weak base. One notable feature is that this heterocycle also less acidic) nitrogen nucleophiles, including anilines (44 and 45,
C–N forming mechanism exhibits excellent regioselectivity (Fig. 4) 55% and 70%, respectively), aryl sulfonamides (46, 59% yield), alkyl
with substrates that possess several N-alkylation sites (for example, sulfonamides (47, 51% yield), aryl amides (48, 79% yield), phthalimides
pyrazoles, imidazoles, triazoles, indazoles and benzimidazoles). At (49, 61% yield) and cyclic carbamates (50, 71% yield), were found to
this stage, we presume that the considerable steric bulk of the ligated participate readily in this sp3 C–N coupling. Notably, functional groups
copper complex ensures that the sp3 C–N coupling takes place at the including aryl iodides (44, 55% yield), aryl bromides (46, 59% yield)
least hindered site of these heteroaromatic nucleophiles. This outcome and ketones (45, 70% yield) were readily tolerated, a useful feature with
is in sharp contrast to classical alkylation methods that typically lead respect to further synthetic manipulation.
to regioisomeric mixtures. Several of these nitrogen heterocycles were
A long-established problem in the functionalization of primary
also tested using our non-photonic conditions, and the corresponding amines with alkyl halides is the formation of polyalkylation products,
yields are shown in parentheses in Fig. 4. It is clear that although C–N given that the initial secondary amine adduct is more nucleophilic
formation can be achieved with these nucleophiles in the absence of light than the starting amine. Notably, as shown in Fig. 4, only monoalky-
(51–57, 7–39% yield), the dual copper and photoredox protocol enables lated products are obtained when primary amides, sulfonamides and
a more extensive scope and substantially higher efficiencies across the anilines are used in this new copper-catalysed protocol (44–48, also
board, providing a more general protocol for this new C–N heterocyclic see Supplementary Information for additional examples using primary
coupling reaction.
alkyl acids). Moreover, an additional 27 examples using other electron-
As shown in Fig. 4, this decarboxylative C–N coupling method deficient nitrogen nucleophiles are detailed in Supplementary
is not limited to the cross-coupling of nitrogen heterocycles. Under Information and Extended Data Fig. 3. As already highlighted, this
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Letter reSeArCH
NBoc
a
O
O
H
CO2H
BocN
CO2H
N
O
N
N
H
H
N
MesI(OAc)2 (premixed)
MesI(OAc)2 (premixed)
N
H
N
N
N
H
N
No exogenous base
2 equiv. BTTP
64
65
88% yield
66
H
Ir Cu
Ir Cu
51% yield
Dual C–N cross-coupling
80% yield (gram scale)
Cl
b
SN2 or SN1
SN2 or SN1
MeO2C
Br
N
No reaction
11c
Br
No reaction
7 conditions
N
7 conditions
H
11c
67
68
Then 11c
Then 11c
MesI(OAc)2
CO2H
N
N
MeO2C
N
MeO2C
CO2H
MesI(OAc)2
Ir Cu
5 min
N
Ir Cu
30 min
Cl
Cl
69
60% yield,>20:1 r.r.
70
44% yield,>20:1 r.r.
Fig. 5 | Sequential C–N couplings and comparisons with nucleophilic
substitutions. a, Sequential decarboxylative C–N couplings can be
realized using indazole derivative 64 that contains two nucleophilic
sites, demonstrating the construction of molecular complexity. The
N,Nʹ-dialkylated product, which contains two different alkyl groups,
can be easily generated through two C–N coupling reactions using
different alkyl acids under different reaction conditions. All yields in this
section are isolated yields for the decarboxylative C–N coupling step.
b, Comparing the current decarboxylative C–N coupling protocol with
classical nucleophilic substitution methods using two alkyl electrophiles
demonstrates the complementary nature of this new method. All yields
in this section were determined by 1H NMR studies with an internal
standard. See Supplementary Information for full experimental details and
additional examples. BTTP, tert-butylimino-tri(pyrrolidino)phosphorane;
r.r., regiomeric ratio.
coupling protocol does not appear to be negatively influenced by steric of relative N–H acidities will have substantial benefit with respect to the
constraints, as ortho-substituted and ortho-,ortho-disubstituted ani- step economy of building complex molecules, by removing the need to
lines, sulfonamides and amides can be used readily (44, 46, and 48, install and remove nitrogen protecting groups.
