Native Directed Site-Selective δ-C(sp3)-H and δ-C(sp2)-H Arylation of Primary Amines

Article abstract of DOI:10.1021/acscatal.8b04927

A Pd(II)-catalyzed, selective δ-C(sp³)-H and δ-C(sp²)-H arylation method for free primary aliphatic amines using NH₂ as a native directing group has been developed. A variety of free primary amines with adjacent quaternary

Full text of DOI:10.1021/acscatal.8b04927

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Article
3
Native Directed Site-Selective #-C(sp)-
2
H and #-C(sp)-H Arylation of Primary Amines
Hua Lin, Xiaohong Pan, Adam L. Barsamian, Theodore M. Kamenecka, and Thomas D. Bannister
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04927 • Publication Date (Web): 15 Apr 2019
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ACS Catalysis
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Native Directed Site-Selective δ-C(sp3)-H and δ-C(sp2)-H Arylation
of Primary Amines
Hua Lin,1,‡ Xiaohong Pan,1,2,3,‡ Adam L. Barsamian,1,3 Theodore M. Kamenecka,1 Thomas D.
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Bannister1,3*
1Department of Molecular Medicine, Scripps Research, Jupiter, Florida, 33458, USA
2State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian 350002, China.
3Department of Chemistry, Scripps Research, Jupiter, Florida, 33458, USA
ABSTRACT: A Pd(II)-catalyzed, selective δ-C(sp3)–H and δ-C(sp2)–H arylation method for free primary aliphatic amines using
NH2 as a native directing group has been developed. A variety of free primary amines with adjacent quaternary centers and/or with
alpha esters react with a diverse range of aryl and heteroaryl iodides to provide -aryl and -heteroaryl amines.
KEYWORDS free primary amine • native directing • δ-C–H arylation • Pd-catalysis • six-membered palladacycle
Most marketed small molecule drugs contain one or more amine
groups, either aromatic heterocyclic or aliphatic.1 “Escaping
from flatland” with high sp3 vs. sp2 character (aliphatic amines)
enhances clinical success.2 The percentage of sp3-hybridized
carbon atoms in a potential lead guides candidate selection,
presumably by improving drug-likeness while imparting a
defined 3D shape to better fit into the binding pocket of a
biological target.2
picolinamide-protected amino acids and peptides;9c,d and the δ-
C(sp3)−H arylation of picolinamide by Wang and co-workers,
using 3-pinanamine as a substrate.9e
Herein we report efforts towards a Pd-catalyzed site-selective
δ-C(sp3)−H and δ-C(sp2)−H arylation of primary aliphatic
amines, with the NH2 group as the directing group (Scheme 1f),
to give -aryl or heteroaryl amines.
R2
R2
R3
[Pd]
R3
Substantial effort has been directed toward developing efficient
methods for the synthesis and selective derivatization of
aliphatic amines.3 Prominent among these are reactions using
transition-metal-catalyzed site-selective C–H functionalization4
mediated through directing groups (DGs).5 A limitation of DG-
based strategies has been the stepwise attachment and later
removal of the DG from the amine, often over multiple steps or
requiring harsh conditions. A preferred alternative developed
by many groups uses transient directing groups6 (TDGs) that
are both installed and removed in situ. Even more preferred
would be a method using the unmodified amine itself is a native
directing group. Secondary amines have previously been used
in this way (Scheme 1a and 1b),7 however, only one example of
an unmodified primary amine as a native directing group for
C(sp3)–H activation had appeared, Shi’s amine-directed ɤ-
C(sp3)–H acetoxylation (Scheme 1c).8
R1
R1
a)
b)
c)

N

N
H
H
FG
H
R2
[Pd]
R3
R2
R1
R3
R1
N
FG
N
H

H

H
H
R1
R2
H
R2
AcO
R1
R2
H
R1
N


Pd
NH2
NH2
via five-membered palladacycle
R1 R2
R3
[Cu]
R1 R2
R3
d)
e)
f)
Ar
R
R
N
H
H
N


F
R1 R2
R1 R2
[Pd]
R1 R2
R3
R3
R3
FG
DG
H
DG
H
N
H
N
NH2


H

H
H
R1 R2
R2
R3
R3
N
[Pd]
Pd
Het(Ar)
NH2

this work

R1
Pd-catalyzed δ-selective C–H functionalization of aliphatic
amines has been less well-developed in comparison to -
selective C–H activation, presumably due to the requirement for
via six-membered palladacycle
free primary amines
NH2 as native directing group
substrate scope interrogated
reaction scales up to 2 mmol
a
kinetically less favorable six-membered palladacycle
Scheme 1. Aliphatic Amine C(sp3)-H Functionalization
intermediate.9 However, copper-catalyzed arylation of δ-
C(sp3)−H of amides via radical relay has been reported recently
(Scheme 1d).10 Also, DG-assisted-δ-C(sp3)−H functionalization
of amines has also been realized by many groups (Scheme 1e).
Examples are the Chen group’s study of the intramolecular
amination of alkyl picolinamides;9a Daugulis and co-worker’s
δ-C(sp3)−H oxidation of alkyl picolinamides;9b The Shi
laboratory’s δ-C(sp3)−H alkenylation and alkylation of
Free amines are not typically good substrates for palladium
catalyzed C−H bond activation reactions because they form
stable bis-amine palladium complexes. A sterically hindered
secondary amine can facilitate dissociation of this complex to
enable C−H bond activation.7b For primary amines, weak acid
additives such as acetic acid can aid dissociation of the
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ACS Catalysis
complex,8 while not halting coordination to palladium through
complete conversion to ammonium salts. Accordingly, we
investigated δ-C(sp3)−H arylation in the presence of AcOH with
2,4-dimethylhexan-2-amine (1a) and iodobenzene (2a). To our
delight, using Pd(OAc)2 and Ag2CO3 in AcOH at 130 °C for 12
hours provided 60% yield of the desired product (yields
reported herein are NMR yields, based upon NMR integration
vs. an internal standard, unless otherwise noted).
Page 2 of 6
56-65%, 3a-3f, 3h, 3i). Using p-nitrophenyl iodide (3g) gave a
diminished yield (45%). We found that meta-substituted phenyl
iodides were often slightly less suitable (yields 42−60%,
3j−3p), while ortho-substituted phenyl iodides (2-F, 2-Me and
2-OMe) gave the poorest results (<20% NMR yield, and the
products were not separated). Only methyl 2-iodobenzoate
provided the product in acceptable yield (43%, 3q). A
heteroaryl iodide, 5-iodo-1-tosyl-1H-indole, notably gave 3r in
reasonable yield (62%) after acetylation (see supporting
information for all experimental details). 12
1
2
3
4
5
6
7
8
Solvents that were used in other CH arylation processes thought
to proceed by ion-pairing mechanisms11 were less well-suited
for this conversion, including THF,11a toluene,11b and 1,4-
dioxane (see supporting information P12; TFA and formic acid
were also ineffective as solvents).
9
Table 2. Screening of Aryl Iodidesa,b
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Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 eq.)
A8
(30 mol%)
H
Het(Ar)
+
(Het)Ar-I
NH2
NH2
Given the importance of acetic acid as the reaction solvent, we
explored the possibility of using a small amount (30 mol%) of
another acidic additive. (Table 1). The additive had only a
modest effect. The highest yield (73%) was obtained using 2-
nitrobenzoic acid (A8). Acids with a metal-coordinating
heterocycle impeded conversion (A16, A17).
AcOH (0.2 M)
130 oC, 12 h