55%–79% yield).
Finally, to further showcase the utility of this new sp3 C–N coupling
To illustrate the utility of this new transformation with respect to method, we performed a series of experiments to compare the
drug discovery, we examined this decarboxylative sp3 C–N coupling decarboxylative protocol with traditional nucleophilic substitution
using six known pharmaceuticals (Celebrex, Axitinib, Zelboraf, Actos, reactions (Fig. 5b). Under various classical SN2 and SN1 alkylation
Rilutek and Skelaxin). Using three separate carboxylic acids, we were conditions, tertiary alkyl bromide 67 and bromocyclopropane (68)
able to achieve decarboxylative alkylation in all cases in good to excel- failed to react with 3-chloroindazole to generate the desired N-alkyl
lent yields (58–63, 44%–90% yield). An additional ten examples of products, which is consistent with a lack of literature precedent for
pharmaceutical functionalization using this technology are described using these alkyl bromides with indazole nucleophiles. By contrast,
in Supplementary Information and Extended Data Fig. 4.
through decarboxylative C–N couplings using commercially available
For substrates with several nucleophilic sites, achieving regiose- carboxylic acids 69 and 70 and our mild catalytic protocol, the desired
lective monofunctionalization has been a long-standing challenge27. N-alkyl products can be obtained in good yields and excellent regio-
Therefore, we were pleased to find that this new alkylation technology selectivities within 30min at room temperature using an integrated
can be applied sequentially to the same drug molecule to achieve selec- photoreactor30. As such, we anticipate that this new decarboxylative
tive alkylation at two discrete nitrogen positions through the judicious coupling strategy will provide a useful, complementary new approach
choice of reaction conditions. As demonstrated in Fig. 5a, heterocycle to sp3 C–N alkylation.
64 contains both an indazole nitrogen and a primary amide; however,
when the coupling protocol is performed without an exogenous base,
regioselective N-alkylation of the indazole was observed in 80% yield.
Online content
Any Methods, including any statements of data availability and Nature Research
Moreover, we have carried out this regioselective N-alkylation step on a
7.4-mmol scale to prepare 1.45g of the N-cyclohexyl indazole derivative
65. The origins of regioselectivity in this decarboxylative coupling arise
from the relative acidity of the two N–H moieties in substrate 64 (that
is, indazole and amide). More specifically, when no exogenous base is
used, the carboxylate anion (formed by reduction of the iodomesitylene
dicarboxylate 8) can function as a weak base and thereby selectively
deprotonate the more acidic indazole nitrogen (pKa (indazole) <19.8
reporting summaries, along with any additional references and Source Data files,
are available in the online version of the paper at https://doi.org/10.1038/s41586-
018-0234-8.
Received: 25 January 2018;Accepted: 13April 2018;
Published online xx xx xxxx.
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Acknowledgements This research was supported by the National Institutes
of Health National Institute of General Medical Sciences (R01 GM103558-03)
and gifts from Merck, Bristol-Myers Squibb, Eli Lilly, Genentech and Johnson
& Johnson. X.Z. is grateful for a postdoctoral fellowship from the Shanghai
Institute of Organic Chemistry. We thank C. Liu and Y. Y. Loh for assistance in
preparing this manuscript.
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Reviewer information Nature thanks S. Bagley and the other anonymous
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Author contributions Y.L. and X.Z. performed and analysed the experiments.
Y.L., X.Z. and D.W.C.M. designed the experiments. Y.L., X.Z. and D.W.C.M.
prepared the manuscript.
Competing interests The authors declare no competing interests.
Additional information
Extended data is available for this paper at https://doi.org/10.1038/s41586-
018-0234-8.
Supplementary information is available for this paper at https://doi.
org/10.1038/s41586-018-0234-8.
Reprints and permissions information is available at http://www.nature.com/
reprints.