1a
3
2
aryl / heteroaryl =
O
EtO2
C
Cl
Br
F3C
3a
3b
3c
3d
3e
3f
, 68%
, 56%
, 57%
, 65%
, 65%
, 57%
Table 1. Screening of Additivesa,b
O2
N
Me
MeO
F3
C
Br
3j
F
Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 eq.)
additive (30 mol%)
I
3g
3h
3i
3k
3l
, 42%
, 45%
, 63%
, 64%
, 58%
, 50%
+
H
Ph
NH2
NH2
AcOH (0.2 M)
130 °C, 12 h
Ts
CO2Me
1a
0.1 mmol
3a
2a
N
3 eq.
MeO2
C
Me
3o
MeO
O
3m
c
3n
3p
3q
, 43%
, 54%
, 48%
, 42%
, 60%
3r
, 62%
O
P
O
additive:
O
SO3H
OH
aThe reactions used 1a (0.2 mmol), 2 (0.6 mmol), Pd(OAc)2 (10
mol%), Ag2CO3 (0.3 mmol, 1.5 eq.), A8 (30 mol%), AcOH (1
mL), 130 ºC, 12 hr; Isolated yield; Isolated yield of product
following N-acetylation.
none
(BnO)2PO2
H
TFA
Cl
CO2
H
A1
A2
A3
A4
A5
b
c
60%
55%
55%
53%
68%
67%
F
CO2
H
F
F
CO2
F
H
CO2
NO2
H
CO2
H
CO2
NO2
H
MsOH
The amine substrate scope of the δ-C(sp3)−H arylation with
iodobenzene was then explored (Table 3).12 δ-C(sp3)−H
arylation of amines with α,α-dimethyl group substitution
proceeded well with yields between 63% to 77% (3s-3y). With
two equivalent methyl groups containing C(sp3)−H bonds, 2,4-
dimethylpentan-2-amine was more reactive, and gave both
mono and diarylation products in 77% combined yield (3u,
mono:di=2.2:1). A triarylation product formed when three
equivalent methyl groups containing C(sp3)−H bonds were
present, and 2,4,4-trimethylpentan-2-amine provided 3v in 70%
combined yield (di:tri=1.5:1) at 130 ºC and 50% combined
yield (mono:di=1:1) at 110 ºC. Furthermore, amines with larger
α-substituents gave products only in low yield (3z and 3aa). ɤ-
C(sp3)−H arylation also proceeded, with the appropriate starting
material. 3ab and 3ac were produced in 38% and 48% yields
respectively, under the same reaction conditions. It is
noteworthy that in certain instances an alpha ester was tolerated
(see 3ac, 3ad, 3af, and 3ag) and in the latter three examples a
quaternary primary amine was not required for conversion. 6k, 13
The ɤ-C(sp2)−H arylation process may be generally more
favorable due to the presence of a C(sp2)−H bond, which is
more reactive toward insertion.
F3
C
O2
N
CO2
A11
H
F
A6
A7
A8
A9
A10
67%
69%
73%
54%
53%
54%
CO2
H
CF3
CO2
H
SO3H
CO2
Ph
H
CO2
CF3
H
CO2
H
CO2
CF3
H
N
N
F3C
NO2
A12
A13
A14
A15
A16
A17
48%
62%
70%
59%
trace
trace
aThe reactions were run with 1a (0.1 mmol), 2a (0.3 mmol),
Pd(OAc)2 (10 mol%), Ag2CO3 (0.15 mmol, 1.5 eq.), additive
(30 mol%), AcOH (0.5 mL), 130 ºC, 12 hr; bNMR yield, 1,3,5-
trimethoxybenzene was used as internal standard.
Other silver salts were somewhat suitable, for example Ag2O
gave only slightly reduced yields (see supporting information
P12). Variations of reaction temperature gave no additional
improvement. To study the potential importance of CO2 in this
process,6j we studied the Ag2O-mediated reaction under an
argon atmosphere using degassed solvent and also under a CO2
atmosphere. Neither modification had a significant effect (see
supporting information P12). These control experiments
strongly suggest that neither dissolved nor in situ generated CO2
is involved in this directed C-H activation process.
Table 3. Screening of Primary Alkyl aminesa,b
We then used these preferred reaction conditions to explore the
scope of the reaction with respect to the aryl iodide reagent
(Table 2). Aryl iodides with most para functional groups, either
electron-withdrawing (CO2Et, Cl, Br, CF3, Ac) or electron-
donating (Me, OMe) gave similar conversion to products (yield
2
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ACS Catalysis
1) Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 eq.)
0-5% yield:
Ph
NH2
R
NH2
1
2
3
4
5
6
7
8
A8
(30 mol%)
AcOH (0.2 M)
130 °C, 12 h
R2 R3
NH2
R2 R3
NH2
R2 R3
NH2
H2N
Ph
ArI
or
+
Ac
4a, 4b:
4c
4d
4e
R=H,CO2Et
Ph
Ph
R'
N
2) acetylation
H
Ar
Ar
3u-3aa
CO2Et
3u 3aa
-
CO2Et
for
NH2
3s-3t
3ab-3ag
Ph
1
2
Ph
Ph
NH2
NH2
4f
4g, 4h:
4i
R'=H,Me
(Ph)/H
Ac
8% yield:
H2N
25% yield:
N
29% yield:
 = 1:1
Ph
H
Ph
Ph
3u
NH2
NH2
CO2Et
NH2
R'
Ph
NH2
Ph
c
, 77%
R
3t
, 63%
3s
, 65%
9
mono:di=2.2:1
BnO
4l:
R=H, R'=Ph
4m:
10
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R=Ph, R'=H
4j
4k
EtO2C
(Ph)/H
Ph
Ph
Ph
(Ph)/H
Scheme 2. Less successful attempts
Ac
N
Ac
H
N
H
Ph
Ac
N
H
To test the efficiency of our δ-C(sp3)−H arylation methodology
on a more preparative scale, 2 mmol of substrate gave 66%
isolated yield of product without chromatography, not
significantly altered from the 68% NMR yield obtained on a 0.2
mmol scale (Scheme 2).
c
c
, 70%c (di:tri=1.5:1)
3x
, 71%
3w
, 68%
3v
50%c (mono:di=1:1)
Ph
Ac
(Ph)/H
Ph
Ph
Ph
Ph
Ac
Ac
Ph
N
N
N
H
H
H
Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 eq.)
c, d
c
c
3aa
, 45%
3z
3y
, 42%
, 64%
A8
(30 mol%)
mono:di=2:1
di:mono>10:1
Ph
H
PhI
2a,
+
NH2
66% isolated
NH2
2 mmol
AcOH (0.2 M)
130 °C, 12 h
-(sp2) arylation
-(sp3) arylation


3a,
1a,
3 eq.
no chromatography
NH2
CO2Et
Ph

H2N CO2Et
Ph/H
Scheme 3. Scale-up Reaction
Ph
NH2
Ph

Scheme 4 shows other reactions investigated to define the
reaction scope. N-acylated substrate 1a-Ac gave no desired
product under standard conditions (4a), confirming that the free
amino group plays a vital role as a native directing group. The
bis-palladium intermediate 1i was obtained using amine 1a and
Pd(OAc)2 in chloroform. Treatment of complex 1i with
iodobenzene under standard conditions gave product 3a in
modest yield, suggesting that acetic acid can aid in the
dissociation of the stable bis-amine palladium complex (4b).
Treatment of 2e with Pd(OAc)2 (10 mol%) in CD3CO2D at 130
°C for 6 hours gave 17% deuterium incorporation at the δ-
methyl groups (4c).9b
e
3ad
, 48%
3ab
3ac
, 48%
mono:di=7:1
, 38%
mono:di=8:1
-(sp2) arylation

Ph/(H)
Me
CO2Et
NH2
CO2Et
Me
CO2Et
NH2
NH2
Ph
Ph
Me
e
e
e
3ae
, 73%
3af
, 62%
3ag
, 60%
mono:di=1.3:1
aThe reactions were run with 1 (0.2 mmol), 2 (0.6 mmol),
Pd(OAc)2 (10 mol%), Ag2CO3 (0.3 mmol, 1.5 eq.), A8 (30
mol%), AcOH (1 mL), 130 ºC, 12 hr; bIsolated yield; c Isolated
yield of product following acetylation; d.r. = 1:1 for mono-
product; eAgSbF6 (0.6 mmol, 3 eq.) was used instead of
Ag2CO3, HFIP:AcOH=9:1 (1 mL) was used instead of AcOH.
Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 eq.)
d
A8
(30 mol%)
N.R.
PhI
H
Ac
+
a)
N
AcOH (0.2 M)
130 °C, 12 h
H
1a-Ac
2a
OAc
Scheme 2 shows products obtained in low yields under these
conditions. From 4a-4e we see that the steric environment of
the amines should be crowded for catalyst turnover and suggests
that perhaps placing more bulky ligands on the metal may
compensate in the case of less sterically-demanding amine
substrates. Subtle electronic effects are also apparent (4f-4h,
4k) and  selectivity may be problematic (4l-4m). The
supporting information (P13) describes these and other
challenging reactions.
Pd(OAc)2
(1 eq.)
H2
N
H2
N
Pd
H
OAc
b)
NH2
CHCl3
60 oC, 12 h
1a
1i
1i
, 44%
PhI (6 eq.)
Ag2CO3 (3 eq.)
A8
(60 mol%)
Ph
NH2
AcOH (0.1 M)
130 °C, 12 h
3a,
32%
Pd(OAc)2 (10 mol%)
CsOAc (2 eq.)
Me-dn
Me-dn
Me
Me
Me
Me
Me
Me
c)
CD3CO2D
130 oC, 6 h
NH2 Me-dn
NH2 Me
17% D incorporation
2e
Scheme 4. Additional control experiments
As the review and revision of this manuscript was underway,
related work on the δ-C(sp3)–H arylation of free primary amines
mediated by transient directing groups (which are absent in the
3
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Page 4 of 6
C(sp3)-H bonds. Chem. Soc. Rev. 2011, 40 (10), 4902-4911; (c) Li, H.;
methodology discussed here) was reported by Yu and
colleagues.14
Lia, B. J.; Shi, Z. J., Challenge and progress: palladium-catalyzed sp3
C-H activation. Catal. Sci. Technol. 2011, 1 (2), 191-206; (d) White,
M. C., Adding Aliphatic C-H Bond Oxidations to Synthesis. Science
2012, 335 (6070), 807-809; (e) Yamaguchi, J.; Yamaguchi, A. D.;
Itami, K., C-H Bond Functionalization: Emerging Synthetic Tools for
Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012,
51 (36), 8960-9009; (f) Colby, D. A.; Bergman, R. G.; Ellman, J. A.,
Rhodium-Catalyzed C-C Bond Formation via Heteroatom-Directed C-
H Bond Activation. Chem. Rev. 2010, 110 (2), 624-655; (g) Daugulis,
O.; Roane, J.; Tran, L. D., Bidentate, Monoanionic Auxiliary-Directed
Functionalization of Carbon-Hydrogen Bonds. Acc. Chem. Res. 2015,