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Correspondence and requests for materials should be addressed to D.W.C.M.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
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Letter reSeArCH
MEthodS
34-W blue LED lamps (3cm away, with cooling fan to keep the reaction at room
Here we describe a typical procedure for the decarboxylative sp3 C–N cou- temperature) for 1h. The reaction mixture was removed from the light, cooled to
pling reaction; a summary of general conditions is included in Supplementary ambient temperature, diluted with water (15ml) and ethyl acetate (25ml), and the
Information (Supplementary Fig. 36) and further experimental details are also aqueous layer was extracted with ethyl acetate (3×25ml). The combined organic
provided in Supplementary Information.
layers were washed with brine, dried over Na2SO4, filtered and concentrated. The
Procedure for decarboxylative sp3 C–N couplings. To a 20 ml or 40 ml vial residue was purified by flash chromatography on silica gel to afford the desired
equipped with a stir bar was added photocatalyst, nitrogen nucleophile, iodome- decarboxylative C–N coupling product. For aniline substrates, a solution of these
sitylene dicarboxylate, copper salt, and ligand. Dioxane was added followed by nitrogen nucleophiles in dioxane was used; additionally, if the iodomesitylene
addition of the base. The solution was sonicated for 1–3min until it became homo- dicarboxylate is a liquid, its solution in dioxane was used.
geneous. Next, the solution was degassed by sparging with nitrogen for 5–10min Data availability. The findings of this study are available within the paper and
before sealing with Parafilm. The reaction was stirred and irradiated using two its Supplementary Information.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

reSeArCH Letter
Cl
−
Me
PF6
Cl
O
a) MesI(OAc)2 w/o purification
N
t-Bu
t-Bu
Ph
Ph
N
+
F
F
OH
N
N
N
N
N
N
b) 1 mol% 1, 20 mol% CuTC,
30 mol% BPhen, BTMG
Ir
N
Cu
TC
H
N
blue LED, dioxane, r.t., 1 h
carboxylic acid
(2 equiv)
C–N coupled product
N-nucleophile
Me
1
Secondary alkyl acids
O
O
O
Me
O
O
O
HO
Me
HO
HO
HO
HO
HO
N
O
Me
NBoc
R
Cl
Cl
Cl
Cl
Cl
Cl
N
N
Me
N
N
N
N
N
N
N
N
Me
N
N
Me
O
N
R
NBoc
S1, 60% yield
S3, 84% yield
S4, 56% yield
S6, 90% yield
S2, 62% yield
14:1 d.r.#
S5, 75% yield
R = 2-pyrimidyl
Extended Data Fig. 1 | Decarboxylative sp3 C–N couplings with a series
of secondary alkyl acids. An array of secondary alkyl carboxylic acids
can be cross-coupled with 3-chloroindazole. The protocol provides the
product as a single regioisomer in all cases. All yields are isolated. All
reactions were replicated at least twice for consistency. See Supplementary
Information for full experimental details. d.r., diastereomeric ratio. #d.r.
was determined by 1H NMR.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Letter reSeArCH
Indazoles
CN
N
Ac
Br
CO2Me
N
N
N
N
N
N
N
N
N
S7, 73% yield
S8, 94% yield
S9, 95% yield
S10, 78% yield
S11, 96% yield
*
*
*
*
*
Br
Cl
N
N
N
N
N
N
N
N
Br
Br
S12, 76% yield
S13, 88% yield
S14, 85% yield
S15, 41% yield
*
*
*
*
Azaindoles
Cl
N
Br
Br
Ac
Br
Br
N
N
N
Cl
N
N
N
N
N
N
N
N
N
N
S16, 80% yield
S17, 82% yield
S18, 79% yield
S19, 74% yield
S20, 83% yield
S21, 82% yield
S22, 64% yield
Indoles
Cl
Br