48 (4), 1053-1064; (h) Lyons, T. W.; Sanford, M. S., Palladium-
Catalyzed Ligand-Directed C-H Functionalization Reactions. Chem.
Rev. 2010, 110 (2), 1147-1169; (i) Rouquet, G.; Chatani, N., Catalytic
Functionalization of C(sp2)-H and C(sp3)-H Bonds by Using Bidentate
Directing Groups. Angew. Chem., Int. Ed. 2013, 52 (45), 11726-11743;
(j) Chen, Z. K.; Wang, B. J.; Zhang, J. T.; Yu, W. L.; Liu, Z. X.; Zhang,
Y. H., Transition metal-catalyzed C-H bond functionalizations by the
use of diverse directing groups. Org. Chem. Front. 2015, 2 (9), 1107-
1295; (k) He, G.; Wang, B.; Nack, W. A.; Chen, G., Syntheses and
Transformations of alpha-Amino Acids via Palladium-Catalyzed
Auxiliary-Directed sp3 C-H Functionalization. Acc. Chem. Res. 2016,
49 (4), 635-645; (l) Yoo, W. J.; Li, C. J., Cross-Dehydrogenative
Coupling Reactions of sp3-Hybridized C-H Bonds. Top. Curr .Chem.
2010, 292, 281-302; (m) Yeung, C. S.; Dong, V. M., Catalytic
Dehydrogenative Cross-Coupling: Forming Carbon-Carbon Bonds by
Oxidizing Two Carbon-Hydrogen Bonds. Chem. Rev. 2011, 111 (3),
1215-1292; (n) Girard, S. A.; Knauber, T.; Li, C. J., The Cross-
Dehydrogenative Coupling of C-sp3-H Bonds: A Versatile Strategy for
C-C Bond Formations. Angew. Chem., Int. Ed. 2014, 53 (1), 74-100.
5. (a) He, J.; Wasa, M.; Chan, K. S. L.; Shao, O.; Yu, J. Q.,
Palladium-Catalyzed Transformations of Alkyl C-H Bonds. Chem.
Rev. 2017, 117 (13), 8754-8786; (b) Spangler, J. E.; Kobayashi, Y.;
Verma, P.; Wang, D. H.; Yu, J. Q., alpha-Arylation of Saturated
Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp3)-H
Coupling. J. Am. Chem. Soc. 2015, 137 (37), 11876-11879; (c) Pastine,
S. J.; Gribkov, D. V.; Sames, D., sp3 C-H bond arylation directed by
amidine protecting group: alpha-arylation of pyrrolidines and
piperidines. J. Am. Chem. Soc. 2006, 128 (44), 14220-14221; (d)
Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi,
F.; Murai, S., Carbonylation at sp3 C-H bonds adjacent to a nitrogen
atom in alkylamines catalyzed by rhodium complexes. J. Am. Chem.
Soc. 2000, 122 (51), 12882-12883; (e) Topczewski, J. J.; Cabrera, P. J.;
Saper, N. I.; Sanford, M. S., Palladium-catalysed transannular C-H
functionalization of alicyclic amines. Nature 2016, 531, 220-224; (f)
Zaitsev, V. G.; Shabashov, D.; Daugulis, O., Highly regloselective
arylation of sp3 C-H bonds catalyzed by palladium acetate. J. Am.
Chem. Soc. 2005, 127 (38), 13154-13155; (g) Rodriguez, N.; Romero-
Revilla, J. A.; Fernandez-Ibanez, M. A.; Carretero, J. C., Palladium-
catalyzed N-(2-pyridyl)sulfonyl-directed C(sp3)-H gamma-arylation of
amino acid derivatives. Chem. Sci. 2013, 4 (1), 175-179; (h)
ChanKelvin, S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu,
J.-Q., Ligand-enabled cross-coupling of C(sp3)–H bonds with
arylboron reagents via Pd(II)/Pd(0) catalysis. Nat. Chem. 2014, 6 (2),
146-150; (i) Huang, Z. X.; Wang, C. P.; Dong, G. B., A Hydrazone-
Based exo-Directing-Group Strategy for C-H Oxidation of Aliphatic
Amines. Angew. Chem., Int. Ed. 2016, 55 (17), 5299-5303; (j) Aspin,
S.; Goutierre, A. S.; Larini, P.; Jazzar, R.; Baudoin, O., Synthesis of
Aromatic alpha-Aminoesters: Palladium-Catalyzed Long-Range
Arylation of Primary C-sp3-H Bonds. Angew. Chem., Int. Ed. 2012, 51
(43), 10808-10811; (k) Nadres, E. T.; Santos, G. I. F.; Shabashov, D.;
Daugulis, O., Scope and Limitations of Auxiliary-Assisted, Palladium-
Catalyzed Arylation and Alkylation of sp2 and sp3 C–H Bonds, J. Org.
Chem. 2013, 78 (19), 9689–9714
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In summary, we have developed a Pd(II)-catalyzed, selective δ-
C(sp3)−H and δ-C(sp2)−H arylation of free primary aliphatic
amines using the unmodified NH2 group as a directing group.
Acetic acid as the solvent is essential for successful conversion.
Using 2-nitrobenzoic acid as an additive also modestly
improves yields in the process. Reactions are likely amenable
to scale-up without loss of efficiency. While the substrate scope
is somewhat limited with respect to the amine substrate, certain
non-quaternary amines are suitable. The scope is quite broad
with respect to the aryl/heteroaryl iodide component. Synthetic
applications, particularly to improve yields and to broaden
substrate scope are under investigation, as are mechanistic
studies. Improvements to these procedures will be
communicated rapidly upon their discovery.
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ASSOCIATED CONTENT
*Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
General information and procedures, experimental details
and data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: tbannist@scripps.edu
ORCID
Hua Lin: 0000-0002-0840-6553
Theodore M. Kamenecka: 0000-0002-3077-0167
Thomas D. Bannister: 0000-0003-0683-8886
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript. ‡These authors contributed equally.
ACKNOWLEDGMENT
We thank Scott J. Novick for HRMS analysis.
REFERENCES
1. McGrath, N. A.; Brichacek, M.; Njardarson, J. T., A Graphical
Journey of Innovative Organic Architectures That Have Improved Our
Lives. J. Chem. Educ. 2010, 87 (12), 1348-1349.
2. (a) Lovering, F.; Bikker, J.; Humblet, C., Escape from flatland:
increasing saturation as an approach to improving clinical success. J.
Med. Chem. 2009, 52 (21), 6752-6756. (b) Ritchie, T. J.; Macdonald,
S. M., Physicochemical Descriptors of Aromatic Character and Their
Use in Drug Discovery (Miniperspective). J. Med. Chem. 2014, 57
(17), 7206-7215.
3. (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W., Synthesis of
secondary amines. Tetrahedron 2001, 57 (37), 7785-7811; (b) Hager,
A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D., Synthetic
approaches towards alkaloids bearing alpha-tertiary amines. Nat. Prod.
Rep. 2016, 33 (3), 491-522.
4. (a) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q., Palladium(II)-
Catalyzed C-H Activation/C-C Cross-Coupling Reactions: Versatility
and Practicality. Angew. Chem., Int. Ed. 2009, 48 (28), 5094-5115; (b)
Baudoin, O., Transition metal-catalyzed arylation of unactivated
6. (a) Jun, C. H.; Lee, H.; Hong, J. B., Chelation-assisted
intermolecular hydroacylation: Direct synthesis of ketone from
aldehyde and 1-alkene. J. Org. Chem. 1997, 62 (5), 1200-1201; (b)
4
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
Rousseau, G.; Breit, B., Removable Directing Groups in Organic
Palladacycle. J. Am. Chem. Soc. 2016, 138 (34), 10750-10753; (d)
Zhan, B. B.; Li, Y.; Xu, J. W.; Nie, X. L.; Fan, J.; Jin, L.; Shi, B. F.,
Site-Selective -C(sp3)-H Alkylation of Amino Acids and Peptides
with Maleimides via a Six-Membered Palladacycle. Angew. Chem., Int.
Ed. 2018, 57 (20), 5858-5862; (e) Cui, W.; Chen, S. W.; Wu, J. Q.;