Cl
Br
N
N
N
N
Cl
Br
N
N
S23, 55% yield
S24, 59% yield
S25, 53% yield
S26, 58% yield
S27, 60% yield
S28, 50% yield
Pyrazoles
O
Br
CO2Et
CF3
N
Ph
N
Ar
Ar1
NH2
N
N
N
N
N
N
N
N
N
N
N
N
S35, Ar1 = 4-Cl-C6H4
S34, Ar = 4-Br-C6H4
*
S29, 92% yield S30, 72% yield
S31, 98% yield
S32, 62% yield
S33, 72% yield
*
*
*
*
85% yield
82% yield
*
*
Extended Data Fig. 2 | Decarboxylative sp3 C–N couplings with
a series of nitrogen heterocycles. Various nitrogen heterocycles,
including indazoles, azaindoles, indoles and pyrazoles, can cross-couple
with carboxylic acids with good efficiency. All yields are isolated. All
reactions were replicated at least twice for consistency. See Supplementary
Information for full experimental details. *Single regioisomer.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

reSeArCH Letter
Other N-Heterocycles
Br
Ph
Ph
Br
Ph
Br
Br
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
n-pentyl
S36, 81% yield
S37, 80% yield
S38, 82% yield
S39, 30% yield
S40, 88% yield
S41, 40% yield
S42, 20% yield
*
*
*
*
*
*
*
O
Cl
Ph
N
N
Ac
Br
Cl
N
N
N
N
N
N
N
N
S43, 80% yield
S44, 60% yield
S45, 85% yield
S46, 48% yield
S47, 51% yield
S48, 45% yield
Anilines
COOMe
H
F
H
N
R
H
N
F3C
N
H
H
H
N
N
N
N
N
N
N
F
CF3
Cl
S49, R = Br, 66% yield
S50, R = Ac, 66% yield
S51, R = CN, 61% yield
S52, 53% yield
S53, 51% yield
S54, 34% yield#
S55, 58% yield
S56, 52% yield
Sulfonamides
O
O
F
S57, R = Me, 67% yield
S58, R = F, 67% yield
S59, R = Cl, 53% yield
S60, R = Br, 63% yield
O
O
O
O
O
O
F
S
N
S
S
F
Br
S
H
N
N
N
H
H
H
R
F
S61, 50% yield
S62, 55% yield
S63, 52% yield
Amides
O
O
O
O
O
O
MeO
N
H
F3C
N
N
H
N
H
N
N
H
H
H
CF3
Br
Br
OMe
S64, 74% yield
S65, 71% yield
S66, 74% yield
S67, 74% yield
S68, 77% yield
S69, 74% yield
O
O
O
O
Br
O
O
N
N
N
H
N
N
H
F3C
N
H
N
N
Cl
Cl
S70, 81% yield
S71, 70% yield
S72, 84% yield
S73, 78% yield
S74, 17% yield&
S75, 28% yield
*
Extended Data Fig. 3 | Decarboxylative sp3 C–N couplings with a series
of nitrogen nucleophiles. Various nitrogen nucleophiles, including
nitrogen heterocycles, anilines, sulfonamides and amides, can cross-
couple with carboxylic acids with good efficiency. All yields are isolated
unless otherwise noted. All reactions were replicated at least twice for
consistency. See Supplementary Information for full experimental details.
#Yield was determined by 19F NMR with an internal standard. &Yield was
determined by gas-chromatography analysis with an internal standard.
*Single regioisomer.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Letter reSeArCH
Pharmaceutical compounds
n-Pr
S
O
O
HN
O
O
O
F
N
O
S
S
N
N
O
H
Cl
H
N
N
N
N
F3C
F3C
N
F
N
S
N
N
NHMe
O
Me
Me
*
*
S76, 61% yield
S77, 75% yield
S78, 57% yield
S79, 40% yield
O
N
O
Me
O
O
S
N
Me
O
Me
Me
O
N
N
N
O
O
N
N
F3CO
N
N
N
N
S
N
H
N
NH
N
N
N
N
O
N
N
OAc
N
Me
Me
Me
AcO
Et
S80, 82% yield
S81, 80% yield
S82, 83% yield
S83, 40% yield
S84, 68% yield
S85, 40% yield
*
*
*
Extended Data Fig. 4 | Decarboxylative sp3 C–N couplings with a series
of pharmaceutical compounds. Several drug molecules can cross-couple
with carboxylic acids with good efficiency. All yields are isolated. All
reactions were replicated at least twice for consistency. See Supplementary
Information for full experimental details. *Single regioisomer.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.