Zhao, X.; Hu, W. H.; Wang, H. G., Palladium-Catalyzed Remote
C(sp3)-H Arylation of 3-Pinanamine. Org. Lett. 2014, 16 (16), 4288-
4291.
10. (a) Li, Z. D.; Wang, Q.; Zhu, J. P., Copper-Catalyzed Arylation
of Remote C(sp3)-H Bonds in Carboxamides and Sulfonamides.
Angew. Chem., Int. Ed. 2018, 57 (40), 13288-13292; (b) Zhang, Z.;
Stateman, L.; Nagib, D. δ C–H (hetero)arylation via Cu-catalyzed
radical relay. Chem. Sci., 2019, 10 (4), 1207-1211..
11. (a) Mihai, M. T.; Davis, H. J.; Genov, G. R.; Phipps, R. J. Ion
Pair-Directed C−H Activation on Flexible Ammonium Salts: meta-
Selective Borylation of Quaternized Phenethylamines and
Phenylpropylamines. ACS Catal. 2018, 8, 3764−3769. (b) Wu, J.;
Wang, Y-M.; Drljevic, A.; Rauniyar, V.; Phipps, R. J.; Toste, F. D. A
combination of directing groups and chiral anion phase-transfer
catalysis for enantioselective fluorination of alkenes. PNAS 2013, 110
(34), 13729-13733.
12. Free amine products of 3r and 3u-3aa could be isolated by
simple acid/base work-up or by reverse-phase preparative HPLC in
lower yields than the isolated yields of Ac-protected products shown in
Table 2 and Table 3. It’s worth poiting out under our experimental
conditions, there were no Ac-protected products detected by crude
LCMS or NMR analysis. This is in contrast to Shi’s work (ref. 8),
wherein mixtures of free amines and Ac-protected amines were
obtained under their reaction conditions.
Synthesis and Catalysis. Angew .Chem., Int. Ed. 2011, 50 (11), 2450-
2494; (c) Mo, F. Y.; Dong, G. B., Regioselective ketone alpha-
alkylation with simple olefins via dual activation. Science 2014, 345
(6192), 68-72; (d) Zhang, F. L.; Hong, K.; Li, T. J.; Park, H.; Yu, J. Q.,
Functionalization of C(sp3)-H bonds using a transient directing group.
Science 2016, 351 (6270), 252-256; (e) Xu, Y.; Dong, G., sp3 C-H
activation via exo-type directing groups. Chem. Sci. 2018, 9 (6), 1424-
1432; (f) Gandeepan, P.; Ackermann, L., Transient Directing Groups
for Transformative C-H Activation by Synergistic Metal Catalysis.
Chem 2018, 4 (2), 199-222; (g) Xu, Y.; Young, M. C.; Wang, C. P.;
Magness, D. M.; Dong, G. B., Catalytic C(sp3)-H Arylation of Free
Primary Amines with an exo Directing Group Generated In Situ.
Angew. Chem., Int. Ed. 2016, 55 (31), 9084-9087; (h) Liu, Y.; Ge, H.,
Site-selective C–H arylation of primary aliphatic amines enabled by a
catalytic transient directing group. Nat. Chem. 2016, 9, 26; (i) Yada,
A.; Liao, W. Q.; Sato, Y.; Murakami, M., Buttressing Salicylaldehydes:
A Multipurpose Directing Group for C(sp3)-H Bond Activation.
Angew. Chem., Int. Ed. 2017, 56 (4), 1073-1076; (j) Kapoor, M.; Liu,
D.; Young, M. C., Carbon Dioxide-Mediated C(sp3)-H Arylation of
Amine Substrates. J. Am. Chem. Soc. 2018, 140 (22), 6818-6822; (k)
Lin, H.; Wang, C.; Bannister, T. D.; Kamenecka, T. M., Site-Selective
gamma-C(sp3)-H and gamma-C(sp2)-H Arylation of Free Amino Esters
Promoted by a Catalytic Transient Directing Group. Chem. –Eur. J.
2018, 24 (38), 9535-9541; (l) St. John-campbell, S.; Ou, A. K.; Bull, J.
A. Palladium-Catalyzed C(sp3)-H Arylation of Primary Amines Using
a Catalytic Alkyl Acetal to Form a Transient Directing Group. Chem.
–Eur. J. 2018, 24 (38), 17838-17843.
1
2
3
4
5
6
7
8
9
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
7. (a) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J.,
Palladium-catalysed C-H activation of aliphatic amines to give strained
nitrogen heterocycles. Nature 2014, 510, 129-133; (b) Calleja, J.; Pla,
D.; Gorman, T. W.; Domingo, V.; Haffemayer, B.; Gaunt, M. J., A
steric tethering approach enables palladium-catalysed C-H activation
of primary amino alcohols. Nat. Chem. 2015, 7 (12), 1009-1016; (c)
He, C.; Gaunt, M. J., Ligand-Enabled Catalytic C-H Arylation of
13. (a) Lazareva, A.; Daugulis, O., Direct Palladium-Catalyzed
Ortho-Arylation of Benzylamines, Org. Lett., 2006, 8, (23), 5211–
5213; (b) Ling, P. X.; Fang, S. L.; Yin, X. S.; Chen, K.; Sun, B. Z.; Shi,
B. F., Palladium-Catalyzed Arylation of Unactivated ɤ-Methylene
C(sp3)-H and -C-H Bonds with an Oxazoline-Carboxylate Auxiliary.
Chem.-Eur. J. 2015, 21 (48), 17503-17507.
14. Chen, Y. Q.; Wang, Z.; Wu, Y. W.; Wisniewski, S. R.; Qiao, J.
X.; Ewing, W. R.; Eastgate, M. D.; Yu, J. Q., Overcoming the
Limitations of gamma- and delta-C-H Arylation of Amines through
Ligand Development. J. Am. Chem. Soc. 2018, 140 (51), 17884-17894.
Aliphatic Amines by
a Four-Membered-Ring Cyclopalladation
Pathway. Angew. Chem., Int. Ed. 2015, 54 (52), 15840-15844; (d)
Smalley, A. P.; Gaunt, M. J., Mechanistic Insights into the Palladium-
Catalyzed Aziridination of Aliphatic Amines by C–H Activation. J.
Am. Chem. Soc. 2015, 137 (33), 10632-10641; (e) Zakrzewski, J.;
Smalley, A. P.; Kabeshov, M. A.; Gaunt, M. J.; Lapkin, A. A.,
Continuous-Flow Synthesis and Derivatization of Aziridines through
Palladium-Catalyzed C(sp(3))-H Activation. Angew. Chem. Int. Ed.
2016, 55 (31), 8878-8883; (f) He, C.; Gaunt, M. J., Ligand-assisted
palladium-catalyzed C–H alkenylation of aliphatic amines for the
synthesis of functionalized pyrrolidines. Chem. Sci. 2017, 8 (5), 3586-
3592; (g) Hogg, K. F.; Trowbridge, A.; Alvarez-Pérez, A.; Gaunt, M.
J., The α-tertiary amine motif drives remarkable selectivity for Pd-
catalyzed carbonylation of β-methylene C–H bonds. Chem. Sci. 2017,
8 (12), 8198-8203; (h) Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi,
M.; Ozaki, K.; Gaunt, M. J., Selective Palladium(II)-Catalyzed
Carbonylation of Methylene beta-C-H Bonds in Aliphatic Amines.
Angew. Chem. Int. Ed. 2017, 56 (39), 11958-11962; (i) Smalley, A. P.;
Cuthbertson, J. D.; Gaunt, M. J., Palladium-Catalyzed Enantioselective
C–H Activation of Aliphatic Amines Using Chiral Anionic BINOL-
Phosphoric Acid Ligands. J. Am. Chem. Soc. 2017, 139 (4), 1412-1415.
8. Chen, K.; Wang, D.; Li, Z. W.; Liu, Z.; Pan, F.; Zhang, Y. F.; Shi,
Z. J., Palladium catalyzed C(sp3)-H acetoxylation of aliphatic primary
amines to gamma-amino alcohol derivatives. Org. Chem. Front. 2017,
4 (11), 2097-2101.
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9. (a) He, G.; Zhao, Y. S.; Zhang, S. Y.; Lu, C. X.; Chen, G., Highly
Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via
Palladium Catalyzed Intramolecular Amination of C(sp3)-H and
C(sp2)-H Bonds at gamma and delta Positions. J. Am. Chem. Soc. 2012,
134 (1), 3-6; (b) Nadres, E. T.; Daugulis, O., Heterocycle Synthesis via
Direct C-H/N-H Coupling. J. Am. Chem. Soc. 2012, 134 (1), 7-10; (c)
Xu, J. W.; Zhang, Z. Z.; Rao, W. H.; Shi, B. F., Site-Selective
Alkenylation of -C(sp3)-H Bonds with Alkynes via a Six-Membered
